tbuckley/cabot-search huggingface dataset:
How does met regulate the survival/apoptosis balance?
Authors: Alessandro Furla, David Tulasne
Journal: Hepatology (2013)

The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor/scatter factor (HGF/SF), are involved in development and regeneration of the liver.1 Indeed, HGF/SF-Met signaling is able to trigger efficient hepatocyte proliferation and survival, involving well-described signaling pathways.2 However, recent findings demonstrated that Met can regulate survival/apoptosis balance through an unexpected mechanism. Indeed, the team of R. Zarnegar3 showed in an article in Hepatology that the human Met receptor displayed at its C-terminal tail a double consensual caspase site able to inhibit caspase 3 activity, a mechanism reminiscent of viral proteins. This direct caspase 3 inhibition contributes to survival of hepatocytes in cell culture and animal models and reinforces the antiapoptotic function of the receptor. Nevertheless, we previously demonstrated that during apoptosis Met is cleaved by caspases at another site located in the juxtamembrane region.4 This cleavage generates a 40-kDa fragment found in apoptotic murine hepatocytes in vivo. We recently showed that this fragment favors mitochondria permeabilization, leading to an acceleration of apoptosis,5 an opposite response when compared to the C-terminal cleavage. These novel data raise the question of whether Met caspase cleavages are inhibitors or activators of hepatocyte cell death. Interestingly, we previously demonstrated that these two cleavages of Met are sequential, with the C-terminal cleavage occurring before the juxtamembrane one.6 In light of the results of Zarnegar's team, we can propose the following integrated model. In the early steps of apoptosis, the Met C-terminal caspase site could act as a "death-defying domain" able to inhibit caspase 3 activity and to protect cells from apoptosis. In this context, the Met receptor is still inducible by its ligand and potentially able to promote survival (Fig. 1). In the later steps of apoptosis, when caspase activation reaches a higher level, Met is then cleaved at the juxtamembrane site leading to generation of a proapoptotic fragment able to promote mitochondrial permeabilization. At this stage, Met is not any longer inducible by its ligand. Therefore, Met could regulate survival/apoptosis balance through opposite functions according to the level of caspase activity. In human hepatocellular carcinoma (HCC) tissues, Met was found cleaved at the C-terminal site, suggesting an action of the Met "death-defying domain" in this pathological situation.3 Thus, the overexpression of Met often observed in HCC could directly inhibit caspase activity, contributing to apoptosis resistance. It would be now interesting to evaluate whether, in the opposite manner, the proapoptotic juxtamembrane cleavage of Met is inhibited in HCC. Alessandro Furlan, Ph.D. David Tulasne, Ph.D. CNRS UMR 8161 Institut de Biologie de Lille Institut Pasteur de Lille Université de Lille 1 Université de Lille 2 IFR142, SIRIC OncoLille Lille, France
Having a BLAST with bioinformatics (and avoiding BLASTphemy)
Authors: Alexander Pertsemlidis, John W Fondon
Journal: Genome biology (2001)

Searching for similarities between biological sequences is the principal means by which bioinformatics contributes to our understanding of biology. Of the various informatics tools developed to accomplish this task, the most widely used is BLAST, the basic local alignment search tool. This article discusses the principles, workings, applications and potential pitfalls of BLAST, focusing on the implementation developed at the National Center for Biotechnology Information.
The Tumor Antigen Repertoire Identified in Tumor-Bearing <i>Neu</i> Transgenic Mice Predicts Human Tumor Antigens
Authors: Hailing Lu, Keith L. Knutson, Ekram Gad, Mary L. Disis
Journal: Cancer Research (2006)

