tbuckley/cabot-search huggingface dataset:
Emerging landscape of oncogenic signatures across human cancers
Authors: Giovanni Ciriello, Martin L Miller, Bülent Arman Aksoy, Yasin Senbabaoglu, Nikolaus Schultz, Chris Sander
Journal: Nature Genetics (2013)

Chris Sander and colleagues have extracted significant functional events from 12 tumor types. Tumors can be classified as being driven largely by either mutation or copy number changes, and, within this division, subclasses of cross-tissue patterns of events are discerned that suggest sets of combinatorial therapies. Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ∼500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies.
The role of xanthine oxidase in platelet activating factor induced intestinal injury in the rat
Authors: X W Qu, R A Rozenfeld, W Huang, G B Bulkley, W Hsueh
Journal: Gut (1999)

Background Xanthine oxidase (XO) is an important source of reactive oxygen species in the small intestine. Aims To examine the interaction of platelet activating factor (PAF), XO, and neutrophils in mediating intestinal injury in rats. Methods Two doses of PAF were used to induce either reversible hypotension, or irreversible shock with intestinal necrosis. The activities of XO, and its precursor xanthine dehydrogenase (XD), in both the whole intestinal tissue and epithelial cells, were measured. XO was localised by histochemical staining. Results PAF dose dependently induced an increase in XO activity, predominantly in the ileal epithelium, without altering the total activity of XD+XO. Most of the XD to XO conversion was via proteolysis. PAF induced XO activation and intestinal injury were prevented by prior neutrophil depletion. PAF induced XO activation is probably not due to reperfusion, as XO activation preceded the recovery of mesenteric flow. Allopurinol pretreatment substantially inhibited intestinal neutrophil sequestration induced by high dose (but not low dose) PAF. Conclusions PAF rapidly activates intestinal XO through proteolytic XD-XO conversion, predominantly in the ileal epithelium. This effect is mediated by neutrophils. XO activation promotes PAF induced polymorphonuclear leucocyte sequestration in the intestine.
Reduction of disulfide bonds during antigen processing: evidence from a thiol-dependent insulin determinant.
Authors: P E Jensen
Journal: The Journal of Experimental Medicine (1991)

Previous studies have demonstrated that insulin, like other protein antigens, requires processing in metabolically active antigen-presenting cells (APC) before it can be recognized by class II-restricted T lymphocytes. Unlike many other proteins, insulin peptides of minimal size retain the requirement for antigen processing. We demonstrate that this requirement can be bypassed by incubation of insulin with reducing agents in the presence of aldehyde-fixed APC. Fixed APC treated in this way were able to stimulate I-Ab- and I-Ad-restricted T cell hybridomas. Data are presented that demonstrate that cloned and polyclonal T cells recognize a determinant within the NH2-terminal 14 residues of the beef insulin A chain with no requirement for B chain residues. The common feature among peptides capable of stimulating these cells in the presence of live APC is the chemical form of the cysteine thiol groups. Those forms that produce free thiols upon reduction are active, whereas those with irreversibly protected sulfhydryls are not. Functional experiments with fixed APC and competition binding experiments with purified I-Ad indicate that only A chain peptides with free thiols are able to stably associate with the peptide-binding site on class II in a form that is recognized by specific T cells. Our findings indicate that reduction of disulfide bonds is both necessary and sufficient for presentation of insulin to a major population of class II-restricted T cells. The results provide strong support for the hypothesis that protein disulfides can be reduced during physiologic antigen processing.
TREATMENT OF CEREBRO-SPINAL MENINGITIS BY ANTIMENINGOCOCCUS SERUM COMBINED WITH AUTOGENOUS VACCINE
Authors: J. R. Collins
Journal: BMJ (1915)

