Applied Genomics & Molecular Medicine

Subvert the Paradigm - Reprogramming the Cell: Part 5 | First successful production of induced pluripotent stem cells from adult somatic cells

2007-11-29T14:01:00.001-05:00

Image courtesy: hetemeel.com

Just a few months after the landmark studies performed by three independent biologists - Yamanaka, Maherali and Wernig, researchers are back with results which may end saga of human embryonic stem cell (hESC) controversy. Last week, Yamanaka et al. have published results in Science journal ¹ showing successful transformation of human dermal fibroblasts into induced pluripotent stem cells (iPS) by retroviral transduction of same four transcription factors - Oct3/4, Sox2, Klf4, and c-Myc which were earlier used in mouse models.² In an another study, Thomson J. and group published study in journal Cell³ showing OCT4, SOX2, NANOG, and LIN28 mediated conversion of human somatic cells into iPS. Both studies yielded iPS which are exhibiting strong genetic and functional similarity to hESC. This could lead to paradigm shift in current methods which requires use of hESC, mainly in drug development and potential to treat degenerative diseases like Alzheimer's and many others. However, team leaders expect a long run before this new principle would be available widely across the globe for further applications.

To note,

1. Role of c-Myc as a potential teratogen needs to be tested in human iPS, particularly in-vivo which is way far considering existing controversy surrounding hESC.

2. Recently^{4, 5}, Oct4 is identified as a dispensable gene rather critical one in inducing pluripotency in adult somatic cells. Since both of above studies involved Oct4 reactivation, further research would be of importance to define role of Oct4 more precisely.

Reference:

1, 3: See Wikipedia edits under induced pluripotent stem cell for original article links

2: Related post on generations of iPS | Reprogramming the Cell - Serial posts 1 to 4

4: Lenger, C. J. et al. Oct4 is dispensable for somatic stem cell self-renewal. Cell Stem Cell 1, 403–415 (2007)

5: Oct4 is dispensable for somatic stem cell self-renewal | Nature Reports Stem Cells 18-Oct-2007
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RNAi and now, RNAa - The bubble effect

2007-08-23T10:06:00.001-04:00

RNAi mediated gene silencing is now considered a pivotal theory which is one of the most promising method of gene therapy in coming years. Synthetic short hairpin / short interfering (shRNA / siRNA) or naturally present micro RNA (miRNA) mediates translational silencing of particular gene(s) occurring in cytoplasm (co-driven by RNA-induced silencing complex - RISC). What if similar process is happening within nucleus by naturally occurring miRNA? Then it's called transcriptional repression, although the outcome would be the identical - inhibiting target protein production. Few studies showed such nuclear phenomenon in recent years. The bubble (DNA>RNA>Protein) bursts.

Now, think of the mirror side if one can generate the bubble. RNA mediated gene activation?!? logic and not the serendipity! Scientists are currently arguing a lot on RNAa effect, that is RNA mediated transcription activation and thereby, promoting protein synthesis. After consecutive failed several attempts to convince this theory since 2004, young scientists from UCSF laboratory, Long-Cheng Li, Rajvir Dahiya and R F Place have showed small dsRNA induced transcriptional activation in human cells with supporting study from separate team at UT SouthWestern in Dec-2006. Although they have yet to depict exact mechanism of such phenomenon, if at all it is present in reality. Skeptics who have pioneered in RNAi theory believe this could be the indirect inhibition of repressor genes or another miRNA who is naturally responsible for certain protein inhibition (i.e.: Tumor growth proteins). Interestingly, new research of RNAa is becoming more common among fresh graduates rather masters who demand solid evidence until RNAi terminology can be grounded off.

To bubble more !?!, co-relate this idea with following: the central dogma of molecular biology, dynamic dna, dna replication and holiday junction model, reprogramming.

To be continued.....

Courtesy: Nature magazine (Read full news article for detailed explanation and references)

News report by Erika Check: RNA interference: Hitting the on switch | Nature 2007:448;855-858 | doi:10.1038/448855a

Reference:
1. Long-Cheng Li, Robert F. Place, Rajvir Dahiya, et al. | Small dsRNAs induce transcriptional activation in human cells | PNAS 2006 (Nov 14):103;17337-17342
2. Janowski AB, Younger ST, Hardy DB, et al. | Activating gene expression in mammalian cells with promoter-targeted duplex RNAs | Nature Chemical Biology 2007:3;166-173 | doi:10.1038/nchembio860
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ENCODE - Code within the code

2007-08-06T16:36:00.000-04:00

Pillars of Creation (Eagle nebula M16; image by NASA)

The code is getting more enigmatic as scientists have begun to unwind it, now raising more curiosity and challenges to understand the beautiful life! The National Human Genome Research Institute (NHGRI)'s project ENCODE, the Encyclopedia Of DNA Elements, started in September 2003 is a multi-institutional, multiphasic, collaborative project has just finished its pilot phase, first of planned three phases (now remaining, a technology development phase and a planned production phase) which aims towards identification of functional elements and organization of entire genome rather genes of particular interest and thereby, having clear insight of human genome and linked expression. ENCODE team is conducting series of experimental procedures to identify not only genes that code for proteins but also for non-protein coding genes, regulatory elements controlling transcription of genes; and elements that maintain the structure of chromosomes and mediate the dynamics of their replication.

In the pilot phase, researchers focused on 44 targets, which together cover 29,998 kilobases (kb) of the human genome, equivalent to about 1 percent of the human genome sequence, or about 30 million of 3 billion DNA base pairs. Results of pilot project are challenging the established fundamentals, particularly of non-protein coding genes and their overlapping on protein-coding loci, lack of evolutionary constraint (that is, the rejection of mutations at a particular location) of genes and dynamism in DNA replication and structure of its supporting proteins (i.e. histone) influencing transcription and gene expression. As ENCODE is advancing further, better understanding of genome and importantly its functional structure would eventually helpful to sidestep current obstacles of applied genetics. Below are few lines from the original article (see citation) that may make you dream to see glimpse of dynamics within the pillars of creation!

The protein-coding component of these genes makes up just a small fraction of the human genome - 1.5 percent to 2 percent. Evidence exists that other parts of the genome also have important functions.

The majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another. This broad pattern of transcription challenges the long-standing view that the human genome consists of a relatively small set of discrete genes, along with a vast amount of so-called junk DNA that is not biologically active.

Simple view of the genome as having a defined set of isolated loci transcribed independently does not seem to be accurate.

ENCODE effort found about half of functional elements in the human genome do not appear to have been obviously constrained during evolution, at least when examined by current methods used by computational biologists. This lack of evolutionary constraint may indicate that many species' genomes contain a pool of functional elements, including RNA transcripts, that provide no specific benefits in terms of survival or reproduction. As this pool turns over during evolutionary time, researchers speculate it may serve as a "warehouse for natural selection" by acting as a source of functional elements unique to each species and of elements that perform the similar functions among species despite having sequences that appear dissimilar.

Regulatory sequences are just as likely to be located downstream of a transcription start site on a DNA strand as upstream.

Chromatin accessibility and histone modification patterns are highly predictive of both the presence and activity of transcription start sites.

Critical questions are raised by the presence of a large amount of unannotated transcription with respect to how the corresponding sequences are organized in the genome - do these reflect longer transcripts that include known loci, do they link known loci, or are they completely separate from known loci?

Original article:

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
The ENCODE Project Consortium
Nature 2007;447:799-816 (14 June 2007)
doi:10.1038/nature05874

Reference:

1. ENCODE at NHGRI
2. Press release from NHGRI: New Findings Challenge Established Views on Human Genome ENCODE Research Consortium Uncovers Surprises Related to Organization and Function of Human Genetic Blueprint 13 June 2007
3. Image courtesy: Pillars of Creation: Eagle nebula M16 by NASA Accessed 6-Aug-2007
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Gal1 gene silencing in Hodgkins's lymphoma

2007-08-03T17:36:00.000-04:00

Margaret Shipp and team at Dana-Farber Cancer Institute (DFCI) have published novel target for Hodgkins' lymphoma (HL) and possibly other malignant tumor gene targeted therapy. In a study published in PNAS, Shipp et al. showed overexpression of specific protein Gal1 or Galectin 1 in pathognomic Reed-Sternberg cells of HL, at least 30 times higher than in normal cells. Galectin 1 showed to induce apoptosis and inhibit Th1 cells - a type of regulatory helper T-lymphocytes which recognize and kill foreign infectious agents and sometimes tumors. Relative increase in other helper T-cells, namely Th2 and Treg cells promote tumor survival and growth by inhibiting immune response to altered (tumor) cells by Th1 cells. Team documented reversal of Th1 activity and increase in Th1 cell count following RNAi mediated gene silencing of Gal1 gene. Earlier animal experiment by other team also showed possible role of Gal1 silencing in treatment of malignant melanoma. DFCI team is now developing targeted therapy to to counteract Gal1 induced tumor survival and hope to get fast-track experimental approval for clinical trials like other immunomodulatory agents..

Original article:
Margaret A. Shipp, et al. | The AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma | Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0706017104 (ahead of print publication) 1-Aug-07

Reference:
1. Press release from DFCI (30 july 2007)

Reprogramming the Cell | Part 4: iPS - Introducing next generations

2007-08-01T02:09:00.000-04:00

Stem cells as a potential therapy for Diabetes, Parkinson's disease, Alzheimer's and many more - Ever since birth of the Dolly (1996) ¹, this line has became a hope for millions of victims of these high-burden diseases. However, stem cell research is often surrounded in ethical controversy which hindered its applied research to target potentially curable diseases. With the recent advancement in stem cell science and reprogramming the adult cell, scientists are now more optimistic than ever before to translate stem cell research on the clinical desk. Here is the remaining story of stop press article, posted on June 8.

Mature somatic unipotent adult cell can be reprogrammed to pluripotent form, known as induced Pluripotent Cell (iPS). Currently used methods, somatic cell nucleus transfer (SCNT, i.e.: Dolly) and cell fusion to cultivate embryonic stem cells (ESC) and cloning purpose are surrounded by ethical issues. Stem cells (i.e. blood stem cell) currently produced using SCNT (for autologus cell transplants and other therapies) lack long-term self-renewal capacity. Also, use of ESC poses increase chances of immune rejection compare to using patient's own adult cells. Overriding these hurdles, scientists are now exploring possible indirect ways to reprogram the adult cell back to embryonic state by manipulating signal pathways and genes related to cell differentiation using epigenetic reprogramming. Experimental animal studies in mouse revealed several critical genes related to pluripotency power of ESC, namely OCT3/4 (Pou5f1), SOX2, c-Myc and KLF4. ² These four transcription factors are involved in maintaining pluripotency (self-renewal) and upon subsequent cell differentiation of (fertilized) ESC, these factors are found to be silent by mechanisms yet to be identified.

The first generation of iPS was produced from mouse fibroblasts in 2006 by Takahashi and Yamanaka ³ using retroviral mediated transduction of these four factors and then selecting resulting cells expressing specific marker protein coded by Fbx15 ² thought to be marker of ESC pluripotency. This procedure did not require use of ESC at all for production of iPS cells (given name, Fbx15 iPS cells) which are similar to ESC in morphology, proliferation and teratoma (differentiation property) formation. However, subsequent gene expression and DNA methylation patterns of Fbx15 iPS cells were different from ESC and they fail to produce viable chimeras (offspring) indicating alternative pathways linked with cell differentiation or selecting incorrect marker of expression. i.e. Fbx15 in this case.

Within six months (in June 2007), same group published a breakthrough study along with two other independent research groups making successful reprogramming of mouse fibroblasts into iPS and even producing viable chimera. Maherali's team also documented reactivation of somatically silenced X chromosome in female iPS using same reprogramming method. ^4,5,6 This time, they used different selection marker, Nanog (from 'Tir Na Nog, the mythological Celtic land of the ever young) instead of Fbx15. Second generation of iPS is emerged as outcomes of all studies showed successful conversion of mouse fibroblast in iPS (now, named Nanog iPS cells) which are more similar to ESC in terms of gene expression, DNA methylation patterns and producing viable chimeras (and thereby contributing to subsequent germ-line production) indicating Nanog is a major determinant of cellular pluripotency. However, researchers also showed following hurdles before effective iPS can be substituted for ESC.

1. Nanog iPS cells have strong silencing of retrovirally expressed OCT3/4 (Pou5f1), SOX2, c-Myc and KLF4 c-Myc, indicating they are only required for the induction, but not the maintenance of pluripotency (pluripotency is then maintained by endogenous activated Oct3/4 and other genes in Nanog iPS cells). Yamanaka's team reported tumor development in approx. 20% of viable offspring which was attributable to reactivation of c-Myc through retrovirus activity. Since these factors are only required for induction of iPS synthesis, research is now focusing on using transient expression methods (i.e. using host-friendly Adeno-Associated Virus delivery of genes) rather retroviral induction of transcription factors.

2. Efficiency of Nanog cell induction is just 0.1% which points towards additional genes and epigenetic events required for successful formation of iPS.
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Although not precisely labeled as third generation of iPS, recently published paper documenting first ever successful parthenogenetic (meaning reproduction without sexual act or need of mating partner) activation of human oocytes and production of parthenogenetic human ESC (phESC) may be an another method to produce MHC matching cells for patient-specific cell-based therapy and minimizing immune rejection problem associated with ESC or SCNT. ⁷ Parthenogenetic stem cells are produced from unfertilized oocytes and contain genetic material 'exclusively' from the oocyte donor (the potential patient). Further research analysis is ongoing till this simple approach (in terms of procedure and equipment wise) may open new doors in treating degenerative diseases.

