tbuckley/cabot-search huggingface dataset:
Association between Helicobacter pylori infection and interleukin 1 polymorphism predispose to CpG island methylation in gastric cancer
Authors: A. O. O. Chan, K.-M. Chu, C. Huang, K. F. Lam, S. Y. Leung, Y. W. Sun, S. Ko, H. H Xia, C. H. Cho, W. M. Hui, S. K. Lam, A. Rashid
Journal: Gut (2007)

Interleukin1β (IL1β) is upregulated in the presence of Helicobacter pylori infection.1 IL1β polymorphisms with T/T and T/C genotypes enhance IL1β production, and are associated with an increased risk of H pylori -induced hypochlorhydria2 and gastric cancer.3 The relationship between H pylori and CpG island methylation has been repeatedly reported.4–6 It has been reported that IL1β can modulate CpG island methylation through activation of DNA methyltransferase and hence repress gene expression.7 We therefore hypothesised that patients with H pylori infection and IL1 polymorphism, by the production of IL1β, are predisposed to gastric cancer development through the CpG island methylation pathway.

We obtained surgical specimens and their corresponding peripheral blood from 98 consecutive patients with gastric cancer admitted to Queen Mary Hospital, Hong Kong. This study was approved by the ethics committee. The …
Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis
Authors: Gregory H. Tesch, Andreas Schwarting, Koji Kinoshita, Hui Y. Lan, Barrett J. Rollins, Vicki Rubin Kelley
Journal: Journal of Clinical Investigation (1999)

Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and/or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1–intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1–intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1–deficient mice (histopathology, apoptosis). MCP-1–deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1–intact mice compared with MCP-1–deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.
Androgens Modulate Expression of Transcription Intermediary Factor 2, an Androgen Receptor Coactivator whose Expression Level Correlates with Early Biochemical Recurrence in Prostate Cancer
Authors: Irina U. Agoulnik, Ajula Vaid, Manjula Nakka, Misty Alvarado, William E. Bingman, Halime Erdem, Anna Frolov, Carolyn L. Smith, Gustavo E. Ayala, Michael M. Ittmann, Nancy L. Weigel
Journal: Cancer Research (2006)

Abstract Prostate cancer is an androgen-dependent disease; metastatic prostate cancer is typically treated by androgen receptor (AR) blockade. Recurrence after androgen ablation and evidence that AR continues to play a role in many prostate cancers has led to an examination of other factors that potentiate AR activity. AR is a ligand-activated transcription factor whose activity is regulated not only by hormone but also by the levels of coactivators recruited by AR to facilitate transcription. We sought to assess the consequences of reducing expression of the transcription intermediary factor 2 (TIF2) coactivator on prostate cancer cell growth and AR action in cell lines to examine TIF2 expression in prostate cancer and to correlate expression with clinical outcome. Depletion of TIF2 reduced expression of AR-induced target genes and slowed proliferation of AR-dependent and AR-independent prostate cancer cells. Remarkably, we found that TIF2 expression is directly repressed by high levels of androgens in multiple AR-expressing cell lines. Expression of a reporter containing 5′-flanking region of the TIF2 was repressed both by androgens and by the antagonist, Casodex. Expression of TIF2 correlates with biochemical (prostate-specific antigen) recurrence (P = 0.0136). In agreement with our in vitro findings, the highest expression of TIF2 was found in patients whose cancer relapsed after androgen ablation therapy, supporting the idea that AR blockade might activate pathways that lead to stimulation of AR-dependent and AR-independent proliferation of prostate epithelium. The elevated expression of TIF2 at low hormone levels likely aids in inducing AR activity under these conditions; treatment with Casodex has the potential to counteract this induction. (Cancer Res 2006; 66(21): 10594-602)
EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM
Authors: L. Joe Berry, Dorothy S. Smythe, Susannah McC. Kolbye
Journal: The Journal of Experimental Medicine (1962)

