tbuckley/cabot-search huggingface dataset:
Tra2β As a Novel Mediator of Vascular Smooth Muscle Diversification
Authors: Supriya Shukla, Steven A. Fisher
Journal: Circulation Research (2008)

Transformer splicing regulatory proteins determine the sexually dimorphic traits of Drosophila. The role of the vertebrate homologs of Tra-2 in phenotypic specification is undefined. We are using the alternative splicing of the MYPT1 E23 exon as a model for the study of smooth muscle diversification into fast and slow contractile phenotypes. Tra2beta mRNA and protein is expressed at up to 10-fold higher levels in fast smooth muscle tissues such as the rat portal vein and small mesenteric artery, in which E23 is spliced, as compared to the slow smooth muscle tissues of the large arteries and veins, in which E23 is skipped. Tra2beta is upregulated up to 10-fold concordant with the initiation of E23 splicing as the rat portal vein and avian gizzard implement the fast program of gene expression in the perinatal period. In disease models such as portal hypertension and mesenteric artery high/low flow, the portal vein and first order mesenteric artery dynamically downregulate Tra2beta concordant with a shift to E23 skipping and the slow program of gene expression. Tra2beta binds to a highly conserved sequence within E23 and transactivates its splicing in vitro and in vivo; this is abolished with mutation or deletion of this sequence. RNA interference-mediated knockdown of Tra2beta markedly reduces E23 splicing. We propose that Tra2beta has been conserved through evolution and redeployed for the specification of the fast smooth muscle phenotype and may serve as a novel nodal point for the investigation of this process in developmental and disease models.
AN ACCELERATED FEBRILE REACTION IN MONKEYS UPON REINOCULATION WITH POLIOMYELITIS VIRUS
Authors: Claus W. Jungeblut
Journal: The Journal of Experimental Medicine (1931)

1. Primary poliomyelitic infection in the monkey, as a rule, is characterized by no significant increase in the body temperature during the incubation period until 48 or 24 hours before the onset of clinical symptoms, when a critical rise of the temperature occurs. 2. The temperature curve of recovered monkeys on intracerebral reinoculation shows an almost immediate and marked febrile reaction during the first 24 or 48 hours after inoculation. A similar accelerated febrile reaction may be obtained in recovered animals after subcutaneous injection of killed virus. In case the previous infection is of very recent date, reinoculation may lead to no demonstrable reaction whatsoever. 3. Monkeys, which have received a number of parenteral injections of live virus, respond to intracerebral infection with a precocious and prolonged febrile reaction on the 3rd or 4th day after infection which may last until the onset of symptoms. 4. The altered response to reinoculation of monkeys which have previously been in contact with the virus, suggests a close analogy with the accelerated reactions observed in allergic phenomena.
Immunologic Consequences of Signal Transducers and Activators of Transcription 3 Activation in Human Squamous Cell Carcinoma
Authors: Emilia Albesiano, Meghan Davis, Alfred P. See, James E. Han, Michael Lim, Drew M. Pardoll, Young Kim
Journal: Cancer Research (2010)

Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.
A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy
Authors: Talat H. Malik, Peter J. Lavin, Elena Goicoechea de Jorge, Katherine A. Vernon, Kirsten L. Rose, Mitali P. Patel, Marcel de Leeuw, John J. Neary, Peter J. Conlon, Michelle P. Winn, Matthew C. Pickering
Journal: Journal of the American Society of Nephrology (2012)

Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.
Epstein-Barr Virus Infection Is Predictive of CNS Involvement in Systemic AIDS-Related Non-Hodgkin’s Lymphomas
Authors: Antonella Cingolani, Roberta Gastaldi, Lucia Fassone, Francesco Pierconti, Maria Letizia Giancola, Maurizio Martini, Andrea De Luca, Adriana Ammassari, Carla Mazzone, Edoardo Pescarmona, Gianluca Gaidano, Luigi Maria Larocca, Andrea Antinori
Journal: Journal of Clinical Oncology (2000)

