tbuckley/cabot-search huggingface dataset:
Domain Loss Facilitates Accelerated Evolution and Neofunctionalization of Duplicate Snake Venom Metalloproteinase Toxin Genes
Authors: N. R. Casewell, S. C. Wagstaff, R. A. Harrison, C. Renjifo, W. Wuster
Journal: Molecular Biology and Evolution (2011)

Gene duplication is a key mechanism for the adaptive evolution and neofunctionalization of gene families. Large multigene families often exhibit complex evolutionary histories as a result of frequent gene duplication acting in concordance with positive selection pressures. Alterations in the domain structure of genes, causing changes in the molecular scaffold of proteins, can also result in a complex evolutionary history and has been observed in functionally diverse multigene toxin families. Here, we investigate the role alterations in domain structure have on the tempo of evolution and neofunctionalization of multigene families using the snake venom metalloproteinases (SVMPs) as a model system. Our results reveal that the evolutionary history of viperid (Serpentes: Viperidae) SVMPs is repeatedly punctuated by domain loss, with the single loss of the cysteine-rich domain, facilitating the formation of P-II class SVMPs, occurring prior to the convergent loss of the disintegrin domain to form multiple P-I SVMP structures. Notably, the majority of phylogenetic branches where domain loss was inferred to have occurred exhibited highly significant evidence of positive selection in surface-exposed amino acid residues, resulting in the neofunctionalization of P-II and P-I SVMP classes. These results provide a valuable insight into the mechanisms by which complex gene families evolve and detail how the loss of domain structures can catalyze the accelerated evolution of novel gene paralogues. The ensuing generation of differing molecular scaffolds encoded by the same multigene family facilitates gene neofunctionalization while presenting an evolutionary advantage through the retention of multiple genes capable of encoding functionally distinct proteins.
Drug-Related Pneumonitis in Patients With Advanced Renal Cell Carcinoma Treated With Temsirolimus
Authors: Jose Pablo Maroto, Gary Hudes, Janice P. Dutcher, Theodore F. Logan, Charles S. White, Mizue Krygowski, Maria Cincotta, Mark Shapiro, Ignacio Duran, Anna Berkenblit
Journal: Journal of Clinical Oncology (2011)

Purpose Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis. Patients and Methods Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. Results Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P &lt; .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients. Conclusion Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development
Authors: Eugene Izumchenko, Mahendra K. Singh, Olga V. Plotnikova, Nadezhda Tikhmyanova, Joy L. Little, Ilya G. Serebriiskii, Sachiko Seo, Mineo Kurokawa, Brian L. Egleston, Andres Klein-Szanto, Elena N. Pugacheva, Richard R. Hardy, Marina Wolfson, Denise C. Connolly, Erica A. Golemis
Journal: Cancer Research (2009)

Abstract In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9−/− mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9+/+ and Nedd9−/− tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198–206]
Electrical Activity During the P-R Interval
Authors: BRIAN F. HOFFMAN, PAUL F. CRANEFIELD, JACKSON H. STUCKEY, ALBIN A. BAGDONAS, Juan Piera
Journal: Circulation Research (1960)

Electrical activity of the specialized conducting system (His bundle, bundle branches, false tendons and peripheral Purkinje fibers) of canine hearts has been recorded in situ through electrodes attached to the endocardium during total cardiopulmonary bypass. Simultaneous records from multiple sites have been correlated with electrocardiograms to indicate the sequence of activation of the specialized conducting system during normal and retrograde activation and during vagal stimulation. The results obtained indicate that the method employed has several advantages among which are an absence of injury at the recording site and an applicability to chronic studies.
Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes.
Authors: D M Koelle, M A Tigges, R L Burke, F W Symington, S R Riddell, H Abbo, L Corey
Journal: Journal of Clinical Investigation (1993)

