tbuckley/cabot-search huggingface dataset:
The complex pattern of SMAD signaling in the cardiovascular system☆
Authors: G EULERTAIMOR, J HEGER
Journal: Cardiovascular Research (2005)

The SMAD (small mother against decapentaplegic) family comprises transcription factors that function as signal transducers of TGFbeta (transforming growth factor) superfamily members. The number of studies showing expression, activation or involvement of both SMAD and TGFbeta family members in cardiovascular diseases is constantly rising. In this context, the position of SMADs in the diseased heart is particularly interesting because, besides their well-known fibrotic effects, increasing evidence demonstrates direct action of SMADs on cardiomyocytes as well as on the vascular system. In these systems, SMAD proteins are described to have effects on heart development, cell proliferation, cell growth, and apoptosis. As will be discussed in this review, these different consequences of SMAD activation are dependent on different SMAD isoforms, interaction of SMAD with other transcription factors in the particular situation, and modulation of SMAD activity by various kinases. As a result of all these influences, it turns out that activation of SMAD by members of the BMP (bone morphogenetic protein) family, which is a subfamily of the TGFbeta superfamily, is necessary for correct heart development. On the other hand, activation of SMADs by TGFbeta family members results in fibrotic, apoptotic, and anti-hypertrophic processes that are related to a detrimental cardiac remodeling and progression to heart failure.
Abuse, Bullying, and Discrimination as Risk Factors for Binge Eating Disorder
Authors: Ruth H. Striegel-Moore, Faith-Anne Dohm, Kathleen M. Pike, Denise E. Wilfley, Christopher G. Fairburn
Journal: American Journal of Psychiatry (2002)

This study examined whether sexual and physical abuse, bullying by peers, and ethnicity-based discrimination are associated with an increased risk for developing binge eating disorder in black women and in white women and whether any increase in risk is specific for the development of binge eating disorder.A community sample of 162 women with binge eating disorder and 251 healthy and 107 psychiatric comparison subjects was interviewed for exposure to the risk factors under investigation.White subjects with binge eating disorder reported significantly higher rates of sexual abuse, physical abuse, bullying by peers, and discrimination than healthy comparison subjects. Only rates of discrimination were significantly higher in white women with binge eating disorder than in matched psychiatric comparison subjects. In black women with binge eating disorder, rates of sexual abuse, physical abuse, and bullying by peers-but not discrimination-were significantly higher than in healthy comparison women. Rates of sexual abuse were significantly higher in black women with binge eating disorder than in psychiatric comparison subjects.Consistent with previous research examining ethnicity-specific patterns of risk for psychiatric disorder, we found both ethnic similarities (physical abuse and bullying by peers) and differences (sexual abuse and discrimination) in the risk for binge eating disorder.
Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences
Authors: Shu Yuan Yang, Sebastian D. Fugmann, David G. Schatz
Journal: The Journal of Experimental Medicine (2006)

It is thought that gene conversion (GCV) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes occur in two steps: the generation of uracils in DNA by activation-induced cytidine deaminase, followed by their subsequent repair by various DNA repair pathways to generate sequence-diversified products. It is not known how either of the two steps is targeted specifically to Ig loci. Because of the tight link between transcription and SHM, we have investigated the role of endogenous Ig light chain (IgL) transcriptional control elements in GCV/SHM in the chicken B cell line DT40. Promoter substitution experiments led to identification of a strong RNA polymerase II promoter incapable of supporting efficient GCV/SHM. This surprising finding indicates that high levels of transcription are not sufficient for robust GCV/SHM in Ig loci. Deletion of the IgL enhancer in a context in which high-level transcription was not compromised showed that the enhancer is not necessary for GCV/SHM. Our results indicate that cis-acting elements are important for Ig gene diversification, and we propose that targeting specificity is achieved through the combined action of several Ig locus elements that include the promoter.
American Society of Clinical Oncology Perspective: Raising the Bar for Clinical Trials by Defining Clinically Meaningful Outcomes
Authors: Lee M. Ellis, David S. Bernstein, Emile E. Voest, Jordan D. Berlin, Daniel Sargent, Patricia Cortazar, Elizabeth Garrett-Mayer, Roy S. Herbst, Rogerio C. Lilenbaum, Camelia Sima, Alan P. Venook, Mithat Gonen, Richard L. Schilsky, Neal J. Meropol, Lowell E. Schnipper
Journal: Journal of Clinical Oncology (2014)