_Il .RTS greatly distended and the peritoneal coat injected and coveredl wvith lymph.The abscess was carefully packed off from the rest of the abdominal cavity and opened.It contained very offenlsive pus, and the distal end of the diverticulum, which was rotatedl twice, gangrenous and attached by its distal end to the uimbilicus.The pus was carefullv wiped away and the diverti- culuini traced to its origin about 12 in.above the ileo-caecal vanlve.It wvas then resected and its attachment to the small initestinie closed by twvo layers of sutures.One tube was placed in Douglas's pouchl tlhrough a suprapubic inicision and another throuLgh a .smallincision immediately below the um- bilicus lea(ling inlto the abscess cavity.After the operation, saline wvas giveni per recttum, btut the first half-pint was imne- (liately retturned with a large quantity of faeces.For six days tafter operation there wvas slight pyrexia due to mild supplira- tion around the abdominal incision.Subsequent progress uneventful.The patient wvas discharged for EnglandL on January 14th with a small granulatinig area.CASE II.-Btllet Molund of T1high, in-oh-i)iu Fe'iloral Artery I Gangr&ene: Amtputation.P. C., aged 23, three days before admissioni, whlilst walking,t was wouinded at a range of 250 yards.He lost a large quantity of blood, and was taken to the field hospital, wlhere he was dressed, and the bullet, which was lying unlder the skin on the opposite sidle of the tlhigh, extracted.The leg was dressed twice under an anaesthetic before he reached this hospital.On admission the patient was blanched and had evidently lost a
Colony-stimulating factor-1 transfection of myoblasts improves the repair of failing myocardium following autologous myoblast transplantation
Authors: Seyedhossein Aharinejad, Dietmar Abraham, Patrick Paulus, Karin Zins, Michael Hofmann, Wolfgang Michlits, Mariann Gyöngyösi, Karin Macfelda, Trevor Lucas, Karola Trescher, Michael Grimm, E. Richard Stanley
Journal: Cardiovascular Research (2008)

AimsSkeletal myoblasts are used in repair of ischaemic myocardium. However, a large fraction of grafted myoblasts degenerate upon engraftment. Colony-stimulating factor-1 (CSF-1) accelerates myoblast proliferation and angiogenesis. We hypothesized that CSF-1 overexpression improves myoblast survival and cardiac function in ischaemia-induced heart failure.
Community Control of the Community Mental Health Center: II. Case Examples
Authors: WILLIAM M. BOLMAN
Journal: American Journal of Psychiatry (1972)

The author cites some examples from his own and others' experience to illustrate the issues that have emerged in the movement toward community control of mental health centers. Each example was characterized by consumer dissatisfaction, institutional inability to respond, and black-white conflict. He believes that if psychiatrists can work together with citizen and consumer groups, this will both improve delivery of services and—at state and federal levels—work toward the solution of larger societal problems.
Nodal marginal-zone lymphoma associated with monoclonal light-chain and heavy-chain deposition disease
Authors: Philip Went, Stefano Ascani, Erik Strøm, Sverre-Henning Brorson, Maurizio Musso, Pier-Luigi Zinzani, Brunangelo Falini, Stephan Dirnhofer, Stefano Pileri
Journal: The Lancet Oncology (2004)
Science, medicine, and the future: Microbicides in HIV prevention
Authors: S. McCormack
Journal: BMJ (2001)

In 1999 about 5.4 million people were newly infected with HIV.1 In some countries public health programmes have achieved modest gains in reducing HIV transmission through behavioural change, but the worldwide picture is one of increasing rates of infection. Although the use of condoms has slowly increased in countries most severely affected by the HIV epidemic, many vulnerable women are unable to ensure they are used. An effective and affordable vaginal microbicide, whose use could be controlled by women, would represent an important addition to the armamentarium against HIV infection. In this article we examine current progress in microbicide development and discuss their future role in HIV control.

We searched Medline using the key words and phrases “microbicides,” “virucides,” and “vaginal microbicides.” We also obtained the latest product information from the Alliance for Microbicide Development (P Harrison, personal communication),2 and we asked scientific colleagues involved in microbicide research for their comments on products in preclinical development.

Microbicides act by disrupting or disabling organisms or block their entry into host cells by interfering with cell surface receptors. Chemical agents have a long history in the control of sexually transmitted infections and fertility. Penile antiseptics were widely promoted for controlling sexually transmitted disease in both world wars, although their efficacy and effectiveness remain uncertain.3 Intravaginal spermicides have been marketed for decades but have had limited popularity in the era of more reliable contraceptive methods.

The development of microbicides has drawn on existing contraceptive technology to develop safe, effective, acceptable, and accessible agents. As with HIV vaccines, progress with the development of effective microbicides has been slow, and the results of early trials of surfactants such as nonoxinol 9 were disappointing. The Microbicides 2000 conference in Washington, DC, provided new impetus to develop such compounds, and several promising products are …
UK avian flu surveillance system is inadequate, Lords inquiry is told
Authors: Adrian O' Dowd
Journal: BMJ (2005)

The surveillance needed to identify the conditions leading to the spread of avian influenza from poultry to humans is not in place, a House of Lords committee heard last week.