CD8+ cytotoxic T lymphocytes (CTL) clones with specificity for herpes simplex virus (HSV) were derived from two donors with genital HSV-2 infection. These CTL clones specifically lysed HSV-infected autologous B lymphoblastoid cells, but not HSV-infected fibroblasts. Exogenous peptide loading sensitized both cell types to lysis by an HSV-specific CTL clone of known specificity. HSV infection rendered fibroblasts refractory to peptide sensitization. HSV infection also rendered fibroblasts and keratinocytes insensitive to lysis by allospecific CD8+ CTL clones. Lysis of B lymphoblastoid cells in this system was only slightly reduced by HSV infection. Reduction of fibroblast allospecific lysis was dose and time dependent and was blocked by acyclovir, indicating the involvement of a late HSV gene product. HSV caused a reduction of fibroblast cell surface HLA class I antigen, at least in part due to reduction of synthesis of heavy chain-beta 2 microglobulin heterodimers. These results suggest that HSV-induced blockade of antigen presentation by cutaneous cells to CD8+ CTL may be a mechanism by which HSV limits or evades the immune response of the host.
The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice
Authors: Gerold Bongers, David Maussang, Luciana R. Muniz, Vanessa M. Noriega, Alberto Fraile-Ramos, Nick Barker, Federica Marchesi, Nanthakumar Thirunarayanan, Henry F. Vischer, Lihui Qin, Lloyd Mayer, Noam Harpaz, Rob Leurs, Glaucia C. Furtado, Hans Clevers, Domenico Tortorella, Martine J. Smit, Sergio A. Lira
Journal: Journal of Clinical Investigation (2010)

US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice) in which US28 expression was targeted to IECs. Expression of US28 was detected in all IECs of the small and large intestine, including in cells expressing leucine rich repeat containing GPCR5 (Lgr5), a marker gene of intestinal epithelial stem cells. US28 expression in IECs inhibited glycogen synthase 3β (GSK-3β) function, promoted accumulation of β-catenin protein, and increased expression of Wnt target genes involved in the control of the cell proliferation. VS28 mice showed a hyperplastic intestinal epithelium and, strikingly, developed adenomas and adenocarcinomas by 40 weeks of age. When exposed to an inflammation-driven tumor model (azoxymethane/dextran sodium sulfate), VS28 mice developed a significantly higher tumor burden than control littermates. Transgenic coexpression of the US28 ligand CCL2 (an inflammatory chemokine) increased IEC proliferation as well as tumor burden, suggesting that the oncogenic activity of US28 can be modulated by inflammatory factors. Together, these results indicate that expression of US28 promotes development of intestinal dysplasia and cancer in transgenic mice and suggest that CMV infection may facilitate development of intestinal neoplasia in humans.
Erythropoietin Receptor Expression and Correlation to Tamoxifen Response and Prognosis in Breast Cancer
Authors: Anna-Maria Larsson, Karin Jirström, Erik Fredlund, Sofie Nilsson, Lisa Rydén, Göran Landberg, Sven Påhlman
Journal: Clinical Cancer Research (2009)

The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen.EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS).EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression.EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior.
Preventing Occupational Exposures to Antineoplastic Drugs in Health Care Settings
Authors: T. H. Connor, M. A. McDiarmid
Journal: CA A Cancer Journal for Clinicians (2006)

The toxicity of antineoplastic drugs has been well known since they were introduced in the 1940s. Because most antineoplastic drugs are nonselective in their mechanism of action, they affect noncancerous as well as cancerous cells, resulting in well-documented side effects. During the 1970s, evidence came to light indicating health care workers may be at risk of harmful effects from antineoplastic drugs as a result of occupational exposure. Since that time, reports from several countries have documented drug contamination of the workplace, identified drugs in the urine of health care workers, and measured genotoxic responses in workers. Evidence also exists of teratogenic and adverse reproductive outcomes and increased cancers in health care workers. During the past 30 years, professional organizations and government agencies have developed guidelines to protect health care workers from adverse effects from occupational exposure to antineoplastic drugs. Although many safety provisions were advanced to reduce worker exposure in the 1980s, recent studies have shown that workers continue to be exposed to these drugs despite safety policy improvements. In 2004, the National Institute for Occupational Safety and Health (NIOSH) published an alert reviewing the most recent information available and promoting a program of safe handling during their use.
Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8
Authors: Jan Kranich, Nike Julia Krautler, Ernst Heinen, Magdalini Polymenidou, Claire Bridel, Anita Schildknecht, Christoph Huber, Marie H. Kosco-Vilbois, Rolf Zinkernagel, Gino Miele, Adriano Aguzzi
Journal: The Journal of Experimental Medicine (2008)

