tbuckley/cabot-search huggingface dataset:
TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation
Authors: Mohammad Tauseef, Nebojsa Knezevic, Koteswara R. Chava, Monica Smith, Sukriti Sukriti, Nicholas Gianaris, Alexander G. Obukhov, Stephen M. Vogel, Dean E. Schraufnagel, Alexander Dietrich, Lutz Birnbaumer, Asrar B. Malik, Dolly Mehta
Journal: The Journal of Experimental Medicine (2012)

Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca2+ entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca2+ signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca2+ entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca2+ entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca2+ entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R–associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca2+ entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.
Docetaxel, Cisplatin, and Trastuzumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced Breast Cancer
Authors: Judith Hurley, Philomena Doliny, Isildinha Reis, Orlando Silva, Carmen Gomez-Fernandez, Pedro Velez, Giovanni Pauletti, Jodeen E. Powell, Mark D. Pegram, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2006)

To evaluate the efficacy and safety of docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2 (HER2) -positive, locally advanced breast cancer (LABC).Forty-eight patients with immunohistochemistry-confirmed HER2-positive LABC or inflammatory breast cancer received 12 weeks of docetaxel, cisplatin, and trastuzumab with filgrastim, followed by surgery, adjuvant doxorubicin and cyclophosphamide, and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast.Baseline mean tumor size was 9.2 cm (range, 4 to 32 cm). pCR occurred in breast in 11 patients (23%; 95% CI, 12% to 37%) and breast and axilla in eight patients (17%; 95% CI, 8% to 30%). pCR rates in breast (HER2 positive, seven of 30 patients, 23% v HER2 negative, four of 18 patients, 22%; P > .05) and breast and axilla (four of 30 patients, 13% v four of 18 patients, 22%, respectively; P > .05) were similar regardless of HER2 status by fluorescence in situ hybridization (FISH). At a median follow-up time of 43 months, 4-year progression-free survival (PFS) rate was 81% (95% CI, 64% to 90%); overall survival (OS) rate was 86% (95% CI, 71% to 94%). In patients with pCR in breast and axilla, PFS and OS rates were 100% (95% CI, inestimable). In patients without pCR, PFS rate was 76% (95% CI, 57% to 88%; P = .15, log-rank test), and OS rate was 83% (95% CI, 66% to 92%; P = .21). Survival rates were similar regardless of FISH status. There were only two grade 4 adverse events.Twelve weeks of docetaxel, cisplatin, and trastuzumab is clinically active and leads to excellent survival in patients with large, HER2-positive tumors.
Neuropeptide Y and ATP Interact to Control Renovascular Resistance in the Rat
Authors: VITUS OBERHAUSER, OLIVER VONEND, LARS CHRISTIAN RUMP
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Neuropeptide Y (NPY) and ATP are cotransmitters of norepinephrine (NE). Modulation of ATP-mediated purinergic neurotransmission by NPY was investigated in rat perfused kidney. β,γ-Methylene-L-ATP (β,γ-mATP; 1.0 to 1.5 μM, n = 8), NE (0.1 μM, n = 8), and NPY (0.1 μM, n = 14) increased perfusion pressure by maximally 12 ± 1, 17 ± 2, and 9 ± 1 mmHg, respectively. In the presence of NPY, responses to ATP and NE were dramatically enhanced. Renal nerve stimulation in the presence of the α-adrenoceptor antagonist phentolamine (1 μM) induced pressor responses of 54 ± 5 mmHg ( n = 6). α-Blockade-resistant responses were abolished by the P2-purinoceptor blocker suramin (300 μM) and thus mediated by ATP. Purinergic responses were also reduced significantly (50%) by the NPY-Y1 receptor blocker BIBP 3226 (1 μM). NPY (0.1 μM) potentiated purinergic pressor responses and enhanced ATP release from 0.7 ± 0.2 to 4.1 ± 0.9 pmol ( n = 4) associated with a significant increase of soluble ATPase activity. All NPY effects were prevented by BIBP 3226. Pressor responses to renal nerve stimulation delivered at short time intervals, mimicking enhanced sympathetic drive to the kidney, were not constant but showed a progressive rise, which was prevented by BIBP 3226. In this study, it is suggested that purinergic vasoconstriction in rat kidney depends on concomitantly released NPY. NPY by itself is only a weak vasoconstrictor but acts as a modulator of renal vascular resistance by enhancing the effects of its sympathetic cotransmitters, especially during sympathetic overactivity.
Targeted Expression of Major Histocompatibility Complex (MHC) Class II Molecules Demonstrates that Dendritic Cells Can Induce Negative but Not Positive Selection of Thymocytes In Vivo
Authors: Thomas Brocker, Mireille Riedinger, Klaus Karjalainen
Journal: The Journal of Experimental Medicine (1997)

