tbuckley/cabot-search huggingface dataset:
Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts
Authors: Derek P. DiRocco, Akio Kobayashi, Makoto M. Taketo, Andrew P. McMahon, Benjamin D. Humphreys
Journal: Journal of the American Society of Nephrology (2013)

Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/β-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofibroblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myofibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/β-catenin signaling in interstitial pericytes and fibroblasts. Kidneys from these mice exhibited spontaneous myofibroblast differentiation in the absence of injury. Taken together, Wnt4 expression in renal fibrosis defines a population of proliferating medullary myofibroblasts. Although Wnt4 may be dispensable for myofibroblast transformation, canonical Wnt signaling through β-catenin stabilization is sufficient to drive spontaneous myofibroblast differentiation in interstitial pericytes and fibroblasts, emphasizing the importance of this pathway in renal fibrosis.
Alcohol and Illicit Drug Abuse and the Risk of Violent Death in the Home
Authors: Frederick P. Rivara
Journal: JAMA (1997)

While acute alcohol and illicit drug use are common in homicide and suicide victims, the role of chronic substance use in violent death is unclear.To measure the magnitude of risk of violent death in the home associated with alcohol use or chronic abuse and use of illicit drugs.Data obtained from a case-control study of risk factors for homicide and suicide in 3 large metropolitan areas of the United States.Matched case-control study including 388 homicide cases, 438 suicide cases, and equal numbers of controls matched for age, sex, race, neighborhood, and county. Data were analyzed by means of conditional logistic regressions in which other potential risk factors for violent death were also considered. OUTCOME AND EXPOSURE MEASURES: Homicide and suicide victims were identified from medical examiner reports in Shelby County, Tennessee; King County, Washington; and Cuyahoga County, Ohio. Structured interviews were conducted with proxy respondents close to the decedents to obtain information about alcohol or illicit drug use, and history of alcohol-related hospitalization or trouble at work because of drinking by the subject. Data about alcohol use by others living in the same house as the subject were also obtained.The risks of homicide and suicide associated with alcohol or illicit drug use were elevated, as were the risks of violent death associated with several indicators of chronic alcohol abuse. In addition, nondrinkers living in a home with alcohol users were at increased risk of homicide (odds ratio, 1.7; 95% confidence interval, 0.98-3.0), and non-drug-using individuals residing in homes with illicit drug users were at greatly increased risk of homicide (odds ratio, 11.3; 95% confidence interval, 4.4-28.8).Alcohol and illicit drug use appear to be associated with an increased risk of violent death. The risk of homicide was increased for non-substance-abusing individuals living in households in which other members abused alcohol or drugs. The concept of the individual at risk of homicide should be broadened to include not only the abuser but also those who may be at risk because of their exposure to others.
Relationship of Anti-60 kDa Heat Shock Protein and Anti-Cholesterol Antibodies to Cardiovascular Events
Authors: Amarilla Veres, George Füst, Marek Smieja, Matthew McQueen, Anna Horváth, Qilong Yi, Adrienn Bíró, Janice Pogue, László Romics, István Karádi, Mahavir Singh, Judy Gnarpe, Zoltán Prohászka, Salim Yusuf
Journal: Circulation (2002)

Several recent studies have indicated an association between key inflammatory mediators and atherosclerotic diseases. We evaluated whether high levels of antibodies against heat shock proteins and cholesterol (ACHA) predicted cardiovascular (CV) events.We used blood samples from the Heart Outcomes Prevention Evaluation (HOPE) study to conduct a nested case-control study of 386 cases with CV events and 386 age- and sex-matched HOPE study controls without events. We explored the relationship between anti-hsp antibodies, ACHA, and subsequent outcomes (incident myocardial infarction, stroke, or CV death) during a mean follow-up of 4.5 years using conditional logistic regression. High levels of anti-hsp65 antibodies (> or =90th percentile) predicted CV events (OR, 2.1; 95% CI, 1.2 to 3.9, P=0.01). Anti-hsp60 antibodies did not predict any event type, whereas incident stroke developed significantly less frequently in patients with high ACHA levels. Anti-hsp antibodies and ACHA did not correlate with inflammatory (fibrinogen, C-reactive protein, interleukin-6, intracellular adhesion molecule-1) or infectious markers (C pneumoniae or cytomegalovirus antibodies). Anti-hsp65 antibodies (> or =90th percentile) and fibrinogen (highest tertile) had a strong joint effect: patients with high concentrations of both had more CV events (OR, 5.5; 95% CI, 1.8 to 17.5, P=0.004) than patients with low levels of both. A similar joint effect (OR, 2.7; 95% CI, 1.3 to 5.7, P=0.01) was found for high levels of anti-hsp65 and presence of cytomegalovirus antibodies.Serum antibodies to hsp65 were associated with subsequent CV events in this study of high-risk patients, independent of conventional cardiovascular risk factors and other inflammatory markers.
Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy
Authors: Francesca Mascia, Gary Lam, Christopher Keith, Caroline Garber, Seth M. Steinberg, Elise Kohn, Stuart H. Yuspa
Journal: Science Translational Medicine (2013)