The greater susceptibility to the lethal effects of bacterial endotoxin (heat-killed Salmonella typhimurium or Escherichia coli lipopolysaccharide, in mice infected with an attenuated strain of Mycobacterium tuberculosis (BCG) was confirmed. It reached a maximum at 2 weeks postinfection and gradually diminished for an additional 6 weeks. At the time of maximum susceptibility several metabolic and physiological differences became apparent. BCG-infected mice die sooner (4 to 12 hours) and without the diarrhea, conjunctivitis, and general symptomatology associated with endotoxin deaths of normal animals. Reticuloendothelial blockade results in only a small change in reactivity to endotoxin, in contrast to normal mice. Subcutaneous injection of 2 units of ACTH is followed by no significant increase in urinary nitrogen excretion while in control animals it more than doubles. Plasma clearance of intravenously administered inulin is approximately normal in BCG-infected mice 17 hours after an LD(50) dose of endotoxin but control mice similarly treated show renal impairment. In line with this result is the absence of elevated carcass non-protein nitrogen (NPN) following endotoxin poisoning or at the moment of death from endotoxemia in the hyperreactive animals in contrast to the two- to threefold increase in carcass NPN in normal mice under similar conditions. Body carbohydrate is at a minimum and becomes depleted to a level approximating that found at death more rapidly in BCG-infected mice given endotoxin than in controls. There is also a lower ratio of carbohydrate anabolized to protein catabolized following cortisone administration to BCG-infected mice than in control mice. This is found in adrenalectomized mice and in stressed animals and is reported elsewhere. Some of the differences just described can be attributed to a refractory adrenal cortex. There is less depletion of adrenal cholesterol in vivo and lower corticoid synthesis in vitro than in normal mice yet this is not fundamentally responsible for the greater susceptibility of BCG-infected animals to endotoxin since adrenalectomized mice, which are even more susceptible, are metabolically and physiologically more comparable to normal mice than to BCG-infected mice. One can conclude, therefore, that the hyperreactivity of BCG-infected mice is more than an intensification of the normal response to endotoxin.
DRUG ADDICTION IN RELATION TO PROBLEMS OF ADOLESCENCE
Authors: PAUL ZIMMERING, JAMES TOOLAN, RENATE SAFRIN, S. BERNARD WORTIS
Journal: American Journal of Psychiatry (1952)

1. Statistics are cited indicating that drug addiction in adolescents is not a new problem and moreover the opiate addiction involves primarily adolescents and young adults. 2. The problem of heroin addiction is complex and multifaceted involving sociologic, economic, and psychiatric determinants. After all other factors are considered there remains a large and constant psychological factor. 3. A heroin addict personality type among adolescents is delineated and its characteristics are discussed. 4. Drug addiction in young people is related to the critical problem of adolescence, that of making the transition to adult status and responsibility.
AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, and c-Myc pathways
Authors: Coral Ho, Chunmei Wang, Sandra Mattu, Giulia Destefanis, Sara Ladu, Salvatore Delogu, Julia Armbruster, Lingling Fan, Susie A. Lee, Lijie Jiang, Frank Dombrowski, Matthias Evert, Xin Chen, Diego F. Calvisi
Journal: Hepatology (2011)

Activation of v-akt murine thymoma viral oncogene homolog (AKT) and Ras pathways is often implicated in carcinogenesis. However, the oncogenic cooperation between these two cascades in relationship to hepatocellular carcinoma (HCC) development remains undetermined. To investigate this issue, we generated a mouse model characterized by combined overexpression of activated forms of AKT and neuroblastoma Ras viral oncogene homolog (N-Ras) protooncogenes in the liver by way of hydrodynamic gene transfer. The molecular mechanisms underlying crosstalk between AKT and N-Ras were assessed in the mouse model and further evaluated in human and murine HCC cell lines. We found that coexpression of AKT and N-Ras resulted in a dramatic acceleration of liver tumor development when compared with mice overexpressing AKT alone, whereas N-Ras alone did not lead to tumor formation. At the cellular level, concomitant up-regulation of AKT and N-Ras resulted in increased proliferation and microvascularization when compared with AKT-injected mice. Mechanistic studies suggested that accelerated hepatocarcinogenesis driven by AKT and N-Ras resulted from a strong activation of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, elevated expression of FOXM1/SKP2 and c-Myc also contributed to rapid tumor growth in AKT/Ras mice, yet by way of mTORC1-independent mechanisms. The biological effects of coactivation of AKT and N-Ras were then recapitulated in vitro using HCC cell lines, which supports the functional significance of mTORC1, FOXM1/SKP2, and c-Myc signaling cascades in mediating AKT and N-Ras-induced liver tumor development. Conclusion : Our data demonstrate the in vivo crosstalk between the AKT and Ras pathways in promoting liver tumor development, and the pivotal role of mTORC1-dependent and independent pathways in mediating AKT and Ras induced hepatocarcinogenesis.
Randomized Clinical Trial Design for Assessing Noninferiority When Superiority Is Expected
Authors: Boris Freidlin, Edward L. Korn, Stephen L. George, Robert Gray
Journal: Journal of Clinical Oncology (2007)

The randomized clinical trial (RCT) is the gold standard for definitive evaluation of new therapies. RCTs designed to show that the therapeutic efficacy of a new therapy is not unacceptably inferior to that of standard therapy are called noninferiority trials. Traditionally, noninferiority trials have required very large sample sizes. Sometimes, a new treatment regimen with a favorable toxicity and/or tolerability profile is also expected to have some modest improvement in efficacy. In such specialized settings we describe a hybrid trial-design approach that requires a dramatically smaller sample size than that of a standard noninferiority design. This hybrid design can naturally incorporate a formal test of superiority as well as noninferiority.
THE CULTIVATION OF ANAEROBIC TREPONEMATA ON THE SURFACE OF BLOOD AGAR PLATES
Authors: Frederick L. Gates
Journal: The Journal of Experimental Medicine (1923)