See accompanying editorial on page 1186 Lee M. Ellis, University of Texas MD Anderson Cancer Center, Houston, TX; David S. Bernstein and Richard L. Schilsky, American Society of Clinical Oncology, Alexandria, VA; Emile E. Voest, University Medical Center Utrecht, Utrecht, the Netherlands; Jordan D. Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Daniel Sargent, Mayo Clinic, Rochester, MN; Patricia Cortazar, US Food and Drug Administration, Silver Spring, MD; Elizabeth Garrett-Mayer, Medical University of South Carolina, Charleston, SC; Roy S. Herbst and Rogerio C. Lilenbaum, Yale Cancer Center, New Haven, CT; Camelia Sima and Mithat Gonen, Memorial Sloan-Kettering Cancer Center, New York, NY; Alan P. Venook, Helen Diller Family Comprehensive Cancer Center at University of California San Francisco, San Francisco, CA; Neal J. Meropol, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; Lowell E. Schnipper, Beth Israel Deaconess Medical Center, Boston, MA.
Mumps Infection and Insulin-dependent Diabetes Mellitus (IDDM)
Authors: Klaus P Ratzmann, J Strese, S Witt, H Berling, H Keilacker, D Michaelis
Journal: Diabetes Care (1984)

In order to select a population at risk for the development of diabetes for a prospective study of the relationship of islet cell antibodies (ICA),islet cell surface antibodies (ICSA), and glucose tolerance after mumps infection, we carried out a screening program for diabetes. A diabetic survey was conducted among 1581 children (&amp;lt; 16 yr of age) with mumps infection 14 mo before the survey, using a brief questionnaire combined with urinary glucose analysis. Responses to the screening program were obtained from 68.4% (N = 1080) of the children. Out of a total of 1080 subjects, 1069 (99%) had no diabetes mellitus, diabetic symptoms, or glucosuria. A “positive urine glucose screen” was obtained in 11 subjects (1%) of the study group. These individuals all had a normal oral glucose tolerance test according to the new WHO definition. A group of 86 children was randomly selected from the total group of 1080 children for follow-up glucose tolerance, ICA, and ICSA. Irrespective of the negative urine glucose screen impaired glucose tolerance was diagnosed in 3.5% (N = 3) of the 86 children. The prevalence of ICA and ICSA was 78% and 36%, respectively. The simultaneous prevalence of ICA and ICSA was 33%. The pathogenetic role of mumps infection and ICA/ICSA and their possible relationship to slow progressive beta cell destruction remain to be elucidated.
GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity
Authors: A. Vartanian, S. K. Singh, S. Agnihotri, S. Jalali, K. Burrell, K. D. Aldape, G. Zadeh
Journal: Neuro-Oncology (2014)

Gliomas are a heterogeneous group of tumors that show variable proliferative potential, invasiveness, aggressiveness, histological grading, and clinical behavior. In this review, we focus on glioblastoma multiforme (GBM), a grade IV glioma, which is the most common and malignant of primary adult brain tumors. Research over the past several decades has revealed the existence of extensive cellular, molecular, genetic, epigenetic, and metabolic heterogeneity among tumors of the same grade and even within individual tumors. Evaluation of different tumor types has shown that tumors with advanced grade and clinical aggressiveness also display enhanced molecular, cellular, and microenvironmental heterogeneity. From a therapeutic standpoint, this heterogeneity is a major clinical hurdle for devising effective therapeutic strategies for patients and challenges personalized medicine. In this review, we will highlight key aspects of GBM heterogeneity, directing special attention to regional heterogeneity, hypoxia, genomic heterogeneity, tumor-specific metabolic reprogramming, neovascularization or angiogenesis, and stromal immune cells. We will further discuss the clinical implications of GBM heterogeneity in the context of therapy.
Phase I/II trial of total lymphoid irradiation and high-dose chemotherapy with autologous stem-cell transplantation for relapsed and refractory Hodgkin's lymphoma
Authors: A.M. Evens, J.K. Altman, B.B. Mittal, N. Hou, A. Rademaker, D. Patton, L. Kaminer, S. Williams, S. Duffey, D. Variakojis, S. Singhal, M.S. Tallman, J. Mehta, J.N. Winter, L.I. Gordon
Journal: Annals of Oncology (2007)
Leptin, the Product of Ob Gene, Promotes Angiogenesis
Authors: Anne Bouloumié, Hannes C. A. Drexler, Max Lafontan, Rudi Busse
Journal: Circulation Research (1998)