Epidermal EGFR ablation causes a localized cutaneous rash and a systemic inflammatory syndrome.
Combined Functional Genome Survey of Therapeutic Targets for Hepatocellular Carcinoma
Authors: Reiko Satow, Miki Shitashige, Yae Kanai, Fumitaka Takeshita, Hidenori Ojima, Takafumi Jigami, Kazufumi Honda, Tomoo Kosuge, Takahiro Ochiya, Setsuo Hirohashi, Tesshi Yamada
Journal: Clinical Cancer Research (2010)

The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited.To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome.Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice.The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy.
Polysaccharide Nanosystems for Future Progress in Cardiovascular Pathologies
Authors: Amanda Karine Andriola Silva, Didier Letourneur, Cédric Chauvierre
Journal: Theranostics (2014)

Natural polysaccharides have received a lot of attention in the biomedical field. Indeed, sources of polysaccharides, extracted or produced from plants, bacteria, fungi or algae, are diverse and renewable. Moreover, recent progresses in polysaccharide chemistry and nanotechnologies allow elaborating new dedicated nanosystems. Polysaccharide-based nanosystems may be designed for interacting in several biological processes. In particular, the atherothrombotic pathology is highly concerned by polysaccharide-mediated recognition. Atherothrombotic diseases, regardless of the anatomical localization, remain the main causes of morbidity and mortality in the industrialized world. This review intends to provide an overview on polysaccharide-based nanosystems as drug delivery systems and targeted contrast agents for molecular imaging with an emphasis on the treatment and imaging of cardiovascular pathologies.
Enhancing Cancer Vaccine Efficacy via Modulation of the Tumor Microenvironment
Authors: Mary L. Disis
Journal: Clinical Cancer Research (2009)

Abstract The development of therapeutic cancer vaccines is impacted by immunosuppressive elements in the tumor microenvironment. Most immunogenic cancer proteins are “self,” therefore, peripheral tolerance contributes substantially to tumor immune escape. Transforming growth factor β (TGFβ) actively modulates both inflammation and tolerance induction. Combining vaccination with agents that disarm TGFβ will enhance vaccine efficacy. (Clin Cancer Res 2009;15(21):1–3) (Clin Cancer Res 2009;15(21):6476–8)
Osteopenia and osteomalacia after gastrectomy: interrelations between biochemical markers of bone remodelling, vitamin D metabolites, and bone histomorphometry.
Authors: S Bisballe, E F Eriksen, F Melsen, L Mosekilde, O H Sorensen, I Hessov
Journal: Gut (1991)

The prevalence of metabolic disease in a population of 68 postgastrectomy patients was assessed using histomorphometric evaluation of transiliac bone biopsy specimens after tetracycline double labelling. Trabecular bone volume was significantly lower in the postgastrectomy group (p less than 0.01): 62% of the patients had increased osteoid surface, 56% increased osteoid thickness, and 24% increased mineralisation lag time. Only 18%, however, fulfilled the diagnostic criteria for osteomalacia--increased osteoid thickness and increased mineralisation lag time. Postgastrectomy patients had reduced serum concentrations of calcium (p less than 0.01), phosphate (p less than 0.01), and 25-hydroxyvitamin D, while levels of alkaline phosphatase and 1,25 dihydroxyvitamin D were high (p less than 0.01). The severity of the mineralisation defect as reflected by mineralisation lag time was positively correlated to serum 25-hydroxyvitamin D, but unrelated to serum 1,25-dihydroxyvitamin D. Multiple linear regression analysis showed that serum 25-hydroxyvitamin D, age, and the duration of postoperative follow up were significant determinants of the mineralisation defect in a given patient. The limited value of serum markers in the diagnosis of osteomalacia was emphasised by the fact that six of the eight patients with osteomalacia had normal serum levels of calcium and alkaline phosphatase, and five of the eight had values for 25-hydroxyvitamin D in the normal range for healthy control subjects. The results clearly show the need for vitamin D supplementation and regular control after gastric resection.
Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2
Authors: Scott R. Plotkin, Anat O. Stemmer-Rachamimov, Fred G. Barker, Chris Halpin, Timothy P. Padera, Alex Tyrrell, A. Gregory Sorensen, Rakesh K. Jain, Emmanuelle di Tomaso
Journal: New England Journal of Medicine (2009)

Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors.We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline.VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2.VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.
A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow
Authors: Takashi Yahata, Kiyoshi Ando, Tadayuki Sato, Hiroko Miyatake, Yoshihiko Nakamura, Yukari Muguruma, Shunichi Kato, Tomomitsu Hotta
Journal: Blood (2003)
Evolution of Vertebrate Genes Related to Prion and Shadoo Proteins—Clues from Comparative Genomic Analysis
Authors: Marko Premzl, Jill E Gready, Lars S Jermiin, Tatjana Simonic, Jennifer A Marshall Graves
Journal: Molecular Biology and Evolution (2004)