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ “interdigitating cells” in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, if only DC expressed I-E in a class II–deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.
A contemporary survival analysis of individuals with cystic fibrosis: a cohort study
Authors: Anne L. Stephenson, Melissa Tom, Yves Berthiaume, Lianne G. Singer, Shawn D. Aaron, G.A. Whitmore, Sanja Stanojevic
Journal: European Respiratory Journal (2014)

Previously established predictors of survival may no longer apply in the current era of cystic fibrosis (CF) care. Our objective was to identify risk factors associated with survival in a contemporary CF population. We used the Canadian CF Registry, a population-based cohort, to calculate median age of survival and summarise patient characteristics from 1990 to 2012. Clinical, demographic and geographical factors, and survival were estimated for a contemporary cohort (2000–2012) using Cox proportional hazards models. There were 5787 individuals in the registry between 1990 and 2012. Median survival age increased from 31.9 years (95% CI 28.3–35.2 years) in 1990 to 49.7 years (95% CI 46.1–52.2 years) in the most current 5-year window ending in 2012. Median forced expiratory volume in 1 s improved (p=0.04) and fewer subjects were malnourished (p&lt;0.001) over time. Malnourished patients (hazard ratio (HR) 2.1, 95% CI 1.6–2.8), those with multiple exacerbations (HR 4.5, 95% CI 3.2–6.4) and women with CF-related diabetes (HR 1.8, 95% CI 1.2–2.7) were at increased risk of death. Life expectancy in Canadians with CF is increasing. Modifiable risk factors such as malnutrition and pulmonary exacerbations are associated with an increased risk of death. The sex gap in CF survival may be explained by an increased hazard for death in women with CF-related diabetes.
Disease-Modifying Mutations in Familial Hypertrophic Cardiomyopathy
Authors: Denise Hilfiker-Kleiner, Ralph Knöll
Journal: Circulation (2008)

C ardiomyopathies are primary disorders of cardiac muscle associated with abnormalities of cardiac wall thickness, chamber size, contraction, relaxation, conduction, and rhythm.They are a major cause of morbidity and mortality at all ages and, like acquired forms of cardiovascular disease, frequently progress into heart failure. 1 In contrast to dilated cardiomyopathy (DCM), which is characterized by left or biventricular dilation in association with depressed myocardial contractility, 1 familial hypertrophic cardiomyopathy (FHC) is characterized by increased cardiac mass with myocyte and myofibrillar disarray.The disease is associated with electrical instability (ie, atrial and ventricular arrhythmias), which makes it the leading cause of death in young athletes.There is marked diversity in the morphological features and clinical manifestations of both DCM and FHC.
Glomerular Expression of CD80 and CD86 Is Required for Leukocyte Accumulation and Injury in Crescentic Glomerulonephritis
Authors: Dragana Odobasic, A. Richard Kitching, Timothy J. Semple, Jennifer R. Timoshanko, Peter G. Tipping, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2005)

The participation of renal expression of CD80 and CD86 in the immunopathogenesis of crescentic Th1-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) has not been assessed. Immunohistochemical staining demonstrated prominent upregulation of both molecules in glomeruli of mice with anti-GBM GN, suggesting a potential role for the local expression of CD80 and CD86 in nephritogenic effector T cell responses. For testing this hypothesis, control or inhibitory anti-CD80 and/or anti-CD86 mAb were administered to mice during the effector phase of the disease but after the establishment of a systemic immune response. Anti-CD80 or anti-CD86 mAb treatment had no effect on the development of GN or infiltration of leukocytes into glomeruli; however, administration of anti-CD80/86 mAb attenuated glomerular accumulation of CD4+ T cells and macrophages, crescent formation, and proteinuria, correlating with reduced antigen-specific skin delayed-type hypersensitivity. Attenuated glomerular infiltration of leukocytes in mice that were treated with anti-CD80/86 mAb was associated with decreased intraglomerular expression of adhesion molecules P-selectin and intercellular adhesion molecule-1, as well as attenuated renal mRNA levels of proinflammatory cytokines IFN-gamma and migration inhibitory factor, without reducing chemokine and chemokine receptor expression in the kidney or intraglomerular apoptosis and proliferation. The systemic Th1/Th2 balance (assessed by splenocyte production of IFN-gamma and IL-4 and circulating levels of IgG1 and IgG2a) was not affected by the inhibition of CD80 and CD86. These studies show that CD80 and CD86 are expressed in glomeruli of mice with crescentic anti-GBM GN, in which they play a critical role in facilitating accumulation of Th1 effectors and macrophages, thus exacerbating renal injury.
Synthetic lethality: a framework for the development of wiser cancer therapeutics
Authors: William G Kaelin
Journal: Genome Medicine (2009)