Abstract FVB/N mice transgenic for nontransforming rat neu develop spontaneous breast cancers that are neu positive and estrogen receptor negative, mimicking premenopausal human breast cancer. These animals have been widely used as a model for immunobased therapies targeting HER-2/neu. In this study, we used serological analysis of recombinant cDNA expression libraries to characterize the antigenic repertoire of neu transgenic (neu-tg) mice and questioned the ability of this murine model to predict potential human tumor antigens. After screening 3 × 106 clones from 3 different cDNA libraries, 15 tumor antigens were identified, including cytokeratin 2-8, glutamyl-prolyl-tRNA synthetase, complement C3, galectin 8, and serine/threonine-rich protein kinase 1. Multiple proteins involved in the Rho/Rho-associated, coiled coil–containing protein kinase (Rock) signal transduction pathway were found to be immunogenic, including Rock1, Rho/Rac guanine nucleotide exchange factor 2, and schistosoma mansoni adult worm antigen preparation 70. All of the identified antigens are self-proteins that are expressed in normal tissues in addition to breast tumors and the majority of the antigens are intracellular proteins. More than half of the mouse tumor antigens have human homologues that have been reported previously as tumor antigens. Finally, the tumor-specific antibody immunity and marked immune cell infiltration that was observed in mice with spontaneous tumors were not observed in mice with transplanted tumors. Our results indicate that neu-tg mice bearing spontaneous tumors develop humoral immunity to their tumors similar to cancer patients and that tumor antigens identified in transgenic mouse may predict immunogenic human homologues. (Cancer Res 2006; 66(19): 9754-61)
The Impact of National Health Care Reform on Adults With Severe Mental Disorders
Authors: Rachel L. Garfield, Samuel H. Zuvekas, Judith R. Lave, Julie M. Donohue
Journal: American Journal of Psychiatry (2011)

Little is known about the effect recent health care reform legislation will have on coverage of individuals with severe mental disorders. The authors examined current and predicted sources of insurance coverage and use of mental health services among adults with and without severe mental disorders and modeled postreform changes.The authors obtained sociodemographic, health status, mental health care use, and insurance coverage data from the 2004-2006 Medical Expenditure Panel Surveys to estimate changes that will occur after reform is fully implemented in 2019.Adults with severe mental disorders, identified as self-reported severe depression or other psychological distress, were more likely than those without such disorders to be uninsured (21.0% compared with 16.5%). Only one-fifth of individuals with severe mental disorders who lacked full-year insurance coverage had any mental health service use in the 2004-2006 period, compared with approximately half of those who had coverage. The authors estimate that the expansion of insurance coverage under reform will lead to 1.15 million new users of mental health services, which represents a 4.5% increase. The authors estimate an increase of 2.3 million users of mental health services in Medicaid and nearly 2 million in private insurance.Public insurance programs that currently play a major role in financing mental health services will play an even greater role after reform is implemented. Significant increases can be expected both in the overall number of users of mental health services and in their resources to pay for care.
Gene Expression Analysis of Triple Negative Recurrent Lymphangitic Breast Cancer in Patients Receiving Antiangiogenic Therapy
Authors: L. Gelao, V. Bagnardi, M.A. Locatelli, F. Bertolini, C. Criscitiello, A. Esposito, G. Viale, M. Alkalay, A. Goldhirsch, G. Curigliano
Journal: Annals of Oncology (2014)
Alterations in the ribosomal machinery in cancer and hematologic disorders
Authors: Niraj Shenoy, Rachel Kessel, Tushar D Bhagat, Sanchari Bhattacharyya, Yiting Yu, Christine Mcmahon, Amit Verma
Journal: Journal of Hematology & Oncology (2012)

Abstract Ribosomes are essential components of the protein translation machinery and are composed of more than 80 unique large and small ribosomal proteins. Recent studies show that in addition to their roles in protein translation, ribosomal proteins are also involved in extra-ribosomal functions of DNA repair, apoptosis and cellular homeostasis. Consequently, alterations in the synthesis or functioning of ribosomal proteins can lead to various hematologic disorders. These include congenital anemias such as Diamond Blackfan anemia and Shwachman Diamond syndrome; both of which are associated with mutations in various ribosomal genes. Acquired uniallelic deletion of RPS14 gene has also been shown to lead to the 5q syndrome, a distinct subset of MDS associated with macrocytic anemia. Recent evidence shows that specific ribosomal proteins are overexpressed in liver, colon, prostate and other tumors. Ribosomal protein overexpression can promote tumorigenesis by interactions with the p53 tumor suppressor pathway and also by direct effects on various oncogenes. These data point to a broad role of ribosome protein alterations in hematologic and oncologic diseases.
Cytogenetic Studies of Hamster Kidney Cell Cultures Transformed by the Simian Vacuolating Virus (SV40)&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Herbert L. Cooper, M.D., Paul H. Black, M.D.
Journal: JNCI Journal of the National Cancer Institute (1963)