Abstract —The adipocyte-derived cytokine leptin is thought to play a key role in the control of satiety and energy expenditure. Because adipogenesis and angiogenesis are tightly correlated during the fat mass development, we tested the hypothesis that leptin is able to modulate the growth of the vasculature. Experiments were performed using cultured human umbilical venous endothelial cells (HUVECs) and porcine aortic endothelial cells. The presence of 170-kDa endothelial leptin receptor (Ob-R) was assessed in HUVECs by Western blot analysis. Reverse transcriptase–polymerase chain reaction analysis using specific oligonucleotides for the short and long Ob-R forms further revealed the expression of both Ob-R transcripts in endothelial cells. Moreover, leptin evoked a time-dependent tyrosine phosphorylation of a number of endothelial proteins, the most prominent of which were the mitogen-activated protein kinases Erk1/2. Treatment of HUVECs with leptin led to a concentration-dependent increase in cell number that was maximal at 10 ng/mL leptin and equivalent to that elicited by vascular endothelial growth factor. This effect was associated with an enhanced formation of capillary-like tubes in an in vitro angiogenesis assay and neovascularization in an in vivo model of angiogenesis. These results indicate that leptin, via activation of the endothelial Ob-R, generates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. We speculate that this leptin-mediated stimulation of angiogenesis might represent not only a key event in the settlement of obesity but also may contribute to the modulation of growth under physiological and pathophysiological conditions in other tissues.
Constitutively active Rap1 protects from experimental autoimmune encephalomyelitis (EAE) by quantitative and qualitative modulation of auto-reactive T cells
Authors: S. G. Franco, S. Krausz, W. Dontje, P. Tak, D. Baeten, K. Reedquist
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Rap1 is an important signalling molecule downstream of the T-cell receptor (TCR), which can modulate T lymphocyte function upon antigen stimulation. The authors recently demonstrated that transgenic mice with constitutively active Rap1 (RapV12) are protected from experimental arthritis (<i>Abreu, Arthritis Rheum, 2010</i>). Here, the authors aimed to identify the mechanisms of protection by using a TCR transgenic model of myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE) (2D2 mice). <h3>Methods</h3> Flow cytometry and ELISA were used to analyse the phenotype and cytokine profile of MOG-specific autoreactive T cells in 2D2xRapV12, 2D2, RapV12 and wild type (WT) mice (n=5 per genotype), either in basal conditions or after in vivo priming with MOG peptide. In addition, clinical EAE was monitored for 30 days (n=19 mice per genotype) <h3>Results</h3> In basal conditions, there was a strong reduction in the number of autoreactive T cells in 2D2xRapV12 versus 2D2 animals in the naïve and memory compartment (42 vs 24%, p=0.03), indicating that constitutive Rap1 activation enforces central tolerance. Qualitative analysis of the autoreactive T cells that escaped tolerance showed no differences in T cell subsets, proliferation, apoptosis, expression of costimulatory molecules and production of pro-inflammatory cytokines. After in vivo priming with MOG, however, the authors observed a profound inhibition of tumour necrosis factor production by T cells constitutively expressing Rap1 (19% of 2D2 RapV12 CD4s vs 0.4% in 2D2 controls, p=0.002), whereas there was a slight increase in IFN-γ and IL-17 production. To evaluate the pathophysiological relevance of these quantitative and qualitative alterations of the autoreactive T cells, EAE was induced in 2D2xRapV12 versus 2D2 and in RapV12 and WT littermates. In the 2D2 model, where a significant number of autoreactive T cells are still present despite the constitutive RapV12, the authors observed no difference in EAE scores but an improved survival in the 2D2xRapV12 versus 2D2 mice (42 vs 16%; p=0.04). In wild-type mice, constitutive Rap1 expression led to increased survival (100 vs 74%; p=0.02) as well as lower EAE scores (p=0.07). <h3>Conclusion</h3> Constitutive activation of Rap1 reduces the autoreactive T cell pool and affects pro-inflammatory cytokine production by the remaining autoreactive T lymphocytes. As in experimental arthritis, these quantitative and qualitative effects are associated with a protection from autoimmune disease in EAE.
Direct activation of mitochondrial KATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts
Authors: M Tani
Journal: Cardiovascular Research (2001)