Related posts on Reprogramming the Cell
1. Part 1: Basics of Stem Cell
2. Part 2: Road to a unipotent adult cell (Programming Cell)
3. Part 3: Stop press

References:
1. Wilmut I, et. al. | Sheep cloned by nuclear transfer from a cultured cell line | Nature 1996;380:64-6 | PMID: 8598906
2. NCBI OMIM database: Oct3/4 (Pou5f1) | SOX2 | c-Myc | KLF4 | Fbx15 | Nanog
3. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–676 | PMID: 17154061
4. Yamanaka S, et. al. | Generation of germline-competent induced pluripotent stem cells | Nature 2007;448:313-7 | PMID: 17554338
5. Wernig M, et. al. | In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state | Nature 2007;448:318-24 | PMID: 17554336
6. Maherali N, et. al. | Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution | Cell Stem Cell 2007;1:55–70
7. Revazova ES, et. al. | Patient-Specific Stem Cell Lines Derived from Human Parthenogenetic Blastocysts | Cloning Stem Cells. 2007 Jun 26; [Epub ahead of print] | PMID: 17594198 | Crossref.: Activated eggs offer route to stem cells- News@Nature
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Oncolytic Therapy in Cancer Management: An Emerging Approach

2007-07-26T09:00:00.000-04:00

Oncolytic therapy using iatrogenic virus infection is a topic of extensive research for more than two decades and now series of clinical trials are being run in phase 1/2 stage which may bring hope to millions of cancer patients for better prognosis. Oncolytic virus is typically a host-friendly non-pathogenic virus which can preferentially infect cancer cells, leaving normal cells unharmed either because of its intrinsic nature or iatrogenic (designed in laboratory) manipulation.

Two most commonly researched viruses are Adenovirus and Herpes Simplex Virus (HSV) considering their latent to minimal clinical course, ability to self-replicate and stable genome structure (dsDNA). Similarly, virulent strains can be made non-pathogenic by creating their mutants in-vitro which are specifically toxic to abnormal tumor cells but not to normal cells. i.e. PV1(RIPO) mutant of Polio virus was made (Gromeier et al., 2000) to attack selective malignant glioma cells by replacing internal ribosomal entry site (IRES) of polio virus with non-pathogenic rhinovirus IRES.
Such tumor cell selectivity can be achieved by 1) altering virus surface proteins (transductional approach) using cDNA mediated gene expression/repression, modifying their protein structure and/or attaching surface proteins with fusion proteins (antibody to host-cell surface receptor) facilitating transport of virus in the cancer cell through cell surface. Another approach 2) is by non-transductional mechanisms which alter viral genome (transcriptional expression, deletion of genes) allowing virus to replicate within cell and thus, exacerbate cytotoxicity; introducing suicidal genes which facilitate adjuvant drug's actions (i.e. HSV thymidine kinase and ganciclovir) or suppressing angiogenesis genes to halt blood supply to tumor cells. Apart from altering viral genome, virus can also replicate to many folds leading to bursting of cancer cell and eventual death, known as viral cytotoxicity. i.e. Vesicular stomatitis virus (VSV) which is usually non-pathogenic can multiply to nearly 1000 folds in just 24 hr in cancer cells which lacks interferon-linked anti-virus defense machinery.

Oncolytic therapy holds one of promising innovative cancer therapy, especially taking consideration of recent advancement in molecular science and genetics. Here is list of selected upcoming agents of clinical interest. ¹

ONYX-015 (CI-1042), an adenovirus modified selectively to replicate in and kill cells that harbor p53 mutations by deletion of E1B gene of virus which normally inactivates p53 protein. Such alternation leave normal cells unaffected while virus replicates and kills cancer cells having p53 mutation (which is the most common type of genetic abnormality in cancer, in almost 50% cases). Drug showed favorable results in head and neck cancers and went till phase 3 clinical trials in US and even commercial approval in China (Onyx-015/H101). However, further trials and production was suspended (Jan 2003) by Onyx pharma till further update. ^{2, 3}

OncoVex GM-CSF product (phase 2 stage in melanoma) contain added gene that encode human GM-CSF which is a potent stimulator of immune system cells such as dendritic cells, proven to play role in cancer treatment. ⁴

Cell Genesys's CG7870, Prostate-Specific Antigen (PSA) - targeted oncolytic Adenovirus therapy for prostate cancer, has been evaluated in Phase 1/2 clinical trials in combination with chemo-/radio therapy. ⁵ It uses PSA tumour-specific promoter sequence to promote expression of the adenoviral E1A gene, essential for replication.

Respiratory Enteric Orphan virus (Reovirus), an inhabit of respiratory and intestinal systems is capable of replicating in tumour cells lacking the activity of PKR (anti-viral defense mechanism patent in normal cells) which is commonly seen in cancers having an activated Ras pathway. ⁶ Ras signal pathway is believed to play key role in more than two third of all human cancers. Oncolytic's Reolysin® (Reovirus oncolytic therapy) in combination with Docetaxel is just entered (23 July) in phase 2 clinical trial for advanced cases of bladder, prostate, lung and upper gastro-intestinal. ⁷

References:
1. Detailed information and reference links at Wikipedia article: Oncolytic Virus
2. Crompton AM, Kirn DH | From ONYX-015 to armed vaccinia viruses: the education and evolution of oncolytic virus development | Curr Cancer Drug Targets 2007;7:133-139
3. Onyx Pharma Press release: Onyx Increases Development Focus on Bay 43-9006 | Jan 27, 2003
4. Biovex's OncoVex: Product page
5. Cell Genesys's CG7870: Product page
6. Article from hospitalpharma.com
7. Oncolytics Pharma Press release: Oncolytics Biotech Inc. Starts Patient Enrolment in U.K. Combination REOLYSIN®/Docetaxel trial
#end

Cancer: Spark and Shoot by painting

2007-07-15T23:39:00.000-04:00

Researchers at Seattle Children’s Hospital Research Institute and Fred Hutchinson Cancer Research Center have developed innovative method to demarcate tumor cells in "live" operating room from surrounding healthy cells by illuminating tumor cells with fluorescent material, Cy 5.5 (Cyanine) which can be detected by operating surgeon using infrared capable glass/surgical microscope. In an animal study, trial was done on mouse models having glioma . Upon injecting Chlorotoxin:Cy5.5 (where Chlorotoxin is a scorpion derived peptide, currently in clinical trials as a anti-cancer therapy which specifically binds to the surface of glioma cells and impairs their ability to invade), cancer cells as small as 1 millimeter in diameter took up this biconjugate agent and emitted light which was captured by infrared device. This will boost accuracy and safety of surgical approach in managing brain tumors and many others in near future.

This technology claimed very high sensitivity with comparison to currently used MRI of brain with contrast agent. According to team member, Olson JM, MD: This is particularly significant in the brain, where approximately 80% of malignant cancers recur at the edges of the surgical site. MRI can distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. But Cy5.5 can identify tumors with as few as 2000 cancer cells, making it 500 times more sensitive than MRI.

Olson: Chlorotoxin:Cy5.5 could be used in operating rooms in as little as 18 months.

Team has also conducted trial in mouse models having prostate cancer and found favorable results. After injecting Chlorotoxin:Cy5.5, it begins to bind cancer cells in hours and signal lasts for 14 days compare to rapid elimination within minutes of currently used contrast agents in radiology. This can be a promising non-invasive screening tool for early detection of skin, cervical, esophageal, colon and lung cancers as well as identifying positive lymph nodes critical for breast, prostate and testicular cancers management and follow-up. Team is planning to deploy phase 1 clinical trial soon.

Original article: Mandana Veiseh et al. | Tumor Paint: a chlorotoxin:Cy5.5 bioconjugate for intra-operataive visualization of cancer foci | Cancer Research 2007:67 (scheduled for release on July 15, 2007)

Reference:
1. EurelAlert! 15 July 2007 release
2. Deshane J, Garner CC, et al. | Chlorotoxin Inhibits Glioma Cell Invasion via Matrix Metalloproteinase-2 | J Biol Chem 2003;278:4135-4144

Gefitinib, EGFR and Insulin Secretion

2007-06-28T00:33:00.000-04:00

We are once again observing an interesting case which is yet to be confirmed with series of investigations to rule out confounders. We have a case of Non-Small Cell Lung Carcinoma (NSCLC) with type 1 diabetes mellitus (DM), receiving Gefinitib (Iressa®) and Insulin. Opposite to current concepts (Epidermal growth factor and Insulin secretion by beta-islet cells | Gefitinib as a EGFR-TKI) based on fetched literature (PMID: 2477846, 12766123, articles by Brand SJ, others), this patient's requirement of Insulin for optimal blood glucose control decreased significantly upon concurrent administration of Gefinitb. This effect is reversible upon discontinuation of Gefitinib.

To be continued....

References:

Please refer to links given under "MedBuzz" in left side panel of blog junction

Oral Eltrombopag - A possible answer to Platelet Transfusions

2007-06-17T00:33:00.000-04:00

A newer oral form of therapy is expected soon in market for patients of chronic ITP and possibly for other patients suffering from symptomatic thrombcytopenia. Eltrombopag (Promacta ® - GSK pharma) is an investigational agent (SB 497115) of a new drug class, thrombopoeitin receptor (TPO-R) agonist which in turn showed significant increase in megakaryocyte proliferation and differentiation and thereby, raising platelet count with oral dosage of 50-75 mg/day for six-weeks and producing less frequent chances of bleeding. This was concluded from phase III trials, involving 114 patients from worldwide having platelet count less than 30000/cmm. Being a non-peptide, small molecule, drug has less immunogenic potential, compare to platelet antibody issue with platelet transfusions. Till date, no serious side effects have been reported in controlled trials and drug is in phase III trial for further safety checkup. Though drug showed impressive results in chronic ITP non-responders from conventional treatments (steroids, immunotherapy), it is currently not being evaluated in other causes of thrombocytopenia, especially in drug-induced thrombocytopenic cases.

Image courtesy: 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

References:

1. Press Release at GSK | Medical News Today 12 June 2007

2. Ongoing clinical trials:

RAISE (RAndomized placebo controlled ITP Study with Eltrombopag)
REPEAT (Repeat ExPosure to Eltrombopag in Adults with Idiopathic Thrombocytopenic Purpura)
EXTEND (Eltrombopag Extended Dosing Study) and four others at clinicaltrials.gov

3. Original article presented presented at the 12th congress of the European Hematology Association (EHA) in Vienna, Austria

Bussel, J., Provan A., Shamsi T et al. Eltrombopag Raises Platelet Count and Reduces Bleeding compared with Placebo during Short-term Treatment in Chronic Idiopathic Thrombocytopenic Purpura: A Phase III Study. Presented 9th June 2007, 12th Congress of the European Hematology Association, Vienna, Austria

Related articles and Recent Study Outcomes:

Reprogramming the Cell | Part 3: Stop press

2007-06-08T00:32:00.000-04:00

Something BIG is happening! Harvard and MIT team demonstrated reprogramming of mouse fibroblasts to a pluripotent state in vitro through ectopic expression of the four transcription factors (or pluripotency genes), named Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. And the outcome is.....

Yes! Mouse fibroblasts 'can' form viable chimaeras, and can be reprogrammed to behave like a totipotent zygote to form all three germ layers and subsequent entire clone using somatic cell nuclear transfer technology.

Read more about this interesting article at Nature.com

Picture copyrighted by: Marius Wernig, Alexander Meissner, Ruth Foreman, Tobias Brambrink, Manching Ku, Konrad Hochedlinger, Bradley E. Bernstein, Rudolf Jaenisch | In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state | Nature advance online publication 6 June 2007 | doi:10.1038/nature05944

ARMD and Translational Research

2007-06-06T00:31:00.000-04:00

Advancing further in the translational research field and stem cell reprogramming, scientists are now eager to begin clinical trials on a larger basis for knocking down age-related macular degeneration (ARMD) - a leading cause of blindness, which scientists believe could be grouped under "preventable" blindness in coming future. As of now, ARMD is practically incurable besides controlling exudative (wet) ARMD with limited application of high-dose anti-oxidants, photodynamic therapy, surgical and radiotherapeutic approach to halt neovascularization and use of anti-VEGF inhibitors [Ranibizumab, Bevacizumab, Pegaptanib sodium, Cand-5 (siRNA directed against VEGF) and others; some are investigational agents]. ¹

An open access effort with primary base at Moorfields Eye Hospital of London, team of researchers are conducting experiments (with trials dated in 1990 and onwards) to cultivate retinal pigment epithelial cells (RPE) in the lab from extracted healthy RPE of same patient (i.e. autologus RPE). Other sources of RPE are human fetal RPE, cadaver RPE, porcine fetal RPE. ² Although loss of vision in ARMD is attributed to photoreceptors abnormality, RPE dysfunction is believed to be a central mechanism behind ARMD which ultimately leads to dysfunction of photoreceptors. Currently, researchers are focusing on using autologus RPE and RPE derived from embryonic stem cells. In FDA controlled phase I/II clinical trials, RPE cells are transplanted (usually in size of four by 6 mm sheet of cells) using transplantation, translocation and Encapsulated Cell Technology (ECT) by anterior transvitreal and the internal posterior transscleral approaches. So far, studies are ongoing without major adverse events. ^{2, 3, 4}

An open access global project named, "The London Project", led by UCL Institute of Ophthalmology is set up to speed up clinical application of basic molecular research and cure AMD which is the leading cause of irreversible blindness.
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About ARMD:

Source: http://www.avtxinc.com/macular-degeneration.html

In a healthy retina, the blood vessels of the choroid supply nutrients and oxygen to the retina and remove waste products. In dry age-related macular degeneration, the efficient removal of waste products is diminished resulting in the accumulation of debris or drusen, depicted as yellow matter, under the RPE layer. In wet age-related macular degeneration, new, defective blood vessels grow from the choroid into the retina. These vessels leak and bleed and damage the retina rapidly leading to blindness. The graph displays the course of dry and wet age-related macular degeneration. While dry age-related macular degeneration results in a gradual loss of visual acuity over time, progression to wet age-related macular degeneration results in the rapid loss of vision.