PURPOSE: This study aimed at correlating Epstein-Barr virus (EBV) infection of systemic AIDS-related non-Hodgkin lymphomas (AIDS-NHL) with the development of a CNS localization of the tumor. PATIENTS AND METHODS: Demographic, epidemiologic, clinical, histologic, and virologic features were collected for all systemic AIDS-NHL patients included in the study (n = 50). Pathologic specimens were classified according to the working formulation for NHL and the Revised European-American Lymphoma classification. EBV infection in tumor tissue samples was studied by EBV small encoded RNA in situ hybridization; EBV-DNA detection in CSF was carried out by nested polymerase chain reaction using Epstein-Barr nuclear antigen-1–specific primers. In addition, selected EBV-positive lymphomas were subjected to a detailed characterization of EBV molecular heterogeneity. RESULTS: Eleven patients had a CNS involvement at some point during their clinical history (four at diagnosis and seven at relapse). Thirty patients (11 with CNS involvement and 19 without) harbored EBV infection of the tumor. Sensitivity, specificity, and positive and negative predictive values of EBV-DNA detection in CSF for CNS involvement by lymphoma were 90%, 100%, 100%, and 97.6%, respectively. Factors significantly predictive of CNS involvement were EBV infection of the tumor (P = .003), an extranodal disease at diagnosis other than CNS (P = .006), and a non-CNS relapse (P = .01). In four cases of CNS involvement, EBV-DNA in CSF preceded any other sign of disease by a mean of 35 days. CONCLUSION: These results show that EBV infection of the tumor clone significantly increases the risk of CNS involvement by systemic AIDS-NHL, without regard of specific molecular features. The detection of EBV-DNA in the CSF of AIDS-NHL patients may select cases with higher risk of CNS involvement and, therefore, may prove useful in the therapeutic stratification of these tumors.
How Genetic Variant Libraries Effectively Extend Gene Testing Patents: Implications for Intellectual Property and Good Clinical Care
Authors: Sean McElligott, Robert I. Field, Mirar Bristol-Demeter, Susan M. Domchek, David A. Asch
Journal: Journal of Clinical Oncology (2012)

Genetic testing for inherited cancer susceptibility is an increasingly valuable tool in medical oncology. The identification of mutations in the BRCA1 and BRCA2 genes, for example, leads to specific clinical recommendations for screening or surgery that can improve survival.1 However, genetic testing can also identify variants of uncertain significance (VUS), changes in the genetic code that have an unknown effect on disease risk. Roughly 7% of women tested for BRCA1 and BRCA2 have one of these variants.2 Test results with VUS increase, rather than decrease, uncertainty for the patient in a situation with particularly high stakes and present a challenge to the clinician in devising appropriate responses.
Phospholipid Metabolite 1-Palmitoyl-Lysophosphatidylcholine Enhances Human <i>Ether-a-Go-Go</i> -Related Gene (HERG) K <sup>+</sup> Channel Function
Authors: Jingxiong Wang, Huizhen Wang, Hong Han, Yiqiang Zhang, Baofeng Yang, Stanley Nattel, Zhiguo Wang
Journal: Circulation (2001)

Background Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K + accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood. Methods and Results We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human ether-a-go-go -related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (I HERG ). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased I HERG at voltages between −20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of I HERG activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0±2.2 mV shift in half-inactivation voltage relative to control. Conclusions Our results indicate that apart from being a well-recognized target for drug inhibition, I HERG can also be enhanced by natural substances. An increase in I HERG by Pal-LPC may contribute to K + loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.
THE MODIFYING EFFECT OF BCG ON THE IMMUNOLOGICAL INDUCTION OF T CELLS
Authors: G. B. Mackaness, P. H. Lagrange, T. Ishibashi
Journal: The Journal of Experimental Medicine (1974)

The inhibition of activated T cells by products of the humoral immune response is almost abolished by systemic infection with BCG. As a result, BCG-infected mice develop very high levels of delayed-type hypersensitivity (DTH) in response to doses of sheep red blood cells (SRBC) that cause complete suppression of DTH in normal mice. This systemic effect of BCG is dose-dependent, and lasts for about 3 wk. Its main effect is to counteract the inhibition of T cells by products of the humoral response. As a result, and in contrast to the T-cell-potentiating effects of cyclophosphamide (CY) which depend on a diminished production of antibodies, increased levels of DTH in BCG-infected mice are associated with increased antibody production. Since BCG and CY act in different ways, their effects are additive. Very remarkable levels of DTH are achieved when they are used in combination.
Rising Incidence of Breast Cancer Among Young Women in Washington State&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Emily White, Janet R. Daling, Tierney L. Norsted, Joseph Chu
Journal: JNCI Journal of the National Cancer Institute (1987)

