tbuckley/cabot-search huggingface dataset:
Effect of chronic AT1 receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters
Authors: I Dixon
Journal: Cardiovascular Research (2000)

Objective: As the pharmacological suppression of angiotensin has been associated with cardioprotective effects in cardiomyopathy, our primary aim was to determine whether the expression of Smad protein components of the cardiac TGF-β signaling cascade is modulated by chronic AT1 receptor blockade. Furthermore, we examined the relationship between cardiac Smad protein expression and altered collagen turnover in the cardiomyopathic heart. Methods: Male UM-X7.1 cardiomyopathic (CMP) Syrian hamsters at early (65 days) and late (200 days) stages of cardiomyopathy were subjected to 4 week losartan (15 mg/kg/day) treatment. Expression of left ventricular (LV) receptor-activated (Smad 2) and common-mediator (Smad 4) Smads from control (F1-β strain) hamsters, non-treated cardiomyopathic (CMP), and losartan-treated CMP animals was assessed. Collagen turnover, including fibrillar collagen synthesis/accretion and cardiac MMP activity was assessed. Results: Elevated mRNA abundance of fibrillar collagens and ANF were present in cardiomyopathic hearts and these trends were normalized in the early stage losartan-treated group. 4-Hydroxyproline and zymographic assays confirmed fibrosis and elevated MMP-1 and -2 activities in CMP hearts. Losartan treatment was associated with a modest reduction of cardiac 4-hydroxyproline concentration, and a significant reduction of both MMP-1 and MMP-2 activities. While TGF-β1 mRNAs were elevated in both CMP groups vs. controls, total TGF-β protein content was not different in CMP vs. controls. In LV preparations containing nuclear extract, elevated Smad 2 and Smad 4 protein expression was noted in cardiomyopathic hearts vs. controls. Losartan treatment of late-stage CMP hamsters was associated with a significant reduction in Smad 2 and a modest reduction of Smad 4 protein expression vs. untreated CMP samples. Conclusions: Altered cardiac Smad expression, present in both early and late stage cardiomyopathy, is positively correlated with the occurrence of cardiac fibrosis and elevated collagen turnover in failing CMP hearts. Four week AT1 blockade is associated with normalized expression of cardiac Smad 2 proteins, and these changes occur in parallel with some aspects of collagen turnover in failing cardiomyopathic hearts.
Genetic predisposition to sarcoidosis: another brick in the wall: Table 1–
Authors: Paolo Spagnolo, David A. Schwartz
Journal: European Respiratory Journal (2013)

The belief that a genetic susceptibility to the development of sarcoidosis exists is supported by several lines of evidence: 1) monozygotic twins are more often concordant for the disease than dizygotic twins; 2) sarcoidosis patients are more likely than healthy subjects to report a sibling or parent affected with the disease; 3) prevalence, incidence and severity of sarcoidosis vary widely amongst different races [1–4]. According to our current understanding of the disease pathophysiology, sarcoidosis is not due to defects in a single major gene or chemical pathway; instead, it is a complex disease that likely results from multiple genetic and environmental factors working together, each contributing a relatively small effect and few, if any, being absolutely required for the disease to occur. Genetics is also likely to contribute to the wide variety of clinical presentations and phenotypes observed in sarcoidosis. In this regard, some believe that sarcoidosis represents a family of diseases (sarcoidoses), including, among others: Lofgren syndrome, which is defined as the acute onset of fever, erythema nodosum, bilateral hilar lymphadenopathy and polyarthralgia; non-resolving/progressive lung disease; and granulomatous uveitis, each with potentially distinct genetic associations [5]. Berylliosis could also be considered as a subset of the broad grouping “sarcoidosis”.

Traditionally, genetic studies have used a “candidate gene case–control” approach, particularly in the context of rare diseases, like sarcoidosis, because of the difficulties in recruiting large numbers of pedigrees (linkage study) or even larger numbers of well phenotyped subjects (genome-wide association study; GWAS). In candidate gene case–control studies, the distribution of common genetic variations (single nucleotide polymorphisms; SNPs) in the gene(s) of interest is compared between unrelated, affected individuals and matched healthy controls. This hypothesis-based methodology requires understanding of the disease pathophysiology, judicious selection of candidate genes based on their biological plausibility, and knowledge …
Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons
Authors: Takashige Kuwabara, Kiyoshi Mori, Masashi Mukoyama, Masato Kasahara, Hideki Yokoi, Yoko Saito, Tetsuro Yoshioka, Yoshihisa Ogawa, Hirotaka Imamaki, Toru Kusakabe, Ken Ebihara, Mitsugu Omata, Noriko Satoh, Akira Sugawara, Jonathan Barasch, Kazuwa Nakao
Journal: Kidney International (2009)
S127 Influenza A and Poly(I:C) Induce α Vβ6-Integrin-Mediated TGFβ Activity in Human Epithelial Cells Via Stimulation of TLR3
Authors: L Jolly, A Stavrou, S Violette, P Weinreb, T Hussell, G Jenkins
Journal: Thorax (2012)