Read more here
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About histology and role of RPE and ARMD newer management strategies: Read at eMedicine

References:
1. Exudative ARMD treatment | eMedicine
2. ARMD, Retinal Electronic Prosthesis and RPE Transplantation | eMedicine
3. Transplantation of Autologous RPE Versus Translocation of Autologous RPE and Choroid in AMD | NCT00401713
4. A Study of an Encapsulated Cell Technology (ECT) Implant for Patients With Atrophic Macular Degeneration | NCT00447954
5. Original articles (free full texts):

Lund et al. | Subretinal transplantation of genetically modified human cell lines attenuates loss of visual function in dystrophic rats | PNAS 2001;98:9942-9947

Kanuga N, Coffey P, et al. | Characterization of genetically modified human retinal pigment epithelial cells developed for in vitro and transplantation studies | Invest Ophthalmol Vis Sci. 2002;43:546-55

Klassen HJ, Coffey P, et al. | Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior | Invest Ophthalmol Vis Sci. 2004;45:4167-73

6. BBC news press release - 5 June 2007

Related Articles:
1. Newer rmAb in ARMD
2. Reprogramming the cell
#end

EASE trial - Airway Bypass Device for Emphysema

2007-05-27T00:30:00.000-04:00

Researchers at Broncus technologies have started a newer airway bypass device trial to know further about use of EASE (exhale airway stents for emphysema) using minimally invasive approach. Using airway bypass principle, team will use drug-eluting stents (named, Exhale®) which will be placed in the lung by creating new airway tracks using flexible bronchoscope. These stents (which are smaller than a pencil's eraser) create new pathways in the lung with the intention of reducing the amount of air trapped in the lungs, overriding basic pathophysiology in emphysema. This is a multi-center study which may last between 15 months to 5 years.

References:

1. EASE trial | Broncus Technologies, Inc.

2. EurekAlert! 17-May-2007

Does Dynamic DNA run cron jobs?

2007-05-16T22:34:00.001-04:00

Wonder if dynamic DNA or a hidden master switch is running cron jobs to maintain cellular physical and physiological assembly? [cron: a computer terminology which stands for Command Run ON - a time-based scheduling service... Wikipedia]
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17 May 2007 0804 +0530
Baroda India

Security is mostly a superstition. It does not exist in nature, nor do the children of men as a whole experience it. Avoiding danger is no safer in the long run than outright exposure. Life is either a daring adventure, or nothing. To keep our faces toward change and behave like free spirits in the presence of fate is strength undefeatable.
- Helen Keller

Prion - Thinking out of the box

2007-05-13T04:13:00.001-04:00

Scientists at Whitehead Institute, MIT have discovered tiny portions (approximately 10% of total prion size) within prions, named 'recognition element' which seems to determine behavior of prion - their folding and mis folding or conformational mechanism, forming abnormal infectious elements, external factors influencing such mis folding. Team used peptide arrays to study protein folding which is said to be used for the first time for understanding complex protein folding study....

To read more, visit EurekAlert! or Nature.com (10.1038/nature05848)
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Stop-codon mutation in immune cells

2007-05-13T04:12:00.001-04:00

Recently discovered a somatic stop-codon mutation by UPMC researchers may provide potential benefit in fighting cancer & infections by allowing immune cells to survive longer at the target site....

Read more at EurekAlert! or PLoS ONE (open access)
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Dynamic DNA - Back to the future

2007-04-25T23:52:00.000-04:00

Today, on April 25, 1953 Watson and Crick presented double helix structure of DNA in an article to Nature magazine with a hint from Photograph 51 taken by Rosalind Franklin. More than 50 years after discovery of the molecule of the life, there is lot more 'to do' list in applied genomics. By using advance molecular technology, scientists are discovering novel applications to fight diseases and at the same time, the master creator is challenging them by revealing hidden elements of the mysterious cell. Dynamic DNA, still in thoughts of few may become one of those elements in coming years!

Reference:

Watson J.D. and Crick F.H.C. | A Structure for Deoxyribose Nucleic Acid | Nature 1953;171:737-738 | Free PDF
Nature magazine's archive on DNA
Photograph 51 of Rosalind Franklin | Wikipedia

SBAmin.com is down: Server Shifting In Progress

2007-04-21T03:36:00.000-04:00

Copy of original post:

Site Status: DOWN | Blog Status: Healthy

Dear Visitor,

Because of an ongoing data corruption error, we are shifting site servers to new, stable ones. Henceforth, SBAmin.com may not be available for next 24-48 hours. However, Blog Junction (status: Healthy) is active throughout site maintenance period.
Also, please note change in email contact information. Kindly do not email me at Instead use this link OR email me at till further update.

I'll be updating here soon as site status becomes OK.

Sorry for inconvenience!

Regards,
Samir
21 April 2007 1227 +0530
Baroda India
T: (0091) 93762 26975
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Mold by-product to kill Multiple Myeloma

2007-04-16T07:28:00.001-04:00

Researchers from Mayo Clinic have revealed chaetocin - a by-product of a common wood mold as a potential multiple myeloma therapy¹. Animal model trials showed chaetocin's following actions:

Kill myeloma cells harboring a diverse array of genetic abnormalities
Cause biological changes and induce oxidative stress in myeloma cells, leading to their death
Selectively kill myeloma cells with superior efficacy to commonly-used anti-myeloma drugs including dexamethasone and doxorubicin
Reduce myeloma growth in mice
Rapidly accumulate in cancer cells

Although chaetocin is structurally similar to upcoming chemotherapeutic class known as histone deacetylase inhibitors (HDACIs). HDACIs (by inhibiting deacetylation) induce hyperacetylation of histones that modulate chromatin structure and gene expression. These inhibitors also induce growth arrest, cell differentiation, and apoptosis of tumor cells². However, team found that at cytotoxic concentration, chaetocin does not act like HDACI. Instead cytotoxicity of chaetocin is more attributed to oxidative stress phenomenon.

Researchers demanded further extensive research before finalizing Chaetocin as a new therapeutic agent. Study was presented on 15 Apr 2007 at the American Association for Cancer Research 2007 annual meeting and is available in the journal Blood.

Original article: Crescent R Isham et al. | Chaetocin, a promising new anti-myeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress | Blood 2007;109(6):2579-2588

Reference:
1. EurekAlert! 15 Apr 2007
2. Histone Deacetylase Inhibitors | sigmaaldrich.com
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Reprogramming Cell

2007-04-09T12:36:00.001-04:00

Reprogramming Cell is perhaps the most thought provoking topic to me ever since I started blogging in applied genomics. Recently, upon reading stem cell bias article¹, I found relevant articles and book chapters on reprogramming the cell which as expected created many unsolved questions, loopholes and finally headache! This post tries to summarize development in stem cell research and current hurdles in application of stem cell based therapies with emphasis on following keywords based sub-topics: signal transduction, self-renewal, differentiation, reprogramming MAPCs, plasticity, RNAi, Dynamic DNA, cellular therapy, therapeutic transgene.

Basics of stem cell^{2, 3}:

Differentiation (-potency) power:

Totipotent: A fertilized egg having potential to generate all the cells and tissues that make up an embryo and that support its development in utero.
Pluripotent: A Stem cells that can give rise to any type of cells derived from all three embryonic germ layers—mesoderm, endoderm, and ectoderm.
Unipotent: A mature adult cell capable of differentiating along only one lineage. i.e. skin, muscle, heart, red blood cell, etc.

A Stem cell is a unspecialized cell having unique property of self-renewal for indefinite period and differentiation (pluripotency) into specialized cells (i.e. hematopoietic cell line, neurons, etc.) under appropriate conditions.

An Embryonic stem cell (ESC) is derived from the inner cell mass of the blastocyst (4-5 days old fertilized egg) at a stage before it would implant in the uterine wall. Because of legal and ethical issue, more precise definition of embryonic stem cell is one that develop from eggs that have been fertilized in vitro - in an in vitro fertilization clinic - and then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body. Under standardized conditions of cell culturing in-vitro, the original 30 cells of the inner cell mass by process of self-renewal yield millions of embryonic stem cells after six or more months without differentiating, meaning they are pluripotent with normal genotype which are then referred to as an embryonic stem cell line.

An Adult stem cell (Somatic stem cell; ASC) is an undifferentiated (unspecialized) cell that is characteristically found in a differentiated (specialized) tissue; Although it has indefinite self-renewal property, it becomes specialized only into certain specialized cell types of the tissue from which it is originated. i.e. a hematopoietic stem cell can give rise to different blood cells and not other tissue cells - neurons, muscle, etc. Unlike ESC, there is no evidence, at this time, of an adult stem cell that is pluripotent. Also, in-vitro culturing ASC is difficult compare to ESC. Sources of adult stem cells are bone marrow, blood stream, cornea and retina of the eye, the dental pulp of the tooth, liver, skin, gastrointestinal tract, and pancreas.

Plasticity (Transdifferentiation) is a recently debated¹ phenomenon of adult stem cell showing possibility that stem cells from one tissue may be able to give rise to cell types of a completely different tissue. i.e. blood cells from neurons or vice versa.

Multipotent adult progenitor cells (MAPCs) are said to be an exceptional population of adult cells which may have pluripotent potential by phenomenon of plasticity (transdifferentiation). This term is surrounded by dispute currently¹.

Clone is a line of cells that is genetically identical to the originating cell.

Applied Genomics is a branch of medicine which deals with exploration of various applications to introduce current genetic cocnepts in preventing / treating diseases.

Therapeutic transgene is a novel method of gene based therapy by which new genetic material is introduced into the patient. It involves introduction or elimination of specific genes by using molecular biology techniques to physically manipulate genetic material - to alter or supplement the function of an abnormal gene by providing a copy of a normal gene, to directly repair such a gene, or to provide a gene that adds new functions or regulates the activity of other genes. Scientists usually deploy viral vector as a delivery vehicle for introducing such transgene into desired cell line.

Cellular (cell based) therapy is a type of therapy in which stem cells are cultured and differentiated in a desired specialized cell in-vitro (sometimes with integrated therapeutic transgene) which are then introduced in the body to replenish deficient or damaged unipotent adult cell line.

Signal Transduction is a mechanism by which internal and external factors bring changes in the cell structure and function. It is the most fundamental key which once understood fully, will bring dramatic shift in applied genomics. e.g. Understanding how stem cells maintain their inherent property of self-renewal and pluripotency, which signals are essential for such properties will help scientists to manipulate signal system in a desired way maintain healthy body system.

Cell Reprogramming is a concept of manipulating signal transduction mechanisms and growth factors so as to give a mature unipotent adult cell power of plasticity and become pluripotent or differentiating into at least one other different cell line.

Why ASC:

Scientists are currently focusing more on making ASC pluripotent in a hope to override ethical issues associated with ESC. Another theoretical advantage of ASC is that autologus ASCs are immune friendly and chances of immune rejections are less compare to use of donor ESCs.

Unsolved questions with ASC:

1. Source(s) of ASC in the body, their quantity.

2. How is ASC formed? - from ESC or de-novo?

3. Signals controlling ASCs self-renewal and property of not being pluripotent (switching off signals?)

4. Understanding plasticity phenomenon, if present.

5. In-vitro culturing of ASC which is currently difficult.

Image courtesy: http://stemcells.nih.gov

To be continued.....(Next: Signaling pathways and Growth Factors in Cell Reprogramming)

Reference:

1. Check E. | Stem Cells: The hard copy | Nature. 2007;446:485-486

2. Stem Cell Basics | From NIH

3. Stem Cells: Scientific Progress and Future Research Directions | 2001 | From NIH

RNAi explained

2007-03-26T16:02:00.000-04:00

Recently, I am curious reading more about RNAi - a novel gene silencing mechanism using custom built dsRNA complementary to target mRNA strand which upon transfection degrades target mRNA and thereby prevents target protein production - In nutshell, RNAi is a post-transcriptional gene silencing (PTGS) mechanism to prevent target protein production by introducing dsRNA. (see image, original image source is copyrighted by Ambion Inc. Captions and Comments added for description)

I may post more about clinical trials of RNAi based products and its future applications in coming days. Below are some useful links for getting started with RNAi!