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMphis). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8(-/-) mice, all splenic Mfge8 was derived from FDCs rather than TBMphis. However, Mfge8(-/-) TBMphis acquired and displayed Mfge8 only when embedded in Mfge8(+/+) stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMphi-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8(-/-) mice. Hence, FDCs facilitate TBMphi-mediated corpse removal, and their malfunction may be involved in autoimmunity.
Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians.
Authors: D P Strachan, K J Powell, A Thaker, F J Millard, J D Maxwell
Journal: Thorax (1995)

BACKGROUND--In a previous retrospective study of tuberculosis in south London among Asian immigrants from the Indian subcontinent Hindu Asians were found to have a significantly increased risk for tuberculosis compared with Muslims. This finding has been further investigated by examining the role of socioeconomic and lifestyle variables, including diet, as risk factors for tuberculosis in Asian immigrants from the Indian subcontinent resident in south London. METHODS--Using a case-control study technique Asian immigrants from the Indian subcontinent diagnosed with tuberculosis during the past 10 years and two Asian control groups (community and outpatient clinic controls) from the Indian subcontinent were investigated. Cases and community controls were approached by letter. A structured questionnaire concerning a range of demographic, migration, socioeconomic, dietary, and health topics was administered by a single trained interviewer to subjects (56 cases and 100 controls) who agreed to participate. RESULTS--The results confirmed earlier findings that Hindu Asians had an increased risk of tuberculosis compared with Muslims. However, further analysis revealed that religion had no independent influence after adjustment for vegetarianism (common among Hindu Asians). Unadjusted odds ratios for tuberculosis among vegetarians were 2.7 (95% CI 1.1 to 6.4) using community controls, and 4.3 (95% CI 1.8 to 10.4) using clinic controls. There was a trend of increasing risk of tuberculosis with decreasing frequency of meat or fish consumption. Lactovegetarians had an 8.5 fold risk (95% CI 1.6 to 45.4) compared with daily meat/fish eaters. Adjustment for a range of other socioeconomic, migration, and lifestyle variables made little difference to the relative risks derived using either community or clinic controls. CONCLUSIONS--These results indicate that a vegetarian diet is an independent risk factor for tuberculosis in immigrant Asians. The mechanism is unexplained. However, vitamin D deficiency, common among vegetarian Asians in south London, is known to affect immunological competence. Decreased immunocompetence associated with a vegetarian diet might result in increased mycobacterial reactivation among Asians from the Indian subcontinent.
Using Benefit-Based Tailored Treatment to Improve the Use of Antihypertensive Medications
Authors: Jeremy Sussman, Sandeep Vijan, Rod Hayward
Journal: Circulation (2013)

Current guidelines for prescribing antihypertensive medications focus on reaching specific blood pressure targets. We sought to determine whether antihypertensive medications could be used more effectively by a treatment strategy based on tailored estimates of cardiovascular disease events prevented.We developed a nationally representative sample of American adults aged 30 to 85 years with no history of myocardial infarction, stroke, or severe congestive heart failure using the National Health and Nutrition Examination Survey III. We then created a simulation model to estimate the effects of 5 years of treatment with treat-to-target (treatment to specific blood pressure goals) and benefit-based tailored treatment (treatment based on estimated cardiovascular disease event reduction) approaches to antihypertensive medication management. All effect size estimates were derived directly from meta-analyses of randomized trials. We found that 55% of the overall population of 176 million Americans would be treated identically under the 2 treatment approaches. Benefit-based tailored treatment would prevent 900 000 more cardiovascular disease events and save 2.8 million more quality-adjusted life-years, despite using 6% fewer medications over 5 years. In the 45% of the population treated differently by the strategies, benefit-based tailored treatment would save 159 quality-adjusted life-years per 1000 treated versus 74 quality-adjusted life-years per 1000 treated by the treat-to-target approach. The findings were robust to sensitivity analyses.We found that benefit-based tailored treatment was both more effective and required less antihypertensive medication than current guidelines based on treating to specific blood pressure goals.
Large-Scale Analysis of <i>KIT</i> Aberrations in Chinese Patients with Melanoma
Authors: Yan Kong, Lu Si, Yanyan Zhu, Xiaowei Xu, Christopher L. Corless, Keith T. Flaherty, Li Li, Haifu Li, Xinan Sheng, Chuanliang Cui, Zhihong Chi, Siming Li, Mei Han, Lili Mao, Aiping Lu, Jun Guo
Journal: Clinical Cancer Research (2011)