Cytogenetic studies were performed on transformed cell cultures arising from hamster kidney cell monolayers infected with the simian vacuolating virus (SV40). After a 3- to 6-week latent period, colonies of rapidly growing cells emerged from infected cultures. The earliest cells in these cultures appeared to have chromosome numbers in the diploid range, with frequent chromosomal aberrations such as breaks, translocations, and deletions. These cells were rapidly overgrown by those with chromosome numbers in the range between triploid and tetraploid during serial passage. There was a constant tendency for the production of cells with greater numbers of chromosomes. The separation of the chromosomes at metaphase into discrete clusters was an unusual tendency. Karyotype analysis revealed irregular replication of different groups of chromosomes without the presence of a unique stemline. Abnormal chromosomes were present in many cells. It is concluded that SV40 produces a biochemical growth stimulus on which are superimposed processes producing aneuploidy.
ENDOTOXIN AS ADJUVATOR TO THE TRANSPLANTATION OF A MOUSE MAMMARY TUMOR
Authors: James Stuart Henderson
Journal: The Journal of Experimental Medicine (1968)

The mouse mammary tumor MT 296 was used in a further series of experiments on the implantation of tumor, plated out in vivo, from suspensions of individual cells. Lipopolysaccharide from S. typhosa was shown to exert an adjuvator influence. But this adjuvator, an endotoxin, had no direct effect on the suspended tumor cells, unlike the liver preparations previously reported. Lipopolysaccharide from S. typhosa was shown to act on the host. It made the host's connective tissue expanses more susceptible to successful implantation by the tumor cells. It did this only if present at the time these connective tissue expanses were split. The increased susceptibility, caused by splitting the connective tissue expanses in the presence of lipopolysaccharide, declined quickly after 24 hr. The structural changes wrought upon the connective tissues by splitting them in the presence of lipopolysaccharide are described. They show kinship to a Schwartzman reaction of the local type. Their possible role in the adjuvator effect on the plating of single cell suspensions of this tumor is discussed.
Prednisolone suppresses ischemia-reperfusion injury of the rat liver by reducing cytokine production and calpain μ activation
Authors: Meng Wang, Masato Sakon, Koji Umeshita, Masaki Okuyama, Ken Shiozaki, Hiroaki Nagano, Keizo Dohno, Shoji Nakamori, Morito Monden
Journal: Journal of Hepatology (2001)
Poly(ADP-Ribose) Polymerase-1 Enhances Transcription of the Profibrotic CCN2 Gene
Authors: Hirokazu Okada, Tsutomu Inoue, Tomohiro Kikuta, Nobutaka Kato, Yoshihiko Kanno, Narumi Hirosawa, Yasushi Sakamoto, Takeshi Sugaya, Hiromichi Suzuki
Journal: Journal of the American Society of Nephrology (2008)

In the fibrotic kidney, tubular epithelial cells express CCN2, formerly known as connective tissue growth factor. Because little is known about the transcriptional regulation of this profibrotic protein, this study investigated the mechanism underlying epithelial cell-selective upregulation of CCN2 in fibrosis. It was found that a previously unidentified cis-regulatory element located in the promoter of the murine CCN2 gene plays an essential role in basal and TGF-beta1-induced gene transcription in tubular epithelial cells; this element acts in conjunction with the Smad-binding element and the basal control element-1. By protein mass fingerprint analysis and de novo sequencing, poly(ADP-ribose) polymerase-1 (PARP-1) was identified as a trans-acting protein factor that binds to this promoter region, which we termed the PARP-1-binding element. In vivo, knockdown of PARP-1 in proximal tubular epithelial cells significantly reduced CCN2 mRNA levels and attenuated interstitial fibrosis in the obstructed kidney. Thus, the PARP-1/PARP-1 binding element complex functions as a nonspecific, fundamental enhancer of both basal and induced CCN2 gene transcription in tubular epithelial cells. This regulatory complex may be a promising target for antifibrotic therapy.
Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space
Authors: A Oliver Sartor
Journal: Journal of Hematology & Oncology (2011)

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.
The Single Nucleotide Polymorphism IVS1+309 in <i>Mouse Double Minute 2</i> Does Not Affect Risk of Familial Breast Cancer
Authors: Stefan Wilkening, Justo Lorenzo Bermejo, Barbara Burwinkel, Rüdiger Klaes, Claus R. Bartram, Alfons Meindl, Peter Bugert, Rita K. Schmutzler, Barbara Wappenschmidt, Michael Untch, Kari Hemminki, Asta Försti
Journal: Cancer Research (2006)