Objectives: This study is aimed to determine whether loss of preconditioning (IP) effects in the middle-aged hearts (MA) is due to the failure of protein kinase C (PKC) activation and, if so, whether direct activation of mitochondrial ATP-sensitive potassium channels (m-KATP) or PKC mimics IP. Background: PKC is a mediator and m-KATP may be its downstream effector of IP in young adult hearts (YA), but we have demonstrated that IP is not effective in MA. Methods and results: Isolated hearts from YA (12-week) and MA (50-week) Fischer 344 rats were preconditioned by three cycles of ischemia and reperfusion (5 min each), and the translocation of PKC isoforms and the effects on reperfusion injury were assessed. In some hearts activation of m-KATP or PKC by diazoxide or 1,2-dioctanoyl glycerol (DOG) was performed before 25 min of global ischemia/30 min of reperfusion. IP could improve the recovery of LV function and resulted in higher content of ATP after reperfusion in YA but these beneficial effects of IP was not found in MA. The effects of IP in YA were abolished by 5-hydroxydecanoate. In YA but not in MA, immunohistochemical analysis revealed that IP translocated PKC-α and δ from the cytosolic or membrane to the perinuclear region but immunoblotting analysis showed translocation of PKC-α, δ and ε to the membrane fraction. Pretreatment with diazoxide or DOG mimicked IP and decreased the creatine kinase release in YA. Diazoxide was also effective but effects of DOG were less in MA as compared with in YA. Conclusions: IP is not effective in MA hearts partly due to failure of translocation of PKC isoforms. Moreover, less efficacy of PKC activation by DOG as compared with activities of m-KATP by diazoxide in MA may suggest that defect(s) of cell signaling downstream to PKC may also be involved in the loss of IP effects in MA.
Construction of 3D MR image-based computer models of pathologic hearts, augmented with histology and optical fluorescence imaging to characterize action potential propagation
Authors: Mihaela Pop, Maxime Sermesant, Garry Liu, Jatin Relan, Tommaso Mansi, Alan Soong, Jean-Marc Peyrat, Michael V. Truong, Paul Fefer, Elliot R. McVeigh, Herve Delingette, Alexander J. Dick, Nicholas Ayache, Graham A. Wright
Journal: Medical Image Analysis (2011)
Risk of Non-Hodgkin Lymphoma and Lymphoproliferative Precursor Diseases in US Veterans With Hepatitis C Virus
Authors: Thomas P. Giordano, Louise Henderson, Ola Landgren, Elizabeth Y. Chiao, Jennifer R. Kramer, Hashem El-Serag, Eric A. Engels
Journal: JAMA (2007)