This warning was given during the opening public session of the inquiry into pandemic influenza being carried out by the Lords'Science and Technology Select Committee. The inquiry will focus on the risk of a pandemic and …
Adverse drug reactions to second line anti tuberculosis drugs: A prospective study in Mumbai, India
Authors: Subramanian Natarajan, Poonam Subramanian
Journal: European Respiratory Journal (2013)

Objective:

Patients of drug resistant tuberculosis are on regimens containing multiple drugs and are at risk for adverse drug reactions (ADR). Our aim was to describe the frequency and nature of ADRs in these patients.

Methods:

A prospective study of sixty patients diagnosed as drug resistant tuberculosis were put on WHO recommended regimen of second line anti tuberculosis drugs. These patients were followed for a period of two years till the completion of treatment and further for a period of one year. Patients were interviewed at monthly intervals for the development of any ADRs.

Results:

Males 35% (n=21), Females 65% (n=39), Age range 13 to 60 years, Mean 28.5 years. 83% of patients had at least one adverse event (AE) till the completion of study. Commonest AEs were as follows: Nausea and vomiting in 83% (n=50), hypothyroidism in 32% (n=19), reddish hyper pigmentation in 27% (n=16), blood eosinophilia in 13% (n=8), tinnitus and hearing loss in 12% (n=7), peripheral neuropathy in 12% (n=7), psychiatric disturbances in 12% (n=7), urticaria and skin rashes in 8% (n=5), intractable vomiting warranting stoppage of therapy in 7% (n=4), gynecomastia in 3% (n=2). Other AEs seen were deranged creatinine, visual disturbances, convulsion, thrombocytopenia, joint pains and swellings. Severe adverse events (SAE) were seen in 25% of patients (n=15) requiring permanent discontinuation of the offending drug. 10% of patients (n=6) were hospitalized due to SAEs. Persistent AEs even on discontinuation of therapy was seen in 17% (n=10) of patients.

Conclusion:

Adverse events with second line tuberculosis drugs are common. AEs have an important role in the management and prognosis of these patients.
Variants in Inflammation Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China
Authors: Ann W. Hsing, Lori C. Sakoda, Asif Rashid, Gabriella Andreotti, Jinbo Chen, Bin-Shen Wang, Ming-Chang Shen, Bingshu E. Chen, Philip S. Rosenberg, Mingdong Zhang, Shelley Niwa, Lisa Chu, Robert Welch, Meredith Yeager, Joseph F. Fraumeni, Yu-Tang Gao, Stephen J. Chanock
Journal: Cancer Research (2008)

To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.
Sulfation of a High Endothelial Venule–Expressed Ligand for L-Selectin
Authors: Kirsten Tangemann, Annette Bistrup, Stefan Hemmerich, Steven D. Rosen
Journal: The Journal of Experimental Medicine (1999)

During lymphocyte homing, L-selectin mediates the tethering and rolling of lymphocytes on high endothelial venules (HEVs) in secondary lymphoid organs. The L-selectin ligands on HEV are a set of mucin-like glycoproteins, for which glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1) is a candidate. Optimal binding in equilibrium measurements requires sulfation, sialylation, and fucosylation of ligands. Analysis of GlyCAM-1 has revealed two sulfation modifications (galactose [Gal]-6-sulfate and N-acetylglucosamine [GlcNAc]-6-sulfate) of sialyl Lewis x. Recently, three related sulfotransferases (keratan sulfate galactose-6-sulfotransferase [KSGal6ST], high endothelial cell N-acetylglucosamine-6-sulfotransferase [GlcNAc6ST], and human GlcNAc6ST) were cloned, which can generate Gal-6-sulfate and GlcNAc-6-sulfate in GlyCAM-1. Imparting these modifications to GlyCAM-1, together with appropriate fucosylation, yields enhanced rolling ligands for both peripheral blood lymphocytes and Jurkat cells in flow chamber assays as compared with those generated with exogenous fucosyltransferase. Either sulfation modification results in an increased number of tethered and rolling lymphocytes, a reduction in overall rolling velocity associated with more frequent pausing of the cells, and an enhanced resistance of rolling cells to detachment by shear. All of these effects are predicted to promote the overall efficiency of lymphocyte homing. In contrast, the rolling interactions of E-selectin transfectants with the same ligands are not affected by sulfation.
Unexpected Repertoire of Metazoan Transcription Factors in the Unicellular Holozoan Capsaspora owczarzaki
Authors: A. Sebe-Pedros, A. de Mendoza, B. F. Lang, B. M. Degnan, I. Ruiz-Trillo
Journal: Molecular Biology and Evolution (2010)