Reference:
1. Ambion Inc. - RNAi resources: Home | Overview | Researcher's guide (PDF)
2. Nature reviews RNAi: Home | Flash animation showing RNAi mechanism
3. RNAi explained: For dummies! - By PBS.org
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Bortezomib (Velcade) in EBV related tumors

2007-03-19T13:41:00.000-04:00

Hopkins researchers have discovered effect of bortezomib (proteasome inhibitor, currently approved for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy) in activating lytic induction cycle by activating dormant Epstein-Barr virus within certain tumors cells. Once cycle is activated, virus replicates to more than 12-fold in numbers and start producing thymidine kinase (EBV-TK)- an enzyme essential for replication. EBV-TK then can be traced and imaged using radiolabelled FAIU. Scientists also observed tumor cell death following rise in viral particles - so called lytic induction cycle. Team also suggested another method to kill tumor cells using therapeutic radionuclides instead of low energy gamma photon used in tracer - FAIU. In recent years, several studies are conducted to activate dormant tumor related virus (i.e. EBV) switching on lytic induction cycle as an alternative path to much complicated and expensive 'reporter' gene transfection methods to kill tumor cells. In 2003, Feng et al. demonstrated effect of gemcitabine and doxorubicin in activating dormant EBV in certain B-cell lymphomas and showed synergistic effect with use of antiviral ganciclovir (GCV) therapy to kill EBV infected tumor cells.

Reference:
1. Fu D. et al. | Imaging by Induction of Viral Gene Expression | Clinical Cancer Research 2007;13:1453-1458
2. Feng W et al. | Lytic Induction Therapy for Epstein-Barr Virus-Positive B-Cell Lymphomas | J Virology 2004;78(4):1893-1902
3. Bortezomib (Velcade) - Product information
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Killing bacteria using Trojan horse theory

2007-03-16T21:04:00.001-04:00

A combined research project of University of - Washington, Iowa and Cincinati have uncovered newer approach to target notorious bacterias. Researchers used to target substrate which bacteria takes up from host for its vital function rather killing bacteria itself. One of such substrate studied was the iron which is essential for many bacterias to form biofilms, thereby favoring chronic course of infection. In a project, team introduced Gallium into mice suffering from Pseudomonas aeruginosa infections of acute and chronic type. Gallium mimics Iron and acts as a trojan horse which is easily taken up by bacterias, especially in low-iron environment. However, gallium does not serve vital functions served by Iron and thus, bacterias which engulfed gallium were unable to synthesize protective biofilms. Gallium showed evidence of killing bacterias which are extracted from chronic lung infections from cystic fibrosis cases and even resistant to multiple antibiotics. Since intravenous gallium (Ganite®) is already approved for treatment of resistant malignant hypercalcemia, scientists are keen to conduct more studies using this novel strategy in a long running fight with bad bugs!

Reference:
1. Original article will be published in April 2nd issue of Journal of Clinical Investigation [Authors: Singh P, Kaneko Y, Britigan B and Thoendel M]
2. Courtesy: EurekAlert! 16-Mar-2007
3. Ganite^® - Gallium nitrate product homepage
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Heated Nanoprobes for Breast Cancer therapy

2007-03-11T18:12:00.000-04:00

Nanotechnology - booming right from Warwick's cyborg theory to futuristic drug delivery system in medicine. In an effort to develop state of art radioimmunotherapy, acclaimed researcher Sally DeNardo¹, MD (IM and Radiology) at UC Davis and colleagues developed nanoprobes which can kill cancer cells by production of heat in-vivo. Known as bioprobes² [Bioprobes are nanoprobes tagged with radiolabeled monoclonal antibodies (mAb) coated with polymers and sugars to camouflage body's immune system - See image 1], team has introduced trillions of the magnetic iron nanoprobes - more than 10,000 can fit on the end of a straight pin in mice bloodstream bearing human breast cancer. ³ Soon upon entering circulation, these mAb tagged probes attach to cancer cell receptors. (See image 2) Subsequent application of alternating magnetic field (AMF) in the tumor region cause magnetic nanoprobes to change their polarity thousands of times per second and thus, generating surrounding heat. (See image 3) Amount of heat generated was calculated according to need for killing tumor mass using parameters related to properties of nanoprobe, tumor mass and frequency of AMF cycles. Author documented decreased rate of tumor growth without bioprobe related adverse events at the end of pre-clinical study and thereby, providing safer, effective, targeted and importantly quantitative dosing of thermoablative bioprobes as newer modality of radioimmunotherapy in cancer treatment. Researchers are now eager to run clinical trials based on their study report.

Original paper:
Sally J. DeNardo et al. | Thermal Dosimetry Predictive of Efficacy of ¹¹¹In-ChL6 Nanoparticle AMF–Induced Thermoablative Therapy for Human Breast Cancer in Mice | J Nucl Med 2007 48: 437-444

Reference:
1. Sally Denardo, MD: Profile at UC Davis
2. Triton Biosystems Inc. press release: Sally Denardo turns up the heat on cancer (Dec 2006) - PDF article showing study details
3. EurekAlert! 6-March-2007
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Targeting tumor cells using p73 (p53 family peptide) signal pathway

2007-03-11T17:39:00.001-04:00

The master regulator of genome p53 is making frequent headlines in last few months.¹ Efforts are being made for therapeutic applications of p53 - a potent tumor suppressor protein in halting tumor cell growth. Unfortunately, about 50 % of cancers in human have acquired deletion or mutation of p53 coding gene and thereby precluding clinical applications, if any of p53 based therapy for cancer. Scientists are now finding a new approach to directly activate common apoptotic pathway of p53 family proteins. UK based researchers have developed a hybrid peptide of 37 amino acids (named, 37 AA) from human p53 protein which killed both p53 sufficient and p53 deficient (or mutated) tumor cells in vitro.² Further, in-vivo studies in mice showed tumor cell apoptosis by similar p53 mediated signals regardless of p53 function status in tumor cells. 37 AA however does not cause direct activation of p53 targeted gene assembly (including inability to activate proapoptotic gene bax); In contrast, 37 AA acts by activating p73 (subtype from p53 family protein) medicated signals. 37 AA binds to iASPP (inhibitory apoptosis stimulating protein of p53) - common inhibitor of p53 family proteins and subsequently depresses endogenous p73, leading to activation of p73 target genes and death of tumor cells by apoptosis. Parallel study suggested comparatively very less mutations of p73 in human tumor cells which will give new directions for developing molecular target therapy using p73 mediated pathway. Authors concluded with current limitations of only 25 % of tumor cells in-vivo expressing 37 AA following transfection, partial tumor regression and subsequent recurrence. Also, they suggested need for knowing chemosensitivity pattern of p73 based products and currently used chemotherapeutic regimes targeting via apoptosis.

Reference:
1. Related posts in this blog
2. Ryan et al. | A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo | J Clin Invest March 8, 2007 (published online ahead of scheduled print article for April issue) Free full text
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p53 and melanoma: guardian or ??

2007-03-08T17:45:00.000-05:00

Researchers at Dana Farber Cancer Institute (DFCI) came up with interesting findings on role of p53 protein (considered as the master regulator of genome functionality) in melanoma - the fastest increasing cancer in the world. Apart from proven tumor suppressive effect of p53, Cui R, Fisher et al. noted evidences suggesting peculiar skin tanning promoting action of p53 in response to sunlight and thereby guarding people against harmful effects of ultra violate (UV) rays on skin cells - the most important risk factor for melanoma. In-vitro study showed role of p53 in raising pro-opiomelanocortin (or POMC) levels to significant level which splits further into alpha-MSH hormone protein, key for stimulating keratinocytes to produce tan pigment - melanin. Subsequent in-vivo animal study showed significant rise in both - POMC and p53 levels in mice after exposure to UV radiation, thus supporting role of p53 as tan promoter in response to sunlight exposure.To rule out possibility of confounding effect of sunlight in independently raising p53 and POMC levels, team documented lack of melanin production (or tanning) in response to UV rays in skin cells genetically engineered to lack p53 (p53 -/- , see picture) Scientists also suggested to evaluate potential role of p53 in causing age related hyper-pigmentation changes in skin known as age spots, which can be explained on basis of increased level of p53 because of stress related DNA damage as age advances.

Interestingly, team has also found effect of p53 in increasing b-endorphin - an endogenous opiod responsible for feeling of pleasure and thereby generating desire to get exposed to more sunlight. This is notably contradicting role of p53 in preventing melanoma as sunlight exposure is the most important risk factor for melanoma!

Reference:
1. EurekAlert! 8-March-2007
2. Image is copyrighted by Dana-Farber Cancer Institute Boston MA (related press release)
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DNA Repair: Double edged sword | Clinical implication in Lung Cancer

2007-02-23T03:11:00.000-05:00

Being an inherent property of nature to repair damaged DNA in an effort to maintain milieu interior sometimes seems as a double edged sword. In an original study performed at H. Lee Moffitt Cancer Center and Research Institute, Tampa FL (one of my favorite cancer center), Zheng et al. have shown significant correlation between over-expression of DNA repair proteins and increase survival of early-stage non-small cell lung cancer patients after surgical resection (possibly by halting progression of molecular events in the early-stage tumor), at the same time showing increase resistance to traditional platinum compound based chemotherapies in the same patient group.

Nucleotide excision repair system is the major mechanism involved in repair of damaged DNA in mammalian cells. This system works by assembly of several repair proteins [among which excision repair cross-complementation group 1 (ERCC1) protein and the regulatory subunit of ribonucleotide reductase (RRM1) are identified in this study as major influencing proteins in surivival of patients] and endonuclease enzymes dealing with excision and subsequent ligation of repaired DNA strand. (see Ref. below) Moffitt study suggested methods to facilitate quantitative detection of newer biomarkers (ERCC1 and RRM1 proteins) in patients with early-stage lung cancer and even in chronic smokers with evidence of pre-neoplastic bronchial epithelium to sort out favorable cases showing over-expression of such proteins and thereby, early surgical resection without subsequent chemotherapy may have longer survival. Same laboratory method will also be useful to identify patients likely to be benefited by platinum based chemotherapy (those having low expression of ERCC1 and RRM1) and other counterparts (having overexpression and advanced stage of cancer) would be ideal candidates for evaluation of newer treatments using targeted therapies, targeting epidermal growth factor receptor signals (Gefitinib and Erlotinib) and angiogenesis (bevacizumab).
Ref.:
1. Zheng et al., DNA Synthesis and Repair Genes RRM1 and ERCC1 in Lung Cancer; N Engl J Med 2007;356:800-808
2. View diagrammatic representation of DNA excision repair system in N Engl J Med 2007;356:771-773

New marker in Polycythemia Vera diagnosis and management

2007-02-10T21:10:00.000-05:00

Polycythemia Vera (PV) is a chronic myeloproliferative disorder (CMD) involving malignant panhyperplasia of marrow cells with typical absolute elevation of red cell mass. Recent study by Scott et al. showed significant association of PV cases and detectable acquired mutation of Janus kinase 2(termed as JAK2 V617F)in peripheral blood. They reported more than 95 % of PV cases having JAK2 V617F copies - resulting from a point mutation (1849G→T) in exon 14, causes the substitution of phenylalanine for valine at codon 617 in the JH2 domain. This specific single amino acid substitution causes uncontrolled activation of JAK2 (cytoplasmic tyrosine kinase receptor transducing signals from hematopoietic growth factors like erythropoietin, in normal and neoplastic cells causing PV and related myeloproliferative disorders.
Further studies revealed exon 12 JAK2 mutations specific for PV. Looking at these new evidences, The World Health Organization’s committee on hematologic cancers

Clinical implications of JAK2 mutation:

Revised classification of CMD
Newer screening test to differentiate PV from secondary polycythemia
Prognostic and Treatment efficacy indicator using quatitative assay
Newer molecular targeted therapy for CMD

is planning to revise its criteria in the coming year to include JAK2 mutations in new classification. Laboratory methods are currently being optimized for accurate assessment of JAK2 V617F using quantitative PCR based assay. Quantitative assay will further determine significance (if any) of JAK2 V617F copies as prognostic and treatment efficacy indicator. Triple tests involving serum erythropoietin, JAK2 V617F quantitative PCR assay and bone marrow biopsy are also being proposed for differentiating PV from secondary polycythemia. Molecular targeted therapy aiming JAK2 receptors may bring newer treatment options for patients.
Ref.:
1. N Engl J Med 2007;356:444-445
2. N Engl J Med 2007;356:459-468

Controlling Master Switches

2007-02-09T21:25:00.000-05:00

Two different teams of scientists working at the Cold Spring Harbor Laboratory (CSHL) and Hopkins discovered novel master switches which can boost up growing 'molecular targeted therapy' applications.

Master Tumor Suppressor: It's not the p53!For the first time in cancer genetics, Mills et al. at CSHL discovered critical tumor suppressor gene loci on chromosome 1 known as 1p36 which encodes for specific protein named, CHD5 which is found to prevent cancer.