People with chronic lung disease are more susceptible to influenza infection which may lead to exacerbation of pre-existing conditions such as fibrosis. Transforming growth factor-β (TGFβ) is a profibrotic cytokine, but its role during influenza infection remains unclear. Toll-like-receptor 3 is located on the endosomal membrane and binds dsRNA, an intermediate product from replicating ssRNAviruses such as influenza. TLR3 activation has been shown to increase RhoA activity, and we have previously shown that RhoA is a key intermediary inactivation of TGFβ by the αVβ6-integrin. Therefore, we hypothesised that influenza infection could stimulate TLR3 leading to activation of latent TGFβ via this integrin in epithelial cells. Immortalised human bronchial epithelial cells (iHBECs) were used in all experiments. To determine whether influenza virus (A/PR/8/34 H1N1), or poly (I:C) (20µg/ml) were able to activate TGFβ the following TGFβ activation assays were used; detection of phospho-smad2/3 in nuclear extracts of cell lysates by ELISA; analysis of TGFβ activity in cells transiently transfected with a TGFβ-sensitive reporterconstruct; and a co-culture of iHBECS with a TGFβ reporter cell line (TMLCs). To confirm the involvement of TLR3, cells were dual transfected with a TGFβ-sensitive reporter and a dominant negative TLR3 construct designed to prevent TLR3 signalling. The role of the RhoA-ROCK pathway, and αVβ6-integrin were investigated using the ROCK inhibitor H1152, and the αVβ6-integrin blocking antibody 6.3G9, respectively. H1N1 infection and poly(I:C) caused an increase in luciferase in iHBECs transiently transfected with a TGFβ reporter construct. Similarly, both H1N1 and poly(I:C) caused an increase in nuclear phospho-smad2/3 which could be blocked by 6.3G9 peaking at 4h. Both agents caused an increase in TGFβ as measured by a co-culture assay and this could be blocked by H1152 and 6.3G9 suggesting the involvement of ROCK, αVβ6-integrin and the requirement for cell-to-cell contact. Finally, arole for TLR3 in this process was confirmed in cells transfected with a dnTLR3 construct which lost the ability to activate TGFβ in response to poly(I:C) orH1N1. In conclusion, these data show that both influenza A and poly (I:C) lead to increased TGFβ activity in iHBECs. This supports the hypothesis that influenza A infection activates TGFβ via TLR3 and the αVβ6 integrin. These data suggest anovel mechanism by which influenza infection of epithelial cells may promoteairway and lung fibrosis.
HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis
Authors: Zachary C. Hartman, Xiao-Yi Yang, Oliver Glass, Gangjun Lei, Takuya Osada, Sandeep S. Dave, Michael A. Morse, Timothy M. Clay, Herbert K. Lyerly
Journal: Cancer Research (2011)

Abstract HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2–IL-6–Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2–IL-6–STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers. Cancer Res; 71(13); 4380–91. ©2011 AACR.
Taking the sting out of the anthrax vaccine
Authors: Laurie Goodman
Journal: Journal of Clinical Investigation (2004)

Staff Sergeant Michael Murphy, of the Boone, Iowa, National Guard Reserve, is ready to do his duty when it comes time for members of his unit to get the next of six shots given over an 18-month period for anthrax vaccination. Although he is not entirely happy about it, he told the JCI, “I really don’t have another choice other than get out, and I’m not prepared to do that.” He said he simply hopes he doesn’t have another adverse reaction. Soon after his third shot, Murphy suffered leg cramps caused by blood clots. “We can’t really pinpoint the real reason I came down with this,” he noted, “other than it’s just a coincidence that I happened to get the shots and then came down with this. But I think the military, or whoever is building this vaccination, should follow up a little more with the people who had issues with it — to see if it did in fact have a reason for it, or was a problem at all, or why it happened.”
Loss of <b> <i>WWOX</i> </b> Expression in Gastric Carcinoma
Authors: Rami I. Aqeilan, Tamotsu Kuroki, Yuri Pekarsky, Omar Albagha, Francesco Trapasso, Raffaele Baffa, Kay Huebner, Pamela Edmonds, Carlo M. Croce
Journal: Clinical Cancer Research (2004)