Recent findings of new genes in fish related to the prion protein (PrP) gene PRNP, including our recent report of SPRN coding for Shadoo (Sho) protein found also in mammals, raise issues of their function and evolution. Here we report additional novel fish genes found in public databases, including a duplicated SPRN gene, SPRNB, in Fugu, Tetraodon, carp, and zebrafish encoding the Sho2 protein, and we use comparative genomic analysis to analyze the evolutionary relationships and to infer evolutionary trajectories of the complete data set. Phylogenetic footprinting performed on aligned human, mouse, and Fugu SPRN genes to define candidate regulatory promoter regions, detected 16 conserved motifs, three of which are known transcription factor-binding sites for a receptor and transcription factors specific to or associated with expression in brain. This result and other homology-based (VISTA global genomic alignment; protein sequence alignment and phylogenetics) and context-dependent (genomic context; relative gene order and orientation) criteria indicate fish and mammalian SPRN genes are orthologous and suggest a strongly conserved basic function in brain. Whereas tetrapod PRNPs share context with the analogous stPrP-2-coding gene in fish, their sequences are diverged, suggesting that the tetrapod and fish genes are likely to have significantly different functions. Phylogenetic analysis predicts the SPRN/SPRNB duplication occurred before divergence of fish from tetrapods, whereas that of stPrP-1 and stPrP-2 occurred in fish. Whereas Sho appears to have a conserved function in vertebrate brain, PrP seems to have an adaptive role fine-tuned in a lineage-specific fashion. An evolutionary model consistent with our findings and literature knowledge is proposed that has an ancestral prevertebrate SPRN-like gene leading to all vertebrate PrP-related and Sho-related genes. This provides a new framework for exploring the evolution of this unusual family of proteins and for searching for members in other fish branches and intermediate vertebrate groups.
Short Telomere Length, Cancer Survival, and Cancer Risk in 47102 Individuals
Authors: Maren Weischer, Børge G. Nordestgaard, Richard M. Cawthon, Jacob J. Freiberg, Anne Tybjærg-Hansen, Stig E. Bojesen
Journal: JNCI Journal of the National Cancer Institute (2013)

Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment. Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.
Contrast-Enhanced Ultrasound May Aid Prostate Cancer Detection
Authors: M. Fillon
Journal: JNCI Journal of the National Cancer Institute (2013)

biochemical signaling analysis techniques will be used to measure activation of key pathways implicated in force transduction and cytoskeletal assembly. her third objective is to build statisti cal models to discover signals that contribute to metastasis across combinations of cell type and extracellular matrix ( eCm) composition. “Correlations between cell signaling and measured markers of metastasis exist and are detectable using a multivariable statistical framework,” said Peyton. “ multivariable models based on robust statistical methods will be used to relate cell type, eCm composition, and signaling nodes contributing to cell migration, proliferation, and, therefore, poor patient prognosis.” Leonid hanin, Ph.D., professor of mathematics and statistics at Idaho State university in Pocatello said he does not expect major breakthroughs from the engineering approaches to cancer, although some ideas and results may be useful. “Physical properties of cancer cells change with cell type and stage of cancer, so these differences and changes can be detected using the methods of engineering. What I like about the involvement of engineers, as well as mathematicians and physicists, in cancer studies is that they bring in an entirely different frame of thinking, which is so much different from that of biomedical scientists.” hanin said although basic cancer biol ogy and clinical oncology generated over the last several decades an enormous body of knowledge, its translational value is very small. “ most importantly , and ominously, cancer incidence and mortality for most types of cancer remain very high, and for some of them mortality continues to rise. michael Sheetz, Ph.D., director of the mechanobiology Institute of Singapore, said we can expect to see engineering and other research disciplines—besides more “traditional medicine”—tackling tough issues such as metastasis and other aspects of cancer in the future. “ the problem with most cancers is that the cells do not respond properly to the cues from the local micro environment, and therefore, cancer cells
Nutrients in Diet and Plasma and Risk of In Situ Cervical Cancer
Authors: K. E. Brock, G. Berry, P. A. Mock, R. MacLennan, A. S. Truswell, L. A. Brinton
Journal: JNCI Journal of the National Cancer Institute (1988)

Both plasma and dietary measures of vitamin A status were investigated along with previously established risk factors (number of sexual partners, age at first intercourse, smoking, and oral contraceptive use) in a study of 117 in situ cervical cancer patients and 196 matched community controls in Sydney, Australia. Neither total calories nor retinol from foods was related to cancer risk, nor was plasma retinol. When plasma and dietary indexes were considered together, vitamin C, fruit juices, and plasma beta-carotene showed protective effects. Plasma beta-carotene reduced risk from top to bottom quartile by 80%, vitamin C by 60%, and fruit juices by 50%. Thus the evidence suggests that cancer risk is associated with some aspect of diet that is reflected in the effect of plasma beta-carotene. There is no clear effect of any one nutrient but fruit juices appear protective. Thus vitamin C and beta-carotene are likely candidates.