Animal model study suggests deletion of a part of 1p36 causes cancer and addition of extra copy of CHD5 triggers extra tumor suppression by causing cells to either stop dividing or to undergo cell suicide by apoptosis. Parallel study in Stanford observed frequently found deletion of CHD5 in glioma suggesting the important role of CHD5 in human cancer. This research will help scientists to develop molecular targeted therapy based on over-expressing CHD5 in tumor cells (gain-of-function).

Ref.
1. Bagchi A., Papazoglu C., Wu Y., Capurso D., Brodt M., Francis D., Bredel M., Vogel H., Mills A.A. , CHD5 is a tumor suppressor at human 1p36, Cell 128, February 9, 2007

Overriding ethical issues: Researchers are now coming up with one more idea to overcome ethical bias on using embryonic stem cells for clinical applications. Georgantas, RW, et al from Johns Hopkins Kimmel Cancer Center revealed a master switch at the protein production level which stalls adult blood cells maturation into RBC and WBC. Known as MicroRNA molecules (earlier considered as cellular debris) are now found to switch off activity of the larger RNA strands which translate into essential proteins of cellular maturation. Revealing RNA interference phenomenon, study shows that one MicroRNA binds to several hundred RNA strands rendering them ineffective similar to breaking electrical circuit by a single switch! Till date, team has found core set of 33 microRNAs matching with more than 1,200 different RNA involved in stem-cell maturation. They also successfully documented effect of microRNA as circuit breaker by using MicroRNA-155 in vitro to halt adult blood stem cell maturation.
Ref.:
1. Georgantas, RW, et al, "CD34+ Hematopoietic Stem-Progenitor Cell MicroRNA Expression and Function. A Circuit Diagram of Differentiation Control." PNAS Online (early release article) Feb 9, 2007
2. www.hopkinskimmelcancercenter.org
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Courtesy: EurekAlert! - Service of AAAS

HIV vaccine phase IIb trial: On the way

2007-02-09T02:01:00.000-05:00

With hope to curtain over AIDS pandemic, researchers are now deploying large scale phase IIb clinical trial of live viral vector vaccine, named HVTN 503 involving 3000 HIV negative men and women in South Africa.

HVTN 503, produced by Merck Inc. (ID: MRKAd5 HIV-1 gag/pol/nef) is a trivalent vaccine which contains three chief genes, namely gag (encodes HIV core proteins), pol (encodes enzymes for reverse transcription and integration) and nef (promotes downregulation of surface CD4 and MHC 1 expression; enhance virion infectivity) of HIV-1 subtype clade B (subtype prevalent in America and Australia region). These genes are embedded in three live attenuated Adenoviruses as vectors to transport and present HIV genes to immune system.

Known as Phambili ("moving forward") in Africa, this new trial is also known as a "test-of-concept" trial is designed to provide preliminary information on vaccine efficacy and thus enable researchers to decide whether or not to conduct a larger Phase III efficacy trial that could lead to licensure. The main objectives of HVTN 503 are to determine whether the candidate vaccine can prevent HIV infection or, in those who do become infected, lower the level of HIV early on. Additionally, the new trial will determine if the vaccine, which is based on clade B HIV, has the potential to protect against the HIV clade C subtype prevalent in South Africa.

ClinicalTrials.gov identifier: (Includes study details and updates)

HVTN 503: NCT00413725
HVTN 502: NCT00183261

Immune responses in the first several hundred volunteers will be assessed to ensure the vaccine induces promising immune responses in this population against the clade C virus before proceeding to full enrollment.

The same vaccine, known as HVTN 502/Merck 023 is currently being evaluated in a companion study with more than 1800 enrollments till January 2007, that began two years ago and is ongoing in the United States, Canada, South America, Australia and the Caribbean. So far, there are no reported serious side-effects from ongoing studies. The new trial vaccine HVTN 503 in Africa will differ from ongoing trial of HVTN 502/Merck 023 in following ways:

1. A primary objective of HVTN 503 is to determine whether the study vaccine, which is based on clade B HIV, could potentially be effective in regions where clade C virus is predominant. HVTN 502 is testing the study vaccine in a region where clade B is predominant, whereas HVTN 503 is being conducted in a region where clade C is predominant.

2. Trial will provide important new data on how the test vaccine might work in a predominantly heterosexual HIV epidemic. HVTN 502 was designed to enroll and study the vaccine primarily in men who have sex with men, with a smaller subset of women. HVTN 503 will be studied primarily in equivalent numbers of heterosexual men and women.

Ref.:
1. National Institute of Allergy and Infectious Diseases (NIAID) press note
2. HIV Vaccine Trials Network (HVTN) - Science behind HIV vaccines
3. ClinicalTrials.gov identifier: (Includes study details and updates)

HVTN 503: NCT00413725
HVTN 502: NCT00183261

Targeting death receptors

2007-02-06T18:26:00.001-05:00

Lexatumumab (HGS-ETR2), an intravenous human agonistic mAb to TNF-related apoptosis inducing ligand (TRAIL) receptor 2 is an upcoming monoclonal agonistic antibody in the treatment of varieties of cancers - hematological and solid tumors.

TRAIL induces apoptosis via the extrinsic pathway in a range of cancer cell types, by binding and activating the death domain-containing TRAIL receptors 1 and 2 (TRAILR1 and TRAIL-R2, alternatively known as death receptor(DR) 4 and 5, respectively), leading to the cleavage and activation of caspase-8. Developed by Human Genome Sciences Inc (HGS), under license from Cambridge Antibody Technology Ltd (CAT), lexatumumab has completed phase I studies and is now in phase II clinical trials for the treatment of a range of cancers, both as a mono therapy and in combination regime. HGS is also developing mapatumumab (HGS-ETR1), a fully human mAb targeting TRAIL-R1 that is undergoing phase II trials. Phase I study conducted in US and Uk claimed safe administration of Lexatumumab in patients with advanced solid tumors (osteosarcoma, chondrosarcoma, myxoid liposarcoma, hepatocellular carcinoma and others) and lymphoma which are resistant to other treatment modalities. Currently observed side effects are elevated liver enzyme, amylase or bilirubin levels and renal failure. Ongoing phase II trials will further determine safety and efficacy profile of this novel agent.

Ref.:
1. ClinicalTrials.gov Identifier: NCT00428272
2. P Marini, Lexatumumab, an intravenous human agonistic mAb targeting TRAIL receptor 2 (Current Opinion in Molecular Therapeutics 2006 8:539-546)
3. HGS-ETR2 - A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors - A conference report

Currently approved molecular targeted therapies:

1. Tyrosine kinase inhibitor imatinib (Gleevec) in treatments for chronic myeloid leukemia and gastrointestinal stromal tumor (GIST)
2. Raf kinase inhibitor sorafenib (Nexavar) in treatment of metastatic renal cell carcinoma
3. Trastuzumab (Herceptin) as an adjuvant treatment for Her2/neu-positive early breast cancer
4. Epidermal growth factor receptor inhibiting antibody cetuximab (Erbitux) as a first-line therapy for metastatic colorectal cancer in combination with irinotecan
5. Bevacizumab (Avastin) in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first-or second-line treatment of patients with metastatic carcinoma of the colon or rectum. It has also demonstrated activity in renal cell cancer and ovarian cancer when used as a single agent, and in lung cancer and breast cancer when combined with chemotherapy. Ranibizumab (Lucentis), a Fab fragment derived from the same parent molecule as bevacizumab, now has FDA approval to treat the "wet" type of age-related macular degeneration (ARMD)
6. More mAbs applications can be seen on Wikipedia

Losartan - Role in muscle healing?

2007-02-04T14:00:00.000-05:00

Losartan - One of the favourite drug of physicians for the treatment of hypertension (because of it's excellent tolerance profile) has recently been discovered to have a healing effect in mice models sufferig from Marfan's syndrome and Duchenne muscular dystrophy (DMD) - diseases causing progressive muscle degenration and scarring.

Dr. Dietz et al. at the Hopkins showed new mechanism as a root cause of progressive muscle degeneration in both diseases. Excess of transforming growth factor-beta (TGF-beta) is involved in halting muscle regeneration - a physiologic response to muscle damage.

Now, team is scheduled to start clinical trial of Losartan in Marfan's syndrome by next month

Researchers gave the mice losartan to inhibit TGF-beta, they showed more efficient muscle repair and even elimination of disease in mices treated over a period of time. Now, team is scheduled to start clinical trial of Losartan in Marfan's syndrome by next month. Similar Clinical trial is also proposed in childrens suffering from DMD who till date have only steroids as treatment - a short-lived and less effective option. Scientists may now focuse on easy and more effective approach to halt disease progression than more complicated efforts to replace deficient gene products (for Marfan syndrome a deficient protein called fibrillin-1; for DMD, a protein called dystrophin). This study was conducted by the National Institutes of Health's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of Neurological Disorders and Stroke (NINDS) and affiliated institutes.
[Source: http://www.niams.nih.gov/ne/press/2007/02_02.htm
Study will be published in February 2007 issue of Nature Medicine]

P.S.: I am unsure whether TGF-beta antibodies / inhibitors may have role in these disaeses. Lerdelimumab [CAT 152], monoclonal antibody directed against TGF-beta is being developed as an adjunct to glaucoma drainage surgery. Overactivity of transforming growth factor--2 is believed to cause scarring in and around the eye after glaucoma surgery. Cambridge Antibody Technology Drugs in R & D. 3(2):106-108, 2002

New test for Down's Syndrome - preliminary study

2007-02-03T13:58:00.000-05:00

Ravgen Inc - an US based company has developed new pre-natal test to diagnose Down's syndrome using maternal blood, eliminating higher risk of fetal loss associated with currently available diagnostic studies.

Dhallan R et al. performed a preliminary study among 60 pregnant women which showed promising results, press release from Lancet on 2-Feb-2007. Test uses fetal DNA extracted from blood samples taken from the mother to screen for chromosomal abnormalities by analyzing an array of single nucleotide polymorphisms (SNPs, pronounced “snips”).

Lancet. 2007, DOI:10.1016/S0140-6736 (07) 60115-9

Can you identify them?

While looking into Ravgen Inc history, I came across this famous photo which to me was unknown before. Picture shows first X-ray diffraction photograph of DNA, taken in 1953 by one of the most controversial woman scientist in the history - Rosalind Franklin (Wikipedia, Info from SDSC.edu)

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) in Huntigton's disease (HD)

2007-02-03T13:57:00.000-05:00

Scientists have found new link in molecular mechanism of Huntington's disease - CAG nucleotide repeat expansion in Huntington gene (Htt) leading to mutated Htt (mHtt). Previously it was postulated that mHtt gene codes for two 'independent' mechanisms leading to neuronal cell death and clinical features. These two mechanisms are 1. interference in transcription mediated by Sp1 and cyclic AMP response-element–binding protein [CREB]–binding protein [CBP] and 2. mitochondrial impairment - are now believed to be 'interdependent' as suggested in three recent studies.

Clinical application?
Augmenting PGC-1α activity might be therapeutic in HD and other neurodegenerative disease related to oxidative stress.

Studies revealed role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) as a transcriptinonal coactivator which controls many of mitochondrial functions, including anti-oxidant function. In HD, mHTT has repressor effect on expression of the gene encoding PGC-1α by binding to its promoter and interfering with its CREB-dependent transcription and thus, leading to
mitochondrial impairment. This is further supported by evidence showing overexpression of PGC-1α improves atrophy of striatal neurons that normally occurs in transgenic mice with Huntington’s disease.
[N Engl J Med 2007;356:518-520]

Researchers at Brown found a crucial protein in deadly prion spread

2007-01-23T15:37:00.001-05:00

Satpute-Krishnan et al. at Brown University found mechanism by which protein-only or prion-only elements propogate phenotypic inheritance and thereby allowing deadly Prion disease to spread as mad cow disease and scrapie in animals and, in rare cases, Creutzfeldt-Jacob disease and kuru in humans. [A relatively new term, Prions are emerging form of new pathogens which are infectious proteinaceous particles devoid of nucleic acid, basic elements of inheritance (Prion protein which replicates from its precursor isoform PrP^C by fundamental α-to-ß conformational changes leading to accumulation of abnormal prion protein PrP^Sc)

Team studied Saccharomyces cerevisiae prion [PSI+], a self-replicating conformer of the Sup35, a yeast protein similar to the human prion protein PrP. They put Sup35 together with molecular chaperone Hsp104, then activated and deactivated Hsp104. They found that the Hsp 104 protein does, indeed, chop up Sup35 complexes – the first direct evidence that this process occurs in a living cell and that Hsp104 is the culprit. Dynamic change in Sup35^[PSI+] is lost when the molecular chaperone Hsp104, a factor essential for propagation of all yeast prions, is functionally impaired.

"To understand how fragmentation speeds the spread of prions, think of a dandelion," Co-author Serio said. "A dandelion head is a cluster of flowers that each carries a seed. When the flower dries up and the wind blows, the seeds disperse. Prion protein works the same way. Hsp104 acts like the wind, blowing apart the flower and spreading the seeds." Serio said that prions still multiply without fragmentation. However, she said, they do so at a much slower rate. So a drug that blocks the activity of Hsp104 could seriously slow progression of prion-related diseases.