By a method of cultivation that proved successful with Bacterium pneumosintes, characteristic surface colonies of old saprophytic strains of Treponema pallidum and Treponema calligyrum have been obtained. The presence of two types of colony in the pallidum cultures requires explanation, but the fact of colony formation may point the way to new methods of isolation and identification and to the utilization of suspensions of treponemata, free from foreign proteins, for serological and immunological purposes.
Bacterial Proteins Predisposed for Targeting to Mitochondria
Authors: Rebecca Lucattini, Vladimir A. Likić, Trevor Lithgow
Journal: Molecular Biology and Evolution (2004)

Mitochondria evolved from an endosymbiotic proteobacterium in a process that required the transfer of genes from the bacterium to the host cell nucleus, and the translocation of proteins thereby made in the host cell cytosol into the internal compartments of the organelle. According to current models for this evolution, two highly improbable events are required to occur simultaneously: creation of a protein translocation machinery to import proteins back into the endosymbiont and creation of targeting sequences on the protein substrates themselves. Using a combination of two independent prediction methods, validated through tests on simulated genomes, we show that at least 5% of proteins encoded by an extant proteobacterium are predisposed for targeting to mitochondria, and propose we that mitochondrial targeting information was preexisting for many proteins of the endosymbiont. We analyzed a family of proteins whose members exist both in bacteria and in mitochondria of eukaryotes and show that the amino-terminal extensions occasionally found in bacterial family members can function as a crude import sequence when the protein is presented to isolated mitochondria. This activity leaves the development of a primitive translocation channel in the outer membrane of the endosymbiont as a single hurdle to initiating the evolution of mitochondria.
Ceramide-Coated Balloon Catheters Limit Neointimal Hyperplasia After Stretch Injury in Carotid Arteries
Authors: Roger Charles, Lakshman Sandirasegarane, Jong Yun, Nicole Bourbon, Ronald Wilson, Raymond P. Rothstein, Steven W. Levison, Mark Kester
Journal: Circulation Research (2000)

Abstract —Neointimal hyperplasia at the site of surgical intervention is a common and deleterious complication of surgery for cardiovascular diseases. We hypothesized that direct delivery of a cell-permeable growth-arresting lipid via the balloon tip of an embolectomy catheter would limit neointimal hyperplasia after stretch injury. We have previously demonstrated that sphingolipid-derived ceramide arrested the growth of smooth muscle cell pericytes in vitro. Here, we show that ceramide-coated balloon catheters significantly reduced neointimal hyperplasia induced by balloon angioplasty in rabbit carotid arteries in vivo. This ceramide treatment decreased the number of vascular smooth muscle cells entering the cell cycle without inducing apoptosis. In situ autoradiographic studies demonstrated that inflating the balloon catheter forced cell-permeable ceramide into the intimal and medial layers of the artery. Intercalation of ceramide into vascular smooth muscle cells correlated with rapid inhibition of trauma-associated phosphorylation of extracellular signal–regulated kinase and protein kinase B. These studies demonstrate the utility of cell-permeable ceramide as a novel therapy for reducing neointimal hyperplasia after balloon angioplasty.
Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells
Authors: Tamer E Fandy, Sharmila Shankar, Rakesh K Srivastava
Journal: Molecular Cancer (2008)