Abstract The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of familial breast cancer in patients with unknown p53 mutation status. Data from 549 women affected by familial breast cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of familial breast cancer. The data were also examined taking into account the presence of any additional cancer after breast cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable breast cancer. (Cancer Res 2006; 66(2): 646-8)
Genetic and Functional Studies Implicate <i>HIF1</i>α as a 14q Kidney Cancer Suppressor Gene
Authors: Chuan Shen, Rameen Beroukhim, Steven E. Schumacher, Jing Zhou, Michelle Chang, Sabina Signoretti, William G. Kaelin
Journal: Cancer Discovery (2011)

Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors ≥ 1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2α is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1α in HIF1α-proficient lines promotes tumor growth. HIF1α activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1α has the credentials of a kidney cancer suppressor gene.Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1α is a target of 14q loss in kidney cancer.
Performance of Standard and Stochastic Branch-Site Models for Detecting Positive Selection among Coding Sequences
Authors: A. Lu, S. Guindon
Journal: Molecular Biology and Evolution (2013)

The branch-site model is a widely popular approach that accommodates for the lineage- and the site-specific heterogeneity of natural selection regimes among coding sequences. This model relies on prior knowledge of the (foreground) lineage(s) evolving under positive selection at some sites. Unfortunately, such prior information is not always available in practice. A more recent technique (Guindon S, Rodrigo A, Dyer K, Huelsenbeck J. 2004. Modeling the site-specific variation of selection patterns along lineages. Proc Natl Acad Sci USA 101:12957–12962) alleviates this issue by explicitly modeling the variability of selection patterns using a stochastic process. However, the performance of this approach for deciding whether a set of homologous sequences evolved under positive selection at some point has not been assessed yet. This study compares the sensitivity and specificity of tests for positive selection derived from both the standard and the stochastic approaches using extensive simulations. We show that the two methods have low proportions of type I errors, that is, they tend to be conservative when testing the null hypothesis of no positive selection if sequences truly evolve under neutral or negative selection regimes. Also, the standard approach is more powerful than the stochastic one when the prior knowledge on foreground lineages is correct. When this prior is incorrect, however, the stochastic approach outperforms the standard model in a broad range of conditions. Additional comparisons also suggest that the stochastic branch-site method compares favorably with the recently proposed mixed-effects model of evolution of Murrell et al. (Murrell B, Wertheim JO, Moola S, Weighill T, Scheffler K, Pond SLK. 2012. Detecting individual sites subject to episodic diversifying selection. PLoS Genet. 8:e1002764). Altogether, our results show that the standard branch-site model is well suited to confirmatory analyses, whereas the stochastic approach should be preferred over the standard or the mixed-effects ones for exploratory studies.
Compositional Heterogeneity and Phylogenomic Inference of Metazoan Relationships
Authors: M. P. Nesnidal, M. Helmkampf, I. Bruchhaus, B. Hausdorf
Journal: Molecular Biology and Evolution (2010)

Compositional heterogeneity of sequences between taxa may cause systematic error in phylogenetic inference. The potential influence of such bias might be mitigated by strategies to reduce compositional heterogeneity in the data set or by phylogeny reconstruction methods that account for compositional heterogeneity. We adopted several of these strategies to analyze a large ribosomal protein data set representing all major metazoan taxa. Posterior predictive tests revealed that there is compositional bias in this data set. Only a few taxa with strongly deviating amino acid composition had to be excluded to reduce this bias. Thus, this is a good solution, if these taxa are not central to the phylogenetic question at hand. Deleting individual proteins from the data matrix may be an appropriate method, if compositional heterogeneity among taxa is concentrated in a few proteins. However, half of the ribosomal proteins had to be excluded to reduce the compositional heterogeneity to a degree that the CAT model was no longer significantly violated. Recoding of amino acids into groups is another alternative but causes a loss of information and may result in badly resolved trees as demonstrated by the present data set. Bayesian inference with the CAT-BP model directly accounts for compositional heterogeneity between lineages by introducing breakpoints along the branches of the phylogeny at which the amino acid composition is allowed to change but is computationally expensive. Finally, a neighbor joining tree based on equal input distances that consider pattern and rate heterogeneity showed several unusual groupings, which are most likely artifacts, probably caused by the loss of information resulting from the transformation of the sequence data into distances. As long as no more efficient phylogenetic inference methods are available that can directly account for compositional heterogeneity in large data sets, using methods for reducing compositional heterogeneity in the data in combination with methods that assume a stationary amino acid composition remains an option for controlling systematic errors in tree reconstruction that result from compositional bias. Our analyses indicated that the paraphyly of Deuterostomia in some analyses is the result of systematic errors that also affected the relationships of Entoprocta and Ectoprocta.