[Read full article free at PLoS Biol 5(2): e24 doi:10.1371/journal.pbio.0050024 ]
[News link: EurekAlert! 23 Jan 2007]
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Imatinib vows and RNAi - concept to find Achilles heel of deadly diseases

2006-12-06T23:18:00.000-05:00

Imatinib vows:
In an outcome of 5 year follow-up study of two groups of CML patients, Imatinib-tyrosine kinase inhibitor (Gleevec, Novartis; formerly called STI571) showed durable response in a high proportion of patients compare to interferon alfa plus cytarabine therapy for newly diagnosed CML in the chronic phase. International Randomized Study of Interferon and STI571 (IRIS) showed estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response. However, sporadic reports suggest that the discontinuation of imatinib, even in patients with undectectable levels of BCR-ABL transcripts, results in relapse. Possible mechanisms of such phenomenon include drug efflux and amplification or mutation of the BCR-ABL gene possibility of Imatinib to not completely inhibit BCR-ABL kinase activity; low levels of activity would allow cells to survive but not proliferate. As an alternative, the malignant clone could persist through mechanisms that are independent of the BCR-ABL kinase.
[Excerpt from N Engl J Med 2006;355(23):2408-2417]
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RNAi - concept to find Achilles heel of deadly diseases
Latest buzz in applied genomics is gene silencing through RNA interference (RNAi) phenomenon [discovered 9 years back by Fire and Mello (Nobel prize 2006)] which is completely different and much more superior to traditional anti sense RNA approach to silence gene expression and thereby knocking down relevant protein production. Silencing bad and/or mutated genes is a newer genotype-specific target therapy approach to kill selective cancer and infected cells ( i.e. HIV infected CD4 T-cells) sparing healthy surrounding cells and avoiding cytotoxic effects which is a big concern with current chemotherapies. Other promising applications are to target drug resistant gene(s) and silent them to overcome drug resistance and logically any abnormality associated with over expression of gene(s). Infact, clinical trial of using small interfering RNA (siRNA) in age-related macular degeneration (ARMD) is ongoing along with several other animal trials for diseases like, amyotrophic lateral sclerosis, spinocerebellar ataxia, atherosclerosis and infections caused by respiratory syncytial virus, parainfluenza virus, herpes simplex virus 2, and the hepatitis B and C viruses.
[Excerpt from N Engl J Med 2006;355(23):2391-2393 (Also shows graphical explanation about mechanism of RNAi)]

Relevant links:

Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998;391 :806-11 PMID: 9486653

A loss-of-function RNA interference screen for molecular targets in cancer Nature 441, 106-110 (4 May 2006)
siRNA targeting Vascular Endothelial Growth Factor Receptor for ARMD:

Latest ARMD treatments and their mechanisms
Cand5 in phase II clinical trial NCT00306904
SiRNA-027 in phase I clinical trial NCT00363714

Indian scientist Utpal Bhadra's contribution in RNAi development: Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent Cell 1997 Aug 8;90(3):479-90 PMID: 9267028

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Also, stop by to read why Thiazolidinediones are not favored to Metformin for Initial Treatment of Type 2 Diabetes? N Engl J Med 2006;355(23):2477-2480
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New drug in phase I trial to restore vascular homeostasis

2006-11-09T00:56:00.000-05:00

Sep 27, 2006:
This may serve a boon for interventional physicians and vascular surgeons. Pervasis Inc. (Cambridge MA) has initiated phase I clinical trial of Vascugel™ - a novel allogeneic cell therapy (gel form) based on concepts of tissue engineering to enable implantation of allogeneic endothelial cells in a controlled state. It can restore natural repair and regeneration pathways in the vasculature with potential to allow traumatized vasculature to return to homeostasis by simultaneously reducing intimal hyperplasia (abd so scar tissue formation), inflammation and thrombosis. Pervasis is conducting its "V-HEALTH" (Vascular intimal Hyperplasia: Extending Arterial and venous patency, Limiting vascular Trauma, and inhibiting Hyperplasia while re-establishing vascular health) Phase I clinical trials in patients with ESRD that require a permanent AV access for hemodialysis. Vascugel(TM) is the first therapy being developed to simultaneously improve outcomes for the two primary forms of surgical arteriovenous access, namely, AV grafts and AV fistulas.
For more information, visit www.pervasistx.com
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Stem cell buzz

2006-11-06T15:28:00.000-05:00

Even stem cells have big mama!

Recent University of Washington (UW) research has found an early indication of two-way cellular communication in the miniscule niches of the body where the futures of stem cells are determined. Stem cells require these niches - nest-like microenvironments made up of regulatory cells – in order to self-renew. Stem cells can divide and turn into many types of new cells. The niches help regulate the amount and kinds of new cells produced to meet current demands. Niches are places where your stem cells can replenish themselves and your tissue cells throughout your lifetime. "Our study now shows that stem cells use the Notch pathway to signal to neighboring cells to maintain an active niche, and in turn, the niche induces and maintains the fate of the stem cells," Ruohola-Baker noted. "This is a first indication of a dialogue taking place between the stem cells and the niche that supports them.....

Read original public release at EurekAlert! News (3-Nov-06):
Stem cells engage in dialogue with the cells that regulate their futures

More in cell signaling:
A protein with the ironic name "Srcasm" can counteract the effects of tumor-promoting molecules in skin cells, according to new research by investigators at the University of Pennsylvania School of Medicine. Using animal models, the researchers discovered that Srcasm acts like a brake in epithelial cells, preventing uncontrolled cell growth caused by a family of proteins called Src kinases. This finding, published online in the Journal of Biological Chemistry, suggests a target for future gene therapy to treat skin, head, neck, colon, and breast cancers. Srcasm might play a role in targeted gene therapies for cancers that are triggered by activated Src kinases. Such a therapy would likely use an adenovirus to carry a gene that codes for Srcasm into skin cells to increase Srcasm production, as used in some other gene therapy treatments.....

Read original public release at EurekAlert! News (3-Nov-06):
Signal protein shows promise for blocking tumor promoters in skin cells

Insult to my favourite protein!

2006-10-09T07:21:00.000-04:00

Recent research is indicating early p53 response may not have role in DNA damage repair at least in tumor pathogenesis. p53 - guardian of genome is now supposed to get activated through oncogene-mediated activation of tumour suppressor protein p19 ^AR which in turn is taking place of p53 as a crucial step in tumor prevention. Interestingly, p19^ARF is only activated in response to oncogene activation and not to DNA damage. Read original article at AfCS-Nature
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Stop Press: Cloning without stem cells

2006-10-02T06:52:00.000-04:00

2 Oct 06:

Hope survives with Adult Stem Cell and Cell Reprogramming technologies.

The Pittsburgh University team created two baby mice from a fully matured white blood cell line. Read more at BBC News
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Moving Neuronal Cells back into cell cycle

2006-09-01T11:17:00.000-04:00

1-Sep-2006

Scientists at Harvard University have identified key compounds that stimulate stem cell growth in the brain, which may one day lead to restored function for people affected by Parkinson's disease, strokes, multiple sclerosis, and a wide range of neurological disorders. These findings, which appear in the September 2006 issue of The FASEB Journal, provide important clues as to which compounds may be responsible for causing key brain cells, neurons, to regenerate and ultimately restore brain function.

The research study focused on two compounds--LTB4 and LXA4. Both play a role in inflammation and are regulators of proliferation of several cell types. When stem cells isolated from the brains of mouse embryos were exposed to LTB4 they proliferated and differentiated, giving rise to additional stem cells and to differentiated neurons with limited or absent capacity to divide. When exposed to LXA4, these cells experienced decreased growth and apoptosis.....
More at EurekAlert!
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Further Positive Phase II Results of Trinam Gene Therapy

2006-08-23T16:18:00.000-04:00

Trinam® (EG004) – target site treatment to prevent blood vessels blocking in kidney dialysis patients who have undergone vascular access graft surgery. The new data (Aug 23, 2006) show that the access grafts of low dose patients remain functional for dialysis on average over five times longer (17.8 months) than control patients in the trial (3.3 months).
More at Trinam page and press report from Pharma Live

You may also like to see other gene based research molecules of Ark Inc.

Alzheimer's can hit middle age persons

2006-07-12T18:38:00.000-04:00

Early signs of the development of Alzheimer's disease can be seen in the cerebrospinal fluid of middle-aged adults who are genetically predisposed to the neurologic condition, according to a report in the July issue of Archives of Neurology. APOE*4(apolipoprotein E*4) allele person develop clinical dementia about 10 to 15 years earlier than those who do not have the APOE*4 allele. APOE*4 is one of the two major risk factors(other is aging) for Alzheimer's disease. Study performed at University of Washington School of Medicine, Seattle also found clinical biomarkers related to the typical plaques of Alzheimer's disease which are predominantly made of protein known as a â-amyloids. â-amyloid proteins, predominately of a type known as Aâ42, clump together to form plaque, fewer are available to circulate through the nervous system. Therefore, lower levels of the Aâ42 in the cerebrospinal fluid serve as biomarkers of the development of Alzheimer's disease and thereby persons who are at risk can be diagnosed at early age.
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11 July 2006 1834 -0400
CT USA

The Brahma's world!

2006-07-11T23:44:00.000-04:00

Have you ever had conflicts with your colleagues or yourself about science and spirituality. Does the force exist? Why do we keep faith in someone? Can we link genes and the god? Is it an evolution or intelligent theory that embarked humans as the most advanced species on the earth?.....

Well! Here is an interesting book written by the visionary Dr. Francis Collins (Know more about him in his detailed interview)

Although I've not read it yet (just read article in the Time July 17 issue), I am going to grab it soon!

Book details:
The Language of God : A Scientist Presents Evidence for Belief (Hardcover)
by Francis S. Collins
Hardcover: 304 pages
Publisher: Free Press (July 11, 2006)
Language: English
ISBN: 0743286391
List Price: $26.00
Price: $15.60 (Amazon); $18.20 (BN) Subject to change
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12 July 2006 0002 -0400
CT

Dz13 - molecular assassin theory

2006-07-03T12:54:00.000-04:00

New buzz in applied genomics:
Researchers at the University of NSW unveiled their "one size fits all" therapy, which they said had already been effective against skin cancer...Interesting article at Hearld Sun website: Gene therapy a silent 'assassin'
Visit Nature Biotechnology for descriptive information.
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3-July-2006 1250 -0400
GA

Nef protein in HIV-1 pathogenesis

2006-04-28T15:06:00.000-04:00

An informative article on Nef protein mechanism

Turning off class switching

The soluble HIV-1 negative factor (Nef) inhibits class-switch recombination in B cells, thus preventing production of the antibody classes that are most adept at clearing the virus.
Nature Immunol. 7, 302 – 310, (2006)
Link to AfCS Nature magazine article
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Articles of Interest on Cell Signaling

2006-03-28T10:44:00.000-05:00

Articles of interest on cell signaling
Fyn
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0xer0EH
Fyn is a tyrosine specific phospho-transferase that is a member
of the Src family of tyrosine protein kinases. It has been shown
that Fyn is required for growth factor and cytokine receptor
signaling, axon guidance, and differentiation of natural killer
cells, oligodendrocytes and keratinocytes.

LYMPHOCYTE DEVELOPMENT: THE JOURNEY BEGINS FOR [alpha][beta]
AND [gamma][delta] T CELLS
A new study reveals differences in Notch-Delta signaling dependence
and gene expression at the earliest stages of divergence between
developing [alpha][beta] and [gamma][delta] T-lineage cells.
Original research paper: Immunity 24, 53–64 (2006)
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0xey0EO

TUMORIGENESIS: CULPABLE KINASE
The ability of cyclin D1 to activate cyclin-dependent kinase CDK4
underlies the critical role for cyclin D1 in breast cancer formation.
Original research paper: Cancer Cell 9, 23–32 (2006)
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0xez0EP

PROTEIN–PROTEIN INTERACTIONS: MUSCLING IN ON P53
A series of small-molecule inhibitors that prevent the association
of p53 with its coactivator, the histone acetyltransferase
p300/Creb-binding protein (CBP), are able to downregulate the
p53-mediated response to DNA damage.
Original research paper: Chem. Biol. 13, 81–90 (2006)
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0xfb0E1

MONOCYTE EMIGRATION FROM BONE MARROW DURING BACTERIAL INFECTION
REQUIRES SIGNALS MEDIATED BY CHEMOKINE RECEPTOR CCR2
Nature Immunology 7, 311 - 317 (2006)
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0u1l0EG

NEUROTROPHINS MEDIATE HUMAN EMBRYONIC STEM CELL SURVIVAL
Nature Biotechnology 24, 344 - 350 (2006)
http://info.nature.com/cgi-bin24/DM/y/eXU20NML4k0Dn0wRJ0EH

Source:
From: AfCS - Nature Signaling Gateway (Nature magazine service)
Date: Mar 27, 2006 9:44 PM
Subject: AfCS-Nature Signaling Update Contents for 27 March 2006

Signaling Update is a one-stop online resource designed to keep you in touch with the latest and most exciting research in cell signaling. New content is uploaded every Friday.

*********************************************************************
(c) 2006 Nature Publishing Group
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Articles of Interest in Cancer Medicine (Myeloma & Melanoma)

2006-03-09T06:01:00.000-05:00

The Changing Landscape of Myeloma Therapy: NEJM Mar 9, 2006

The role of Immunohistochemistry in the differential diagnosis of soft-tissue tumors: CCJ Moffitt USF Tampa FL Jan/Feb 1998

Calcification in a paraspinal malignant melanoma in a child: AJR Stanley et al. 129 (1) 143

Target Site Importance & Clinical Alert!