The challenge in medical oncology has always been to identify compounds that will kill, or at least tame, cancer cells while leaving normal cells unscathed. Most chemotherapeutic agents in use today were selected primarily for their ability to kill rapidly dividing cancer cells grown in cell culture and in mice, with their selectivity determined empirically during subsequent animal and human testing. Unfortunately, most of the drugs developed in this way have relatively low therapeutic indices (low toxic dose relative to the therapeutic dose). Recent advances in genomics are leading to a more complete picture of the range of mutations, both driver and passenger, present in human cancers. Synthetic lethality provides a conceptual framework for using this information to arrive at drugs that will preferentially kill cancer cells relative to normal cells. It also provides a possible way to tackle 'undruggable' targets. Two genes are synthetically lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes leads to death. If one is a cancer-relevant gene, the task is to discover its synthetic lethal interactors, because targeting these would theoretically kill cancer cells mutant in the cancer-relevant gene while sparing cells with a normal copy of that gene. All cancer drugs in use today, including conventional cytotoxic agents and newer 'targeted' agents, target molecules that are present in both normal cells and cancer cells. Their therapeutic indices almost certainly relate to synthetic lethal interactions, even if those interactions are often poorly understood. Recent technical advances enable unbiased screens for synthetic lethal interactors to be undertaken in human cancer cells. These approaches will hopefully facilitate the discovery of safer, more efficacious anticancer drugs that exploit vulnerabilities that are unique to cancer cells by virtue of the mutations they have accrued during tumor progression.
Commentaries on this month's Cardiovascular Controversy: the merits and demerits of animal experimentation From J M Downey
Authors: J. M Downey
Journal: Cardiovascular Research (1994)

Journal Article Commentaries on this month's Cardiovascular Controversy: the merits and demerits of animal experimentation From J M Downey Get access James M Downey James M Downey Department of Physiology, University of South Alabama, Mobile, Alabama, USA. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 7, July 1994, Pages 1107–1108, https://doi.org/10.1093/cvr/28.7.1107b Published: 01 July 1994
Protein Kinase Cβ Inhibition Attenuates Osteopontin Expression, Macrophage Recruitment, and Tubulointerstitial Injury in Advanced Experimental Diabetic Nephropathy
Authors: Darren J. Kelly, Anna Chanty, Renae M. Gow, Yuan Zhang, Richard E. Gilbert
Journal: Journal of the American Society of Nephrology (2005)

Tubulointerstitial macrophage accumulation is an important marker of prognosis that correlates closely with declining renal function in a range of human and experimental diseases, including diabetic nephropathy. These inflammatory cells are rich in the profibrotic growth factor TGF-beta such that their presence in areas of injury is frequently associated with tissue fibrosis. The migration of macrophages occurs in response to the site-specific production of chemokines, with osteopontin closely associated with their trafficking into the tubulointerstitium of the kidney. Although cell culture studies indicate that protein kinase C (PKC) mediates the expression of osteopontin, its role in the in vivo setting is unknown. Accordingly, Ren-2 control and diabetic rats that were treated with or without the specific PKC-beta isoform inhibitor ruboxistaurin (10 mg/kg per d) were examined. After 12 wk, diabetic rats showed increases in osteopontin expression in tubular epithelial cells of the cortex in association with macrophage infiltration, interstitial fibrosis, and activity of TGF-beta as indicated by the expression of its receptor activated protein phospho-Smad2 (P < 0.05 for all parameters). Ruboxistaurin treatment significantly attenuated these parameters (P < 0.05) in diabetic rats without affecting either BP or glycemic control. These findings suggest that osteopontin and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy and that inhibition of osteopontin expression may be one of the mechanisms by which inhibition of the beta-isoform of PKC confers a renoprotective effect.
Special Issue: Significance of Tissue Chromaffin Cells and Mast Cells in Man
Authors: JOHN H. PHILLIPS, GEORGE E. BURCH, RICHARD G. HIBBS
Journal: Circulation Research (1960)

Tissue mast cells have been a source of great curiosity since their conclusive description by Ehrlich over 80 years ago. They have been implicated in a vast majority of connective tissue reactions both of physiologic and pathologic nature. In some species at least, mast cells have been implicated in the production, storage and release of potent cardiovascular substances including heparin, serotonin and histamine. The present report is directed particularly toward man. Evidence is presented suggesting that human tissue cells previously lumped into one large group on the basis of granular metachromasia and termed tissue mast cells, represent at least two morphologically distinct cellular types. Difference in function of these cells may be great. There is evidence that one type may be a local tissue source for epinephrine, norepinephrine, or both. It is suggested that mast cells as a whole may represent a spectrum of cell types having numerous differences in ultrastructure and function. It is believed that their continued study in various physiologic and pathologic states should prove fruitful.
Mutations of the Igβ gene cause agammaglobulinemia in man
Authors: Simona Ferrari, Vassilios Lougaris, Stefano Caraffi, Roberta Zuntini, Jianying Yang, Annarosa Soresina, Antonella Meini, Giantonio Cazzola, Cesare Rossi, Michael Reth, Alessandro Plebani
Journal: The Journal of Experimental Medicine (2007)