Abstract Purpose: WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3–24.1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox. Experimental Design: Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer. A total of 81 primary gastric adenocarcinoma were analyzed. Results: Loss of heterozygosity was observed in 31% of the cases and loss of Wwox protein expression was found in 65% of gastric adenocarcinoma primary specimens and 33% of gastric cancer cell lines. In addition, we found a high correlation between Wwox and Fhit protein expression. Conclusions: Our results indicate that alterations of the WWOX gene may be involved quite frequently in gastric tumorigenesis. Our data could be used in future studies to develop diagnostic and targeted therapy of stomach cancer.
The Sequential Integration of Pharmacotherapy and Psychotherapy in the Treatment of Major Depressive Disorder: A Meta-Analysis of the Sequential Model and a Critical Review of the Literature
Authors: Jenny Guidi, Elena Tomba, Giovanni A. Fava
Journal: American Journal of Psychiatry (2015)

A number of randomized controlled trials in major depressive disorder have employed a sequential model, which consists of the use of pharmacotherapy in the acute phase and of psychotherapy in its residual phase. The aim of this review was to provide an updated meta-analysis of the efficacy of this approach in reducing the risk of relapse in major depressive disorder and to place these findings in the larger context of treatment selection.Keyword searches were conducted in MEDLINE, EMBASE, PsycINFO, and Cochrane Library from inception of each database through October 2014. Randomized controlled trials examining the efficacy of the administration of psychotherapy after successful response to acute-phase pharmacotherapy in the treatment of adults with major depressive disorder were considered for inclusion in the meta-analysis.Thirteen high-quality studies with 728 patients in a sequential treatment arm and 682 in a control treatment arm were included. All studies involved cognitive-behavioral therapy (CBT). The pooled risk ratio for relapse/recurrence was 0.781 (95% confidence interval [CI]=0.671-0.909; number needed to treat=8), according to the random-effects model, suggesting a relative advantage in preventing relapse/recurrence compared with control conditions. A significant effect of CBT during continuation of antidepressant drugs compared with antidepressants alone or treatment as usual (risk ratio: 0.811; 95% CI=0.685-0.961; number needed to treat=10) was found. Patients randomly assigned to CBT who had antidepressants tapered and discontinued were significantly less likely to experience relapse/recurrence compared with those assigned to either clinical management or continuation of antidepressant medication (risk ratio: 0.674; 95% CI=0.482-0.943; number needed to treat=5).The sequential integration of CBT and pharmacotherapy is a viable strategy for preventing relapse in major depressive disorder. The current indications for the application of psychotherapy in major depressive disorder are discussed, with special reference to its integration with pharmacotherapy.
FUNCTION OF MACROPHAGES IN ANTIGEN RECOGNITION BY GUINEA PIG T LYMPHOCYTES
Authors: Alan S. Rosenthal, Ethan M. Shevach
Journal: The Journal of Experimental Medicine (1973)

Antigen activation of DNA synthesis in immune thymus-derived lymphocytes of guinea pigs requires the cooperation of macrophages and lymphocytes. We have investigated the role of histocompatibility determinants in this macrophage-lymphocyte interaction using cells from inbred strain 2 and 13 guinea pigs. The data demonstrate that efficient presentation of macrophage-associated antigen to the lymphocyte requires identity between macrophage and lymphocyte at some portion of the major histocompatibility complex. The failure of allogeneic macrophages to effectively initiate immune lymphocyte proliferation was not the result of the presence of an inhibitor of blastogenesis released in mixtures of allogeneic cells, peculiarities of the antigen or lymphoid cells employed, nor differing kinetics of activation by allogeneic macrophages. In addition, data were presented that demonstrated that alloantisera inhibit lymphocyte DNA synthesis by functional interference with macrophage-lymphocyte interaction.
<i>HER2</i>-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor
Authors: Noa Efrat Ben-Baruch, Ron Bose, Shyam M Kavuri, Cynthia X Ma, Matthew J Ellis
Journal: Journal of the National Comprehensive Cancer Network (2015)

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non–small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted.
The London 2012 Summer Olympic Games: an analysis of usage of the Olympic Village ‘Polyclinic’ by competing athletes
Authors: Ivor S Vanhegan, Debbie Palmer-Green, Torbjørn Soligard, Kathrin Steffen, Philip O'Connor, Sarath Bethapudi, Richard Budgett, Fares S Haddad, Lars Engebretsen
Journal: British Journal of Sports Medicine (2013)