Drug resistance is a major concern in cancer therapy. Here, we investigate the clinical potential of the second mitochondria-derived activator of caspase (Smac/DIABLO) in enhancing the apoptosis-inducing potential of commonly used anticancer drugs (paclitaxel, doxorubicin, etoposide, tamoxifen), irradiation and TRAIL in breast carcinoma.Breast cancer cells were overexpressed with Smac/DIABLO gene (full-length or Delta55 Smac/DIABLO) or treated with Smac/DIABLO peptide to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant cells. Cell viability and apoptosis were measured by XTT assay and DAPI staining, respectively. Protein-protein interaction was determined by immunoprecipitation followed by the Western blot analysis.Overexpression of Smac/DIABLO gene (full-length or Delta55 Smac/DIABLO) or treatment with Smac/DIABLO peptide enhances apoptosis induced by paclitaxel, doxorubicin, etoposide, tamoxifen, and irradiation in breast cancer cells. Overexpression of Smac/DIABLO resulted in an increased interaction of Smac/DIABLO with IAPs, which correlated with an increase in caspase-3 activity and apoptosis. Furthermore, Smac/DIABLO sensitized TRAIL-resistant breast cancer cell lines to undergo apoptosis through caspase-3 activation. These data suggest that apoptotic events down-stream of mitochondria were intact in TRAIL-resistant cells since ectopic expression of Smac/DIABLO or pretreatment of cells with Smac/DIABLO peptide completely restored TRAIL sensitivity.The ability of Smac/DIABLO agonists to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant tumor cells suggests that Smac/DIABLO may induce fundamental alterations in cell signaling pathways. Thus, Smac/DIABLO agonists can be used as promising new candidates for cancer treatment by potentiating cytotoxic therapies.
A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest
Authors: Tom P. Aufderheide, Graham Nichol, Thomas D. Rea, Siobhan P. Brown, Brian G. Leroux, Paul E. Pepe, Peter J. Kudenchuk, Jim Christenson, Mohamud R. Daya, Paul Dorian, Clifton W. Callaway, Ahamed H. Idris, Douglas Andrusiek, Shannon W. Stephens, David Hostler, Daniel P. Davis, James V. Dunford, Ronald G. Pirrallo, Ian G. Stiell, Catherine M. Clement, Alan Craig, Lois Van Ottingham, Terri A. Schmidt, Henry E. Wang, Myron L. Weisfeldt, Joseph P. Ornato, George Sopko
Journal: New England Journal of Medicine (2011)

The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest.We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability).Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge.Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).
ZIFA: Dimensionality reduction for zero-inflated single-cell gene expression analysis
Authors: Emma Pierson, Christopher Yau
Journal: Genome biology (2015)

Single-cell RNA-seq data allows insight into normal cellular function and various disease states through molecular characterization of gene expression on the single cell level. Dimensionality reduction of such high-dimensional data sets is essential for visualization and analysis, but single-cell RNA-seq data are challenging for classical dimensionality-reduction methods because of the prevalence of dropout events, which lead to zero-inflated data. Here, we develop a dimensionality-reduction method, (Z)ero (I)nflated (F)actor (A)nalysis (ZIFA), which explicitly models the dropout characteristics, and show that it improves modeling accuracy on simulated and biological data sets.
Patient champions fail to support BMA's opposition to electronic patient records
Authors: A. O'Dowd
Journal: BMJ (2010)

<i>Drosophila</i> photoreceptors respond to oscillating light of high frequency (∼100 Hz), while the detected maximal frequency is modulated by the light rearing conditions, thus enabling high sensitivity to light and high temporal resolution. However, the molecular basis for this adaptive process is unclear. Here, we report that dephosphorylation of the light-activated transient receptor potential (TRP) ion channel at S936 is a fast, graded, light-dependent, and Ca<sup>2+</sup>-dependent process that is partially modulated by the rhodopsin phosphatase retinal degeneration C (RDGC). Electroretinogram measurements of the frequency response to oscillating lights <i>in vivo</i> revealed that dark-reared flies expressing wild-type TRP exhibited a detection limit of oscillating light at relatively low frequencies, which was shifted to higher frequencies upon light adaptation. Strikingly, preventing phosphorylation of the S936-TRP site by alanine substitution in transgenic <i>Drosophila</i> (<i>trp<sup>S936A</sup></i>) abolished the difference in frequency response between dark-adapted and light-adapted flies, resulting in high-frequency response also in dark-adapted flies. In contrast, inserting a phosphomimetic mutation by substituting the S936-TRP site to aspartic acid (<i>trp<sup>S936D</sup></i>) set the frequency response of light-adapted flies to low frequencies typical of dark-adapted flies. Light-adapted <i>rdgC</i> mutant flies showed relatively high S936-TRP phosphorylation levels and light–dark phosphorylation dynamics. These findings suggest that RDGC is one but not the only phosphatase involved in pS936-TRP dephosphorylation. Together, this study indicates that TRP channel dephosphorylation is a regulatory process that affects the detection limit of oscillating light according to the light rearing condition, thus adjusting dynamic processing of visual information under varying light conditions. <b>SIGNIFICANCE STATEMENT</b><i>Drosophila</i> photoreceptors exhibit high temporal resolution as manifested in frequency response to oscillating light of high frequency (≤∼100 Hz). Light rearing conditions modulate the maximal frequency detected by photoreceptors, thus enabling them to maintain high sensitivity to light and high temporal resolution. However, the precise mechanisms for this process are not fully understood. Here, we show by combination of biochemistry and <i>in vivo</i> electrophysiology that transient receptor potential (TRP) channel dephosphorylation at a specific site is a fast, light-activated and Ca<sup>2+</sup>-dependent regulatory process. TRP dephosphorylation affects the detection limit of oscillating light according to the adaptation state of the photoreceptor cells by shifting the detection limit to higher frequencies upon light adaptation. This novel mechanism thus adjusts dynamic processing of visual information under varying light conditions.