Agammaglobulinemia is a rare primary immunodeficiency characterized by an early block of B cell development in the bone marrow, resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. So far, mutations in Btk, μ heavy chain, surrogate light chain, Igα, and B cell linker have been found in 85–90% of patients with agammaglobulinemia. We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igβ, which is a transmembrane protein that associates with Igα as part of the preBCR complex. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igβ is no longer able to associate with Igα, and that assembly of the BCR complex on the cell surface is abrogated. The essential role of Igβ for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition. These results indicate that mutations in Igβ can cause agammaglobulinemia in man.
Granulomatous Pneumocystis carinii pneumonia in patients with malignancy
Authors: A Y P Bondoc
Journal: Thorax (2002)

Background: A review was undertaken of the clinical features and results of diagnostic tests in non-HIV infected patients who developed granulomatous <i>Pneumocystis carinii</i> pneumonia (PCP). Methods: A retrospective review was performed of the charts and radiographs of patients with a granulomatous reaction to <i>P carinii</i> identified from computerised pathology records at Memorial Sloan Kettering Cancer Center, a university affiliated tertiary care hospital. Results: Three cases were identified; the incidence of granulomatous PCP was 3%. All patients had risk factors for PCP and had received high dose corticosteroids which had been stopped. Two patients had received chemotherapy. Presentation was insidious with only mild symptoms; only one patient had fever. Chest radiographs showed a reticulonodular pattern. Bronchoscopy was negative for PCP in all cases and open lung biopsy was necessary. Conclusion: A granulomatous pathological reaction to PCP occurs rarely in patients with malignancy. In these cases the clinical presentation may be atypical and bronchoscopy can be non-diagnostic.
The Use of Soframycin (Framycetin Sulphate) for Intestinal Sterilization
Authors: N. E. Stidolph, J. M. Alston
Journal: Gut (1960)

From its known properties "soframycin" appears to be valuable for intestinal antisepsis since it has a broad spectrum. The intestinal bacteria are sensitive to it, it acts rapidly, is poorly absorbed from the gastrointestinal tract, and is well tolerated by mouth.
Tuberculin skin testing in uveitis patients and treatment of presumed intraocular tuberculosis in japan1 1The authors have no proprietary interests in the products or devices mentioned herein.
Authors: Yoshihiro Morimura, Annabelle A Okada, Sumie Kawahara, Yuko Miyamoto, Shin Kawai, Akito Hirakata, Tetsuo Hida
Journal: Ophthalmology (2002)
Diabetes Mellitus, Preexisting Coronary Heart Disease, and the Risk of Subsequent Coronary Heart Disease Events in Patients Infected With Human Immunodeficiency Virus
Authors: Signe W. Worm, Stephane De Wit, Rainer Weber, Caroline A. Sabin, Peter Reiss, Wafaa El-Sadr, Antonella D'Arminio Monforte, Ole Kirk, Eric Fontas, Francois Dabis, Matthew G. Law, Jens D. Lundgren, Nina Friis-Møller
Journal: Circulation (2009)

Although guidelines in individuals not infected with the human immunodeficiency virus (HIV) consider diabetes mellitus (DM) to be a coronary heart disease (CHD) equivalent, there is little information on its association with CHD in those infected with HIV. We investigated the impact of DM and preexisting CHD on the development of a new CHD episode among 33,347 HIV-infected individuals in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study).Over 159,971 person-years, 698 CHD events occurred. After adjustment for gender, age, cohort, HIV transmission, ethnicity, family history of CHD, smoking, and calendar year, the rate of a CHD episode was 7.52 times higher (Poisson regression, 95% CI 6.02 to 9.39, P=0.0001) in those with preexisting CHD than in those without preexisting CHD, but it was only 2.41 times higher (95% CI 1.91 to 3.05, P=0.0001) in those with preexisting DM compared with those without DM. No statistical interactions were apparent between either diagnosis and sex; although older people with DM had an increased CHD rate compared with younger people, older people with preexisting CHD had a lower event rate. A statistically significant interaction between preexisting DM and CHD (P=0.003) suggested that the CHD rate in those with preexisting CHD and DM is lower than expected on the basis of the main effects alone.DM and preexisting CHD are both important risk factors for CHD events in HIV-infected individuals. There is a need for targeted interventions to reduce the risk of CHD in both high-risk groups of HIV-infected individuals.