KIT aberrations were described in acral and mucosal melanomas in largely Caucasian populations. Asian populations are more prone to develop acral and mucosal than cutaneous melanomas, and may harbor a high frequency of KIT aberrations.Melanoma subtypes (n = 502) were analyzed histologically to determine melanoma subtype. Tissue samples were analyzed for mutations in exons 9, 11, 13, 17, and 18 of KIT gene in genomic DNA by PCR amplification and Sanger sequencing. The copy numbers of the KIT gene were analyzed by quantitative PCR, and protein expression levels of KIT (CD117) were determined by immunohistochemistry.The most common melanoma subtypes were acral (38.4%) and mucosal (33.3%) melanomas in this population. The overall incidence of somatic mutations within the KIT gene was 10.8% (54/502), and all subtypes of melanoma contained KIT mutations. Increases in KIT gene copy numbers were correlated to CD117 overexpression. The genetic mutations of KIT were unrelated to the age, gender, stage, thickness, and ulceration of primary melanomas. Importantly, the overall survival of melanoma patients with KIT mutations (P = 0.001) or with KIT aberrations (mutation plus amplification, P = 0.0002) was significantly shorter than that of patients without such alterations.In China, the prevalent melanomas are acral and mucosal melanomas. KIT mutations are detected in all melanoma subtypes. Our study suggests that increases in KIT gene copy numbers, but not KIT mutations, may be correlated to CD117 overexpression. For the first time, our study suggests that genetic KIT aberration is an adverse prognostic factor for melanoma.
Controlled Family Study of Anorexia Nervosa and Bulimia Nervosa: Evidence of Shared Liability and Transmission of Partial Syndromes
Authors: Michael Strober, Roberta Freeman, Carlyn Lampert, Jane Diamond, Walter Kaye
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Lifetime rates of full and partial anorexia nervosa and bulimia nervosa were determined in first-degree relatives of diagnostically pure proband groups and relatives of matched, never-ill comparison subjects. METHOD: Rates of each eating disorder were obtained for 1,831 relatives of 504 probands on the basis of personal structured clinical interviews and family history. Best-estimate diagnoses based on all available information were rendered without knowledge of proband status and pedigree identity. Only definite and probable diagnoses were considered. RESULTS: Whereas anorexia nervosa was rare in families of the comparison subjects, full and partial syndromes of anorexia nervosa aggregated in female relatives of both anorexic and bulimic probands. For the full syndrome of anorexia nervosa, the relative risks were 11.3 and 12.3 in female relatives of anorexic and bulimic probands, respectively. Bulimia nervosa was more common than anorexia nervosa in female relatives of comparison subjects, but it, too, aggregated in the families of ill probands; the corresponding relative risks for bulimia nervosa were 4.2 and 4.4 for female relatives of anorexic and bulimic probands, respectively. When partial syndromes of anorexia nervosa and bulimia nervosa were considered, relative risks fell by one-half in each group of ill probands. CONCLUSIONS: Both anorexia nervosa and bulimia nervosa are familial. Their cross-transmission in families suggests a common, or shared, familial diathesis. The additional observation that familial aggregation and cross-transmission extend to milder phenotypes suggests the validity of their inclusion in a continuum of familial liability.