Hepatitis C virus (HCV) infection causes liver cancer and cirrhosis and may also increase the risk of other tumors, particularly hematopoietic malignancies and thyroid cancer. Previous studies have been too small to adequately assess these risks.To test the hypothesis that HCV infection is associated with increased risk for hematological malignancies, related lymphoproliferative disorders, and thyroid cancer.A retrospective cohort study of users of US Veterans Affairs health care facilities from 1997-2004, which included 146,394 patients infected with HCV who had at least 2 visits with a diagnostic code for HCV infection, and 572,293 patients uninfected with HCV. To assemble the HCV-uninfected cohort, we randomly selected up to 4 patients per patient infected with HCV from all veterans who matched on age, sex, and baseline visit date and type (inpatient or outpatient). Individuals with human immunodeficiency virus were excluded.Risks of hematopoietic malignancies, related lymphoproliferative precursor diseases, and thyroid cancer, adjusting for selection factors, race, era of military service, and use of medical services.The mean (SD) age of the patients was 52 (8) years, and 97% were men. Risks for non-Hodgkin lymphoma (n = 1359), Waldenström macroglobulinemia (n = 165), and cryoglobulinemia (n = 551) were increased with HCV infection (adjusted hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.12-1.45; adjusted HR, 2.76; 95% CI, 2.01-3.79; and adjusted HR, 3.98; 95% CI, 3.36-4.72; respectively). We found no significantly increased risk for other hematological malignancies. Although thyroiditis risk was slightly increased, risk for thyroid cancer (n = 320) was not (adjusted HR, 0.72; 95% CI, 0.52-0.99). Adjusted P values for non-Hodgkin lymphoma, Waldenström macroglobulinemia, cryoglobulinemia, and thyroiditis were all <.0038, the Bonferroni threshold for statistical significance considering multiple comparisons.Hepatitis C virus infection confers a 20% to 30% increased risk of non-Hodgkin lymphoma overall, and a 3-fold higher risk of Waldenström macroglobulinemia, a low-grade lymphoma. Risks were also increased for cryoglobulinemia. These results support an etiological role for HCV in causing lymphoproliferation and causing non-Hodgkin lymphoma.
Memory Impairments Identified in People at Ultra-High Risk for Psychosis Who Later Develop First-Episode Psychosis
Authors: Warrick J. Brewer, Shona M. Francey, Stephen J. Wood, Henry J. Jackson, Christos Pantelis, Lisa J. Phillips, Alison R. Yung, Vicki A. Anderson, Patrick D. McGorry
Journal: American Journal of Psychiatry (2004)

While cognitive deficits are frequently reported in psychotic disorders, it is unclear whether these impairments predate the onset of illness and to what extent they are predictive of later transition to psychosis.The authors studied 37 healthy volunteers and 98 symptomatic, help-seeking patients meeting the inclusion criteria of a treatment program for people at ultra-high risk for psychosis. Of the ultra-high-risk patients, 34 (34.7%) developed psychosis over the course of the investigation. Premorbid and current IQ, attention, memory, and executive functioning were measured with instruments including subtests from the Wechsler Memory Scale-Revised (WMS-R). Analyses compared the ultra-high-risk patients who became psychotic, those who did not become psychotic, and the comparison subjects.Overall, the ultra-high-risk subjects had significantly lower performance IQs than the comparison subjects. Further, impairments were also found in the visual reproduction subtest and the verbal memory index (predominantly owing to lower logical memory scores) of the WMS-R that were specific to the ultra-high-risk-patients who developed psychosis. No other memory, attentional, or executive tasks discriminated between any of the groups.These findings suggest that visuospatial processing impairment and some memory deficits were apparent before the full expression of psychotic illness. Cognitive performance on more complex tasks requiring rapid registration and efficient recall may be compromised before development of first-episode psychosis. Further experimental tasks that challenge these cognitive domains are required to clarify the predictive value of these results.
FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline <i>BRCA</i>-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy
Authors: Geoffrey Kim, Gwynn Ison, Amy E. McKee, Hui Zhang, Shenghui Tang, Thomas Gwise, Rajeshwari Sridhara, Eunice Lee, Abraham Tzou, Reena Philip, Haw-Jyh Chiu, Tiffany K. Ricks, Todd Palmby, Anne Marie Russell, Gaetan Ladouceur, Elimika Pfuma, Hongshan Li, Liang Zhao, Qi Liu, Rajesh Venugopal, Amna Ibrahim, Richard Pazdur
Journal: Clinical Cancer Research (2015)

On December 19, 2014, the FDA approved olaparib capsules (Lynparza; AstraZeneca) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) was approved concurrently. An international multicenter, single-arm trial enrolled 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy. Patients received olaparib at a dose of 400 mg by mouth twice daily until disease progression or unacceptable toxicity. The objective response rate (ORR) was 34% with median response duration of 7.9 months in this cohort. The most common adverse reactions (≥20%) in patients treated with olaparib were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/upper respiratory infection, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Myelodysplatic syndrome and/or acute myeloid leukemia occurred in 2% of the patients enrolled on this trial.