2006-02-27T09:30:00.000-05:00

1. 'DNA target' to block HIV found: BBC News

UPenn Team found the cellular protein called, LEDGF which binds to HIV integrase and specific sites on the cell's chromosomes and thus plays a pivotal role in bridging HIV and host's genetic assembly. Researchers also discovered decreased and less efficient capability of HIV to integrate into host genome (via HIV's reverse transcriptase enzyme) in cells made deficient of LEDGF molecules. "This is the first example of a cellular factor that's a clear player in target site selection," - Team Leader comment. This can be one of the major research breakthrough which will help towards gene therapy development for HIV infection.
For original article, go to BBC News Link

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2. Gene therapy: Solving delivery problems: SFGate

Old is Gold - UC Berkeley researcher is working to follow Darwinian Natural Selection method to carry gene therapy code (piece of DNA which acts as therapeutic drug) within the core of human friendly adeno-associated virus (AAV). These AAVs with specifically designed altered capsid material (derived from serial replication of AAV batches with repetitive screening for specific antibodies and finally fetched six variants out of millions screened!) found to be less immune reactive and thus capable of bypassing immune system screening will be of great help to deliver inner therapeutic genes to target cells. However, many cells have efficient power of damaging healing agent even though it was carried by AAVs or similar vehicles to the target cell site. So next focus of research would be at Target Site. Article to be published in Nature magazine.
Read original article at SFGate.com

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3. CORAUTUS GENETICS ANNOUNCES UPDATE ON GENASIS TRIAL

ATLANTA, Feb. 23 /PRNewswire-FirstCall/ -- Corautus Genetics Inc. (Nasdaq: VEGF - News) announced today an update of its GENASIS Phase IIb clinical trial that is evaluating the safety and efficacy of VEGF-2 for the treatment of severe angina resulting from cardiovascular disease. Corautus expects to complete the enrollment of 404 patients in its Phase IIb GENASIS trial around June 30, 2006. Corautus had previously projected that it would complete enrollment by March 31, 2006. To date, 276 patients have been treated in the trial.

In August 2004, Corautus initiated its GENASIS ("Genetic Angiogenic Stimulation Investigational Study") trial to evaluate the safety and efficacy of Vascular Endothelial Growth Factor-2 (VEGF-2) for the treatment of patients with Class III and IV angina who are not candidates for current revascularization techniques and for whom surgery is not advisable. VEGF-2 is a growth factor that is believed to promote the development of supplemental collateral blood vessels, which could provide the heart with sufficient oxygen to relieve the pain of severe angina pectoris. In addition to safety and efficacy, the trial will provide information to determine the optimum dosage of VEGF-2.
Read original article at Corautus Press release

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4. Clinical Alert! - A case of mistaken molecular identity - EurekAlert

Researchers in Argentina have determined that night blindness is a new clinical symptom of Chagas disease. They found that the immune system of individuals with the tropical disease can shut down a key reaction in the retina, causing night blindness.

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"Personality can open doors, but only character can keep them open"

Herceptin and the Heart — A Molecular Modifier of Cardiac Failure

2006-02-23T11:31:00.000-05:00

This article explains thoroughly how ErbB2 deficient (or mutant) heart has propensity to go into failure following use of Herceptin (trastuzumab= humanized monoclonal antibodyagainst the HER2 protein) as an adjuvant therapy in early HER2-positive breast cancer.

Authors have also shown possible mechanisms of cardiotoxicity with concomitant antracyclines use and measures to decrease cardiotoxicity risk. The final line is interesting: Perhaps we should prepare ourselvesfor a new mantra: reverse translation.
NEJM link

More on Avastin® (bevacizumab)

2006-02-22T02:23:00.000-05:00

Avastin® in Pancreatic Tumors:
A Phase II clinical trial is under way at Northwestern Memorial Hospital in conjunction with the Northwestern University Feinberg School of Medicine to determine if bevacizumab (also referred to as Avastin®, an anti-angiogenesis drug that is designed to inhibit the growth of blood vessels in tumors) in combination with abdominal radiation therapy and chemotherapy can reduce localized pancreatic tumors that have not metastasized or spread to other systems or organs in the body. Northwestern Memorial is the sole clinical site where the research trial is being conducted.
EurekAlert! Link
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New hope for diabetics - Islet cell from animals' pancreas

2006-02-19T16:18:00.000-05:00

First successful xenotransplantation of pig's islets cells to treat diabetes (chiefly type 1) into monkeys. Researchers are now hopeful to conduct clinical trials in next three years to solve current complexity remained with expensive human islet cell conservation & transplantation. Read breakthrough conducted by researchers at the University of Minnesota's Diabetes Institute for Immunology and Transplantation at EurekAlert!
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Understanding basics of Cell Signal Transduction

2006-02-17T01:31:00.000-05:00

Here are some of useful links worth navigating for signal transduction knowledge.

http://www.signaling-gateway.org/ : the Signaling Gateway - Provides basic as well as latest updates from research papers, conferences, etc. happening in signal transduction science. Direct link to molecule database
Signal-Transduction Pathways: An Introduction to Information Metabolism : About basics from NCBI Books.
Signal Transduction links library: BioChemWeb.org
Understanding Signal Transduction Cascades : From Rensselaer Polytechnic Institute (RPI), NY
Cell Signaling Pathway Slides & Charts : From Sigma-Aldrich, rich and informative slides on signal cascades.
Cell Signling : Basic mechanisms involved in signaling from Kimball's Biology Pages.

Targeting the Signal Transduction Pathway to halt cancer progression

2006-02-16T15:20:00.000-05:00

New targeted treatment for brain tumors shows promise in pre-clinical models :

Gliomas are the most common primary brain tumors, and also one of the most complicated cancers to treat. Treatment options such as surgery, radiation and chemotherapy are only marginally beneficial and present significant risks for patients. But, a new study published today in Clinical Cancer Research found that treatment with a novel monoclonal antibody (mAb) L2G7 inhibited the growth of glioma cells, induced glioma regression within the brain and prolonged survival - a finding that could be translated into human trials as early as next year.

Targeting the Signal Transduction Pathway in RCC

A must read article on MedScape details promising role of newer TKI (Tyrosine kinases inhibitors) in halting tumor cell replication with interfering cellular transduction signals -

Sorafenib (Nexavar®) and Sunitinib (Phase III trial) : targets VEGF and PDGF receptor
Temsirolimus (Phase III trial) : targets rapamycin (mTOR), which is a protein involved in cell cycle progression
Erlotinib (Tarceva®) : targets EGF receptor
Bevacizumab (my favourite! Avastin®) : a humanized monoclonal antibody that binds to VEGF-A)

MRI drug may improve cancer-killing ability of chemotherapy, study says :

A contrast agent currently used in magnetic resonance imaging (MRI), called mangafodipir, may increase the cancer-killing ability of some chemotherapy drugs while protecting normal cells, according to a study in the February 15 issue of the Journal of the National Cancer Institute.

"Whenever you find yourself on the side of the majority, it is time to pause and reflect."
- Mark Twain

"Simply be honest to yourself, and let others react as they will"

Stem Cell Now : new book

2006-02-14T14:06:00.000-05:00

Stem Cell Now : new book

By bioethics expert Christopher Thomas Scott explores the possibilities of what some consider the greatest discovery since nuclear fusion. Read excerpt at http://www.npr.org/templates/story/story.php?storyId=5204335

This book is worth reading for gene worms;-) I am planning to buy it in next 1-2 months. Please Contact me review in case you have gone through it.

Thanks.

Latest in genes:

Dr. Kalam briefed on stem cell research
Musculoskeletal Manifestations and Autoimmune Diseases Related to New Biologic Agents: Use of Anti-TNF agents (used in the management of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile inflammatory arthritis) and alarm against development of auto-antibodies and lupus-like syndromes. Review of infliximab, adalimumab and etanercept..... Read MedScape article

SBA
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"Nanavaptam avaptavyam varta eva ca karmani" : The God says to Arjuna : Nor I am in want of anything, nor have I need to obtain anything--and yet I am engaged in work. [The Bhagavad Gita - 3.22 @ http://www.asitis.com]

List of Indian Journals Indexed in the MEDLINE Database

2006-02-06T11:33:00.000-05:00

List of Indian Journals Indexed in the MEDLINE Database

Source: http://www.qmedin.com/medsites/medlinejournals.htm

Links to Entrez PubMed Page showing up-to-date indexed articles of respective journals:

Direct Links To Journals (FREE ACCESS)
Related to Oncology / Chest / Paediatrics

Indian Medlars Centre - Indian Medline!

Thanks!
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This Valentine's Special

2006-02-05T09:26:00.000-05:00

Duplicate at all blogs

This Valentine before you hold your breath and say those three golden words to your lover, be alert!

Check out your compatibility with your lover before you say I Love You. Even I, personally don't believe in such tricks as logically they are purely non-sense ! However, I found this link really interesting and who so ever made this software, has used sound algorithm to analyze compatibility between lovers only with use of names as variables. I have tested it with many variables (?!? In real life..I have just 1 though;-) and my friends got amazed after using it.

Worth clicking and filling once..Don't worry! It does not ask for sensitive information - email, date of birth or location. Go ahead and check your love meter!

Good Luck!
Happy Valentine Prep:-)
SBA
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What's new for Revlimid (lenalidomide)

2006-02-05T00:13:00.000-05:00

---------- Forwarded message ----------
From: My NCBI <efback@mail.nih.gov>
Date: Feb 5, 2006 4:25 AM
Subject: What's new for 'Revlimid' in pubmed
To: SBA
This message contains My NCBI what's new results from the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).Do not reply directly to this message.

Sender's message: Search: Revlimid

Sent on Saturday, 2006 Feb 04
Search Revlimid
Click here to view complete results in pubmed. (Results may change over time.)

Highlighted items are read and suggested for reading by interested visitors.

Entrez pubmed Results

Items 1 - 5 of 5

1: Mayo Clin Proc. 2006 Jan;81(1):104-30. Related Articles, Books, LinkOut: The myelodysplastic syndromes: diagnosis and treatment.

Steensma DP, Bennett JM.

Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA. steensma.david@mayo.edu

The myelodysplastic syndromes (MDSs) are common, acquired, clinically challenging hematologic conditions that are characterized by bone marrow failure and a risk of progression to acute leukemia. These disorders can arise de novo, especially in elderly patients or, less often, as a consequence of prior chemotherapy or radiotherapy for an unrelated disease. The MDS classification systems were revised recently and updated. These refined classification and prognostic schemes help stratify patients by their risk of leukemia progression and death; this knowledge can help clinicians select appropriate therapy. Although many treatments for MDS have been proposed and evaluated, at present, only hematopoietic stem cell transplantation offers any real hope for cure, and no available therapy beyond general supportive care offers benefit to more than a minority of patients. However, recent clinical trials enrolling patients with MDS have reported encouraging results with use of newer drugs, including lenalidomide, decitabine, and darbepoetin alfa. Other exciting treatment regimens are being tested. Here, we present a contemporary, practical clinical approach to the diagnosis and risk-stratified treatment of MDS. We review when to suspect MDS, detail how to evaluate patients who may have a form of the condition, explain key features of treatments that are currently available in the United States, and summarize a general, common-sense therapeutic approach to patients with MDS.

PMID: 16438486 [PubMed - in process]

2: Expert Opin Investig Drugs. 2006 Feb;15(2):171-9. Related Articles, Books, LinkOut: Current therapeutic uses of lenalidomide in multiple myeloma.

Hideshima T, Richardson PG, Anderson KC.

Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. teru_hideshima@dfci.harvard.edu

Thalidomide has demonstrated a broad spectrum of pharmacological and immunological effects, with potential therapeutic applications that span a wide spectrum of diseases: cancer and related conditions; infectious diseases; autoimmune diseases; dermatological diseases; and other disorders such as sarcoidosis, macular degeneration and diabetic retinopathy. Immunomodulatory derivative lenalidomide has more potent antitumour and anti-inflammatory effects. The molecular mechanisms of antitumour activity of lenalidomide have been extensively studied in multiple myeloma (MM). It directly induces growth arrest and/or apoptosis of even drug-resistant MM cells; inhibits binding of MM cells to bone marrow extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the bone marrow milieu; and augments host antitumour immunity. Importantly, lenalidomide induces significant clinical responses even in patients with relapsed/refractory MM. Therefore, lenalidomide represents a new class of antitumour agents that is useful in the treatment of MM. Lenalidomide has received fast track designation from the FDA for the treatment of MM and myelodysplastic syndromes.

PMID: 16433596 [PubMed - in process]

3: Ann Pharmacother. 2006 Jan 10; [Epub ahead of print] Related Articles, Books, LinkOut: Role of Lenalidomide in the Treatment of Multiple Myeloma and Myelodysplastic Syndrome (February).

Maier SK, Hammond JM.