The London 2012 Summer Olympic Games involved 10 568 elite athletes representing 204 competing nations. To manage the varied healthcare needs of this diverse population, a Polyclinic was constructed in the athletes' village.This work aims to summarise the usage of the Polyclinic by competing athletes and the facilities available to them.All Polyclinic encounters were entered into a database from which data were exported for the time frame 28 July-12 August 2012, inclusive to cover the first to last full day of competition. Only Polyclinic data involving accredited athletes were analysed. All types of encounters were collected for analysis, not just sports-related issues.There were a total of 3220 encounters within the Polyclinic. This figure combines medical consultations, radiology/pathology investigations and prescriptions dispensed. Of these 3220 encounters, there were 2105 medical consultations; musculoskeletal comprised the greatest number (52%), followed by dental (30%) and ophthalmic (9%). The most frequently used imaging modality was MRI and diagnostic CT was used the least. After correction for multiple entries, Africa provided the largest proportion of athletes attending the Polyclinic (44%) and Europe the least (9%). Peak usage of all facilities was seen around days 9 and 10 of competition, reflecting the busiest time of the competition and the largest number of athletes in the village.The Polyclinic managed a wide variety of both sports-related and non-sports-related injuries and illnesses. The breadth of specialists available for consultation was appropriate as was the ease of access to them. The radiology department was able to satisfy the demand, as were the pharmacy and pathology services. We would recommend a similar structure of facilities and available expertise in one clinic when planning future mass participation sporting events.
Symptom Differences in Schizophrenia with Good and Poor Prognosis
Authors: MICHAEL S. McCABE, RICHARD C. FOWLER, REMI J. CADORET, GEORGE WINOKUR
Journal: American Journal of Psychiatry (1972)

The authors studied 28 good prognosis and 25 poor prognosis schizophrenics, differentiated on the basis of duration of illness and premorbid level of functioning. When compared for differences in symptomatology, the good prognosis group was found to be more likely to have diagnosable mania or depression, visual hallucinations, perceptual disorders, and confusion, and was less likely to have affective blunting and a combination of special types of auditory hallucinations and haptic hallucinations. Like previous reports, which have established that good prognosis schizophrenia is closely related to the affective disorders by family history, this study demonstrated a close clinical relationship between good prognosis schizophrenia and the affective disorders.
Simplicity: the ultimate sophistication
Authors: Philip Glasgow
Journal: British Journal of Sports Medicine (2014)

Efficient movement underpins all great sporting performances. When performed by an expert, complex movements can appear effortless, almost simple; as Leonardo Da Vinci stated, “simplicity is the ultimate sophistication”.

Dynamic control of movement is also central to safe sporting function and is dependent on the sophisticated integration of a range of factors including environment, nature of the task, feedforward input, afferent feedback as well as individual motor capabilities. The current issue of BJSM considers many of these features highlighting the complexity and multifactorial nature of running-related injuries as well as underlining the importance of return to sport decisions.

The interaction of internal and external factors in sports injury has been well described,1 and is highlighted in the current issue. The role of footwear (or absence thereof), foot shape, dynamic proximal control as well as the specific effects of loading are all evaluated and remind us as clinicians that we need …
Why Is Breast Cancer Chemoprevention Such a Hard Sell?
Authors: Judy Peres
Journal: JNCI Journal of the National Cancer Institute (2014)

Antiestrogen agents can dramatically reduce breast cancer incidence. The U.S. Food and Drug Administration has already approved two such drugs, tamoxifen and raloxifene, for primary prevention in high-risk women. Two others, exemestane and anastrozole, appear even more effective at risk reduction.
Sendai virus-specific, H-2-restricted cytotoxic T lymphocyte responses of nude mice grafted with allogeneic or semi-allogeneic thymus glands.
Authors: J P Lake, M E Andrew, C W Pierce, T J Braciale
Journal: The Journal of Experimental Medicine (1980)

The in vitro secondary cytotoxic T lymphocyte (CTL) response to Sendai virus-treated stimulator cells by primed spleen cells from thymus gland-grafted nude mice was examined. BALB/c (H-2d) nude mice grafted with allogeneic C57BL/10 (H-2b) thymus glands developed CTL responses directed exclusively to Sendai virus-infected H-2d target cells. (C57BL/6 X BALB/c)F1 nude mice grafted with thymus glands of either parent developed CTL responses preferentially against infected target cells expressing the MHC antigens present in the parental thymus graft, but also had detectable activity for infected target cells of the parental haplotype not expressed in the thymus. These results provide evidence against the concept that self recognition by MHC-restricted CTL is directed exclusively by the MCH type of the thymus.