The prevalence of several known or suspected risk factors for breast cancer is changing among young women. The time trend in incidence of breast cancer among young women in western Washington was analyzed as a possible predictor of trends in future incidence rates. Data were from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. For women age 25-44 years (n = 1,869 cases), the incidence of breast cancer increased by 22% (P less than .001) between the time periods 1974-77 and 1982-84. The estimated annual increase was 2.5% (P less than .001). The increase in incidence over time appeared to be greater among those residing in low-income census tracts of urban counties and among black women. Possible relationships between the observed increase in rates and trends of risk factors for breast cancer are discussed.
Fractionated Locoregional Low-Dose Radioimmunotherapy Improves Survival in a Mouse Model of Diffuse-Type Gastric Cancer Using a 213Bi-Conjugated Monoclonal Antibody
Authors: Stefanie Bloechl, Roswitha Beck, Christof Seidl, Alfred Morgenstern, Markus Schwaiger, Reingard Senekowitsch-Schmidtke
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Locoregional radioimmunotherapy of i.p. tumor cell dissemination of diffuse-type gastric cancer using the α-emitter 213Bi displayed good therapeutic results after a single application depending on the time interval between tumor cell inoculation and injection of the 213Bi-immunoconjugate. The aim of the present study was to compare single versus double i.p. injection of a tumor-specific antibody (d9MAb) conjugated with low activities of 213Bi in terms of therapeutic efficacy and toxicity. Experimental Design: Nude mice were inoculated i.p. with 1 × 107 human gastric cancer cells (HSC45-M2) expressing tumor-specific mutant d9-E-cadherin (d9-E-cad). After tumor cell inoculation, the mice were injected i.p. with a single injection at day 1 or 8, or double injections at days 1 and 8 or days 8 and 15 with 0.37, 0.74, or 1.48 MBq 213Bi-d9MAb. Therapeutic efficacy was determined by median survival, and toxicity was evaluated by leukocyte and platelet counts. The development of i.p. carcinomatosis was monitored by carcinoembryonic antigen concentrations in the serum of the mice. Results: The median survival of treated animals increased, depending on the time interval (days) between tumor cell inoculation and therapy, and the injected activity, from 22 days of untreated mice to 48 days (0.37 MBq, 1 day), 84 days (0.37 MBq, 1 and 8 days), 37 days (0.37 MBq, 8 days), 46 days (0.37 MBq, 8 and 15 days), 42 days (0.74 MBq, 8 days), 78 days (0.74 MBq, 8 and 15 days), and 44 days (1.48 MBq, 8 days). The injected activities did not reduce leukocyte and platelet counts. Carcinoembryonic antigen, which was not detectable in the serum of tumor-free mice, increased after tumor cell inoculation and tumor proliferation and decreased after each therapeutic application of 213Bi-d9MAb. Conclusions: Double application of only 0.37 MBq of 213Bi-d9MAb at days 1 and 8 after tumor cell inoculation significantly prolonged median survival in nude mice suffering from i.p. tumor cell dissemination compared with a single injection. Even in an advanced stage of the disease, double injection of 0.74 MBq at days 8 and 15 was superior to a single injection of 1.48 MBq at day 8 without any sign of toxicity.
Prostate Carcinogenesis in N-methyl-N-nitrosourea (NMU)-Testosterone-Treated Rats Fed Tomato Powder, Lycopene, or Energy-Restricted Diets
Authors: T. W.-M. Boileau
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Consumption of tomato products or lycopene and energy restriction have been hypothesized to reduce the risk of human prostate cancer. We investigated the effects of these dietary variables in a rat model of prostate carcinogenesis. Methods: Male rats (n = 194) treated with N-methyl-N-nitrosourea and testosterone to induce prostate cancer were fed diets containing whole tomato powder (13 mg lycopene/kg diet), lycopene beadlets (161 mg lycopene/kg diet), or control beadlets. Rats in each group were randomly assigned to either ad libitum feeding or 20% diet restriction. Differences between Kaplan-Meier survival curves for diet composition or restriction were tested with the log-rank test. Cox proportional hazards models were developed to examine the combined effect of diet composition and restriction on survival. Statistical tests were two-sided. Results: Risk of death with prostate cancer was lower for rats fed the tomato powder diet than for rats fed control beadlets (hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.59 to 0.93; P = .009). In contrast, prostate cancer-specific mortality of the control and lycopene-fed rats was similar (P = .63). The proportions of rats dying with prostate cancer in the control, lycopene, and tomato powder groups were 80% (95% CI = 68% to 89%), 72% (95% CI = 60% to 83%), and 62% (95% CI = 48% to 75%), respectively. Rats in the diet-restricted group experienced longer prostate cancer-free survival than rats in the ad libitum-fed group (HR = 0.68, 95% CI = 0.49 to 0.96; P = .029). The proportion of rats that developed prostate cancer was 79% (95% CI = 69% to 86%) for ad libitum-fed rats and 65% (95% CI = 54% to 74%) for rats fed restricted diets. No interactions were observed between diet composition and dietary restriction. Conclusions: Consumption of tomato powder but not lycopene inhibited prostate carcinogenesis, suggesting that tomato products contain compounds in addition to lycopene that modify prostate carcinogenesis. Diet restriction also reduced the risk of prostate cancer. Tomato phytochemicals and diet restriction may act by independent mechanisms.
Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms
Authors: Yibin Yang, Roland Schmitz, Joseph Mitala, Amanda Whiting, Wenming Xiao, Michele Ceribelli, George W. Wright, Hong Zhao, Yandan Yang, Weihong Xu, Andreas Rosenwald, German Ott, Randy D. Gascoyne, Joseph M. Connors, Lisa M. Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Rita M. Braziel, Raymond R. Tubbs, James R. Cook, Dennis D. Weisenburger, Wing C. Chan, Adrian Wiestner, Michael J. Kruhlak, Kazuhiro Iwai, Federico Bernal, Louis M. Staudt
Journal: Cancer Discovery (2014)

Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis.
The role of general practitioners in diagnosis of cutaneous melanoma: a population‐based study in France
Authors: F. Grange, C. Barbe, L. Mas, F. Granel‐Brocard, D. Lipsker, F. Aubin, M. Velten, S. Dalac, F. Truchetet, C. Michel, A. Mitschler, G. Arnoult, A. Buemi, S. Dalle, G. Reuter, P. Bernard, A.S. Woronoff, F. Arnold
Journal: British Journal of Dermatology (2012)

Little data are available concerning the role of general practitioners (GPs) in the diagnosis of melanoma.To evaluate the actual role of GPs in a population-based study covering five regions of France and 8·2 million inhabitants.A survey of cancer registries and pathology laboratories, and questionnaires to practitioners were used to identify incident melanomas in 2008, and evaluate characteristics of patients (age, sex, area of residence, social isolation), tumours (Breslow, ulceration, location, histological type), and GPs (training, conditions of practice), and their influence on patterns of diagnosis and Breslow thickness.Among 898 melanomas, 376 (42%) were first diagnosed in a general practice setting (GP group). Breslow thickness was much higher in the GP group than in other melanomas (median: 0·95 vs. 0·61 mm, P < 0·0001). Multivariate analysis identified an older age, lower limb location, nodular subtype and Breslow thickness as factors associated with the GP group. Within this group, 52·5% of melanomas were detected by patients (median Breslow thickness: 1·30 mm) and 47·5% by GPs (median Breslow thickness: 0·80 mm, P = 0·0009), including 8% during a systematic full-body skin examination. Previous GP training on melanoma was associated with active detection by GPs. Male sex and social isolation of patients were associated with thicker melanomas, whereas active detection by GPs was associated with thinner CMs.GPs play a key role in melanoma diagnosis in France, but still frequently detect thick tumours. Increasing awareness and training of GPs and focusing attention on male and/or socially isolated patients should help to improve early detection of melanoma.
Comparison of Surgical, Stent, and Balloon Angioplasty Treatment of Native Coarctation of the Aorta
Authors: Thomas J. Forbes, Dennis W. Kim, Wei Du, Daniel R. Turner, Ralf Holzer, Zahid Amin, Ziyad Hijazi, Abdolrahim Ghasemi, Jonathan J. Rome, David Nykanen, Evan Zahn, Collin Cowley, Mark Hoyer, David Waight, Daniel Gruenstein, Alex Javois, Susan Foerster, Jacqueline Kreutzer, Nancy Sullivan, Asra Khan, Carl Owada, Donald Hagler, Scott Lim, Joshua Canter, Thomas Zellers
Journal: Journal of the American College of Cardiology (2011)
A Scan for Signatures of Positive Selection in Candidate Loci for Skin Pigmentation in Humans
Authors: Neskuts Izagirre, Iker García, Corina Junquera, Concepción de la Rúa, Santos Alonso
Journal: Molecular Biology and Evolution (2006)

Although the combination of pale skin and intense sun exposure results in an important health risk for the individual, it is less clear if at the population level this risk has possessed an evolutionary meaning. In this sense, a number of adaptive hypotheses have been put forward to explain the evolution of human skin pigmentation, such as photoprotection against sun-induced cancer, sexual selection, vitamin D synthesis or photoprotection of photolabile compounds, among others. It is expected that if skin pigmentation is adaptive, we might be able to see the signature of positive selection on some of the genes involved. In order to detect this signature, we analyze a battery of 81 candidate loci by means of phylogenetic and population genetic tests. Our results indicate that both light and dark skin may possess adaptive value. Of the main loci presenting this signature, TP53BP1 shows clear evidence of adaptive selection in Africans, whereas TYRP1 and SLC24A5 show evidence of adaptive selection in Caucasians. Although we cannot offer a mechanism that based on these genes explains the advantage of light skin, if TP53BP1, and perhaps RAD50, have truly conferred an adaptive value to the African population analyzed, photoprotection against sun-induced skin damage/cancer might be proposed as a mechanism that has driven the evolution of human skin pigmentation.