Department of Pharmacy, Duke University Medical Center, Durham, NC.
< br>OBJECTIVE: To evaluate lenalidomide in the treatment of multiple myeloma and myelodysplastic syndrome (MDS). DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-August 2005), Science Citation Index (1980-August 2005), and Proceedings of the American Society of Hematology (2000-2004). DATA SYNTHESIS: New analogs of thalidomide have been synthesized that are more potent and less toxic. Lenalidomide (CC-5013) is currently in Phase III trials for the treatment of multiple myeloma and MDS. Phase II trials demonstrated lenalidomide's efficacy in patients refractory to thalidomide. The full potential of this agent has yet to be proven, but preliminary data seem promising. CONCLUSIONS: Lenalidomide is a potent immunomodulating drug that offers different mechanisms of action and therapeutic potential for the treatment of multiple myeloma, MDS, and other malignancies.

PMID: 16403850 [PubMed - as supplied by publisher]

4: J Natl Compr Canc Netw. 2006 Jan;4(1):78-82. Related Articles, Books, LinkOut: Developmental therapeutics for myelodysplastic syndromes.

Naing A, Sokol L, List AF.

H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, FL, USA.

The management strategy for patients with myelodysplastic syndromes (MDS) has evolved from sole reliance on supportive measures to active treatment guided by disease risks. Recent progress in understanding the molecular pathogenesis of MDS has accelerated the discovery of new therapeutic targets, and consequently launched the development of several novel therapeutics that are currently in varied stages of clinical testing. One such agent is lenalidomide, which has shown remarkable effectiveness in the cytogenetically defined subset of MDS with the chromosome 5q31 deletion. The advent of new and effective targeted therapeutics may beneficially affect outcomes of an ever-increasing number of patients with MDS. This discussion summarizes the preliminary results of selected novel therapeutics.

PMID: 16403406 [PubMed - in process]

5: Curr Treat Options Oncol. 2005 Sep;6(5):357-65. Related Articles, Books, LinkOut

Promising systemic therapy for renal cell carcinoma.

Cooney MM, Remick SC, Vogelzang NJ.

Nevada Cancer Institute, University of Nevada School of Medicine, Las Vegas, NV 89135, USA.

In the United States, advanced kidney cancer accounts for over 12,000 deaths each year. Immunotherapy with either interferon or interleukin-2 (IL-2) has been the standard of care for over two decades. High-dose IL-2 can apparently cure 10% to 15% of patients treated, but due to the required inpatient care and the attendant toxicities, it is only administered to less than 1,000 patients per year in the United States (Chiron, personal communication). Interferon is a less active agent than IL-2 but it has still been shown to be superior to therapy with either megesterol or vinblastine. Interferon typically results in very few long-term responses and is given to most patients with metastatic kidney cancer. Median survival after interferon therapy is dependent on risk group but is typically 12 to 15 months. Thus, new therapies are urgently needed in this refractory disease. Novel compounds currently being tested in clinical trials are showing promise in advanced kidney cancer. The molecular targets of these drugs include interfering with the vascular endothelial growth factor receptors or the raf kinase pathway, angiogenesis inhibition, and antimicrotubule agents. A review of the preclinical and early clinical development of some of these novel compounds will be discussed.

Publication Types:

Review

PMID: 16107239 [PubMed - indexed for MEDLINE]

SBA

PET and Assessment of Cancer Therapy

2006-02-02T10:14:00.000-05:00

A good article on understanding PET scan (and various tracers) application in Cancer therapy assessment, restaging after therapy. NEJM Link
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Track automatic updates at www.SBAmin.com/blog/feeds.htm

Updates in Molecular Medicine

2006-01-26T15:06:00.000-05:00

Latest alerts from Eureka Alert

Discoveries may advance stem cell therapy for Parkinson's, cancer patients : Two studies in the Jan. 27, 2006 Cell have yielded evidence that could prove a boon for stem cell therapies aimed at patients with Parkinson's disease and those with compromised immune systems due to intensive cancer therapy or autoimmune disease, according to researchers. The basic findings in mice revealed critical factors that determine the fate of one type of nerve cell progenitor and that set bone marrow stem cells into action. Link

New pathway could present an intervention point for cancer treatment : A new cellular pathway leads to destruction of a protein that promotes growth of breast, prostate and similar cancers and could provide a new avenue through which to pursue treatment of such diseases, said a researcher at Baylor College of Medicine. Link

Research breakthrough pinpoints aim of ion beams fired at cancer tumors :Nonsurgical cancer therapy that destroys tumors but leaves healthy surrounding tissue intact could be available at every hospital if research reported this week in the journal Nature eventually comes to fruition. Link
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Master genetic switch found for chronic pain : In experiments with mice, researchers have found that eliminating what appears to be a master genetic switch for the development of pain-sensing neurons knocks out the animals' response to "neuropathic pain." Such pain is abnormal pain that outlasts the injury and is associated with nerve and/or central nervous system changes. The researchers said that their findings, reported in the February 2, 2006, issue of Neuron, could have implications for the design of improved pain therapies. Link

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"Nanavaptam avaptavyam varta eva ca karmani" : The God says to Arjuna : Nor I am in want of anything, nor have I need to obtain anything--and yet I am engaged in work. [The Bhagavad Gita - 3.22 @ http://www.asitis.com]

Hope Survives

2006-01-25T18:11:00.000-05:00

Hope Survives:

Articles worth to read at NEJM -

1. Beyond Fraud — Stem-Cell Research Continues

2. Egg Donation and Human Embryonic Stem-Cell Research

SBA

Breakthrough in stem cell research

2006-01-23T09:39:00.000-05:00

Dr Kuldip Sidhu, an UNSW researcher based at the Diabetes Transplant Unit at the Prince of Wales Hospital has produced a human embryonic stem cell (hESC) line (named, Endeavour 1) without the use of any animal products, using human fetal fibroblast feeder layer devoid of fetal calf serum. The breakthrough eliminates the risk of animal-to-human contamination in potential stem cell therapy treatments.
Read more at UNSW link
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Updates, Updates & Updates......

2006-01-19T02:05:00.000-05:00

Stay Updated! News Updates, Medical/Research News, USMLE/Residency/IMGs info., Sci-Tech, Fun and much more at
http://bloglines.com/public/mcbvadodara : Medical College Baroda Blog Portal (www.mcb.in/blog/world)
http://bloglines.com/public/samblog : SBAmin.com Blog Portal

Thanks
SBA
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Targeting Culprit Molecule - A new approach for antibiotic devp.

2006-01-19T00:59:00.000-05:00

Scientists are now developing antibiotic which targets inhibiting production of toxic (pathogenic) factor(s) rather inhibiting bacterial growth or killing them; thereby avoiding adverse effects related to human/bacterial cell partial homology and facilitating the developmentof immune responses that will prevent subsequent infection. Hung et. al. have shown that a small molecule that blocks theproduction of virulence factors inhibits infection in an animal model of cholera.
> Read more on Disarming Pathogens - N Engl J Med 2006;354:296-297

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SBA

GENGHIS KHAN EFFECT

2006-01-19T00:47:00.000-05:00

Scientists in Ireland may have found the country's most fertile male, with more than 3 million men worldwide among his offspring. His genetic legacy is almost as impressive as Genghis Khan, the Mongol emperor who conquered most of Asia in the 13th century and has nearly 16 million descendants, said Dan Bradley, who supervised the research.
Abstract from Reuters Oddly Enough News (Jan 18, 2006), click here for original link

Isn't it interesting? In future.....someone would be more turned to take pride as Einstein Effect, Marilyn Monroe effect, Bill Gates effect,.... :-)
> Need more leisure posts, visit My Leisure
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SBA

Plasmid DNA Vaccines

2006-01-14T05:43:00.000-05:00

An interesting article from Science Direct (require subscription)

Human Clinical Trials of Plasmid DNA Vaccines

10 November 2005
Abstract:
This article gives an overview of DNA vaccines with specific emphasis on the development of DNA vaccines for clinical trials and an overview of those trials. It describes the preclinical research that demonstrated the efficacy of DNA vaccines as well as an explication of the immunologic mechanisms of action. These include the induction of cognate immune responses, such as the generation of cytolytic T lymphocytes (CTL) as well as the effect of the plasmid DNA upon the innate immune system. Specific issues related to the development of DNA as a product candidate are then discussed, including the manufacture of plasmid, the qualification of the plasmid DNA product, and the safety testing necessary for initiating clinical trials. Various human clinical trials for infectious diseases and cancer have been initiated or completed, and an overview of these trials is given. Finally, because the early clinical trials have shown less than optimal immunogenicity, methods to increase the potency of the vaccines are described.

Original article at Science Direct - Advances in Genetics, Voulme 55, 2005 Pages 25-40
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"Nanavaptam avaptavyam varta eva ca karmani" : The God says to Arjuna : Nor I am in want of anything, nor have I need to obtain anything--and yet I am engaged in work. [The Bhagavad Gita - 3.22 @ http://www.asitis.com]

Signal Transduction & Therapeutic Potentials

2006-01-09T15:55:00.000-05:00

1. Matrix metalloproteinases (MMPs), which include membrane type 1 (MT1)-MMP, are mainly known for their hydrolysis of extracellular matrix (ECM) components. But recently it has become apparent that they have a much wider substrate repertoire. Stephen Weiss and colleagues show that MT1-MMP can modify signal transduction through platelet-derived growth factor B (PDGFB) and its receptor PDGFRß to regulate development of micro-vasculature...

2. ERBB receptor tyrosine kinases & significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response....rational development of ERBB-targeted inhibitors ....recent discovery of kinase-domain mutations in EGFR and ERBB2 and their impact on response to ERBB-targeted therapeutics awaits further clinical and basic research....field of signal transduction will contribute not only to the development of novel therapeutics, but also allow us to optimally use those already in the clinic.

SBA

Welcome to Applied Genomics & Molecular Medicine blog @ SBAmin.com

2006-01-09T12:12:00.000-05:00

Welcome bloggers!
Here I wish to blog a little of ample number of updates happening in the field of Applied Genomics & Molecular Medicine.
Keep exploring.....
Thanks for visit.
SBA

Applied Genomics & Molecular Medicine

Subvert the Paradigm - Reprogramming the Cell: Part 5 | First successful production of induced pluripotent stem cells from adult somatic cells

RNAi and now, RNAa - The bubble effect

ENCODE - Code within the code

Gal1 gene silencing in Hodgkins's lymphoma

Reprogramming the Cell | Part 4: iPS - Introducing next generations

Oncolytic Therapy in Cancer Management: An Emerging Approach

Cancer: Spark and Shoot by painting

Gefitinib, EGFR and Insulin Secretion

Oral Eltrombopag - A possible answer to Platelet Transfusions

Reprogramming the Cell | Part 3: Stop press

ARMD and Translational Research

EASE trial - Airway Bypass Device for Emphysema

Does Dynamic DNA run cron jobs?

Prion - Thinking out of the box

Stop-codon mutation in immune cells

Dynamic DNA - Back to the future

SBAmin.com is down: Server Shifting In Progress

Mold by-product to kill Multiple Myeloma

Reprogramming Cell

RNAi explained

Bortezomib (Velcade) in EBV related tumors

Killing bacteria using Trojan horse theory

Heated Nanoprobes for Breast Cancer therapy

Targeting tumor cells using p73 (p53 family peptide) signal pathway

p53 and melanoma: guardian or ??

DNA Repair: Double edged sword | Clinical implication in Lung Cancer

New marker in Polycythemia Vera diagnosis and management

Controlling Master Switches

HIV vaccine phase IIb trial: On the way

Targeting death receptors

Losartan - Role in muscle healing?

New test for Down's Syndrome - preliminary study

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) in Huntigton's disease (HD)

Researchers at Brown found a crucial protein in deadly prion spread

Imatinib vows and RNAi - concept to find Achilles heel of deadly diseases

New drug in phase I trial to restore vascular homeostasis

Stem cell buzz

Insult to my favourite protein!

Stop Press: Cloning without stem cells

Moving Neuronal Cells back into cell cycle

Further Positive Phase II Results of Trinam Gene Therapy

Alzheimer's can hit middle age persons

The Brahma's world!

Dz13 - molecular assassin theory

Nef protein in HIV-1 pathogenesis

An informative article on Nef protein mechanism

Turning off class switching

Articles of Interest on Cell Signaling

Articles of Interest in Cancer Medicine (Myeloma & Melanoma)

Target Site Importance & Clinical Alert!

Herceptin and the Heart — A Molecular Modifier of Cardiac Failure

More on Avastin® (bevacizumab)

New hope for diabetics - Islet cell from animals' pancreas

Understanding basics of Cell Signal Transduction

Targeting the Signal Transduction Pathway to halt cancer progression

** Targeting the Signal Transduction Pathway in RCC **

Stem Cell Now : new book

List of Indian Journals Indexed in the MEDLINE Database

This Valentine's Special

What's new for Revlimid (lenalidomide)

PET and Assessment of Cancer Therapy

Updates in Molecular Medicine

Hope Survives

Breakthrough in stem cell research

Updates, Updates & Updates......

Targeting Culprit Molecule - A new approach for antibiotic devp.

GENGHIS KHAN EFFECT

Plasmid DNA Vaccines

An interesting article from Science Direct (require subscription)

Human Clinical Trials of Plasmid DNA Vaccines

Signal Transduction & Therapeutic Potentials

Welcome to Applied Genomics & Molecular Medicine blog @ SBAmin.com

Targeting the Signal Transduction Pathway in RCC