How animals (metazoans) originated from their single-celled ancestors remains a major question in biology. As transcriptional regulation is crucial to animal development, deciphering the early evolution of associated transcription factors (TFs) is critical to understanding metazoan origins. In this study, we uncovered the repertoire of 17 metazoan TFs in the amoeboid holozoan Capsaspora owczarzaki, a representative of a unicellular lineage that is closely related to choanoflagellates and metazoans. Phylogenetic and comparative genomic analyses with the broadest possible taxonomic sampling allowed us to formulate new hypotheses regarding the origin and evolution of developmental metazoan TFs. We show that the complexity of the TF repertoire in C. owczarzaki is strikingly high, pushing back further the origin of some TFs formerly thought to be metazoan specific, such as T-box or Runx. Nonetheless, TF families whose beginnings antedate the origin of the animal kingdom, such as homeodomain or basic helix-loop-helix, underwent significant expansion and diversification along metazoan and eumetazoan stems.
The <i>Helicobacter pylori</i> Vacuolating Toxin Inhibits T Cell Activation by Two Independent Mechanisms
Authors: Marianna Boncristiano, Silvia Rossi Paccani, Silvia Barone, Cristina Ulivieri, Laura Patrussi, Dag Ilver, Amedeo Amedei, Mario Milco D'Elios, John L. Telford, Cosima T. Baldari
Journal: The Journal of Experimental Medicine (2003)

Helicobacter pylori toxin, VacA, damages the gastric epithelium by erosion and loosening of tight junctions. Here we report that VacA also interferes with T cell activation by two different mechanisms. Formation of anion-specific channels by VacA prevents calcium influx from the extracellular milieu. The transcription factor NF-AT thus fails to translocate to the nucleus and activate key cytokine genes. A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav. As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated. The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.
The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease
Authors: Justin Ezekowitz, Finlay A. McAlister, Karin H. Humphries, Colleen M. Norris, Marcello Tonelli, William A. Ghali, Merril L. Knudtson
Journal: Journal of the American College of Cardiology (2004)
Relationship Between a GABA<sub>A</sub>α6 Pro385Ser Substitution and Benzodiazepine Sensitivity
Authors: Nakao Iwata, Deborah S. Cowley, Marta Radel, Peter P. Roy-Byrne, David Goldman
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABAAa6 receptor. The authors detected a Pro385Ser [1236C>T] amino acid substitution in the human GABAAa6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. METHOD: Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. RESULTS: The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. CONCLUSIONS: The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.
Nerve growth factor triggers microfilament assembly and paxillin phosphorylation in human B lymphocytes.
Authors: I Melamed, C E Turner, K Aktories, D R Kaplan, E W Gelfand
Journal: The Journal of Experimental Medicine (1995)

Increasing evidence suggests that the nervous system is involved in allergic inflammation. One of the potential regulatory molecules of the neuroimmune system is nerve growth factor (NGF). Recent studies from our group demonstrated the presence of a functional NGF receptor (NGFR) on human B lymphocytes. Moreover, we showed that gp140trk tyrosine kinase, which serves as an NGFR, was involved in transduction of early signaling events in human B lymphocytes. The mechanisms by which NGF initiates the signaling cascade and the link between the neuroimmune systems are unknown. We have focused on the role of the cytoskeleton as a possible mediator for transduction of signals induced by NGF. Polymerized actin (F-actin) content was determined by fluorescent staining and immunoblotting with antiactin antibody. Addition of NGF caused a time- and concentration-dependent increase in F-actin content, and maximum effects were noted after 1 min. These increases in F-actin content and NGF-induced thymidine incorporation could be blocked by incubating the cells with cytochalasin D and botulinum C2 toxin before the addition of NGF. Incubation of human B lymphocytes with 10 nM K252a, an inhibitor of Trk kinase, decreased NGF-induced microfilament assembly by 75%. In immunoprecipitation experiments, addition of NGF to B cells induced a rapid increase in the tyrosine phosphorylation of paxillin, one of a group of focal adhesion proteins involved in linking actin filaments to the plasma membrane. Coimmunoprecipitation studies demonstrated the association between gp140trk kinase and paxillin. Together, these observations suggest that actin assembly is involved in NGF signaling in human B cells, and that paxillin may be essential in this pathway after phosphorylation by gp140trk kinase.