tbuckley/cabot-search huggingface dataset:
B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans
Authors: Danielle T. Avery, Elissa K. Deenick, Cindy S. Ma, Santi Suryani, Nicholas Simpson, Gary Y. Chew, Tyani D. Chan, Umamainthan Palendira, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Sharon Choo, Karl E. Bleasel, Jane Peake, Cecile King, Martyn A. French, Dan Engelhard, Sami Al-Hajjar, Saleh Al-Muhsen, Klaus Magdorf, Joachim Roesler, Peter D. Arkwright, Pravin Hissaria, D. Sean Riminton, Melanie Wong, Robert Brink, David A. Fulcher, Jean-Laurent Casanova, Matthew C. Cook, Stuart G. Tangye
Journal: The Journal of Experimental Medicine (2010)

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Genetic Variation in the Renin–Angiotensin System and Abdominal Adiposity in Men: The Olivetti Prospective Heart Study
Authors: Pasquale Strazzullo, Roberto Iacone, Licia Iacoviello, Ornella Russo, Gianvincenzo Barba, Paola Russo, Andria D'Orazio, Antonio Barbato, Francesco Paolo Cappuccio, Eduardo Farinaro, Alfonso Siani
Journal: Annals of Internal Medicine (2003)

Background: The renin–angiotensin system is involved in adipocyte growth and differentiation and possibly in adipose tissue metabolism. Objective: To investigate the association of polymorphism in the angiotensin-converting enzyme (ACE) I/D gene, angiotensinogen M235T gene, and angiotensin II type 1 receptor A1166C gene with body mass index, body fat pattern, and obesity-associated hypertension. Design: Cross-sectional longitudinal study. Setting: The Olivetti factories in Marcianise and Pozzuoli, suburbs of Naples, Italy. Participants: 959 adult men, 25 to 75 years of age. Measurements: Renin–angiotensin system polymorphism, anthropometric indexes, blood pressure, and serum glucose and insulin levels. Results: No association was detected between angiotensinogen or angiotensin II type 1 receptor gene polymorphism and anthropometric indexes or blood pressure. For ACE I/D polymorphism, significant agegenotype interaction was detected on cross-sectional observation; the relation of body mass index, waist circumference, and diastolic blood pressure to age was significantly greater in persons with the DD genotype than in those with the ID or II genotype. Overweight and abdominal adiposity were more common in men with the DD genotype, particularly among older participants (51.1% vs. 36.5% and 33.1% vs. 22.0%, respectively). Odds ratios were 1.82 (95% CI, 1.16 to 2.87) for overweight and 1.76 (CI, 1.06 to 2.90) for abdominal adiposity. Among 314 untreated men first examined 20 years earlier, those with the DD genotype had greater age-adjusted weight gain (1.45 kg [CI, 0.12 to 2.78 kg]) and change in diastolic blood pressure (2.83 mm Hg [CI, 0.39 to 5.28 mm Hg]). The relative risk for overweight was 2.34 (CI, 1.32 to 4.15) among participants with the DD genotype versus those with the ID or II genotype. Conclusions: The ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity in men. DD homozygosity was associated with larger increases in body weight and blood pressure in aging persons, as well as with higher incidence of overweight.
Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study
Authors: M J K Blomley
Journal: Gut (2003)

<b>Background:</b> A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. <b>Aim:</b> To see if this index can also grade diffuse liver disease. <b>Patients:</b> Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child's A, seven Child's B, and eight Child's C). <b>Methods:</b> Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase &gt;10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. <b>Results:</b> Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child's A 21 (1) s, Child's B 16 (3) s, and Child's C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child's A 8 (1) s, Child's B 4 (4) s, and Child's C 3 (3) s. These differences were highly significant (p&lt;0.001, ANOVA comparison). A HVTT &lt;24 s and a CDT &lt;10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values &lt;10 s and 3/9 had HVTT &lt;24 s. <b>Conclusion:</b> This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.
Recent Advances in the Pharmacotherapy of Smoking
Authors: J R Hughes, M G Goldstein, R D Hurt, S Shiffman
Journal: JAMA (1999)

Since the 1996 publication of guidelines on smoking cessation from the Agency for Health Care Policy and Research and the American Psychiatric Association, several new treatments have become available, including nicotine nasal spray, nicotine inhaler, and bupropion hydrochloride. In addition, nicotine gum and patch have become available over-the-counter. This article reviews the published literature and US Food and Drug Administration and pharmaceutical company reports on these therapies. Based on this review, clinical logic, and experience, we conclude that pharmacotherapy should be made available to all smokers. All currently available therapies appear to be equally efficacious, approximately doubling the quit rate compared with placebo. Concomitant behavioral or supportive therapy increases quit rates and should be encouraged but not required. Combining patch with gum or patch with bupropion may increase the quit rate compared with any single treatment. Because patient characteristics predictive of success with a particular therapy are not yet known, the best treatment choice for an individual patient should be guided by the patient's past experience and preference and the product's adverse effect profile.
Abstract 1023: Transplantation Of Bone Marrow-derived Very Small Embryonic-like Stem Cells (VSELs) Improves Left Ventricular Function And Remodeling After Myocardial Infarction
Authors: Ewa K Zuba-Surma, Hisham Taher, Magdalena Kucia, Yiru Guo, Santosh K SanganalMath, Greg Hunt, Robert J Vincent, Buddhadeb Dawn, Mariusz Z Ratajczak, Roberto Bolli
Journal: Circulation (2007)

Adult bone marrow (BM) contains a rare population of pluripotent Sca-1+/Lin-/CD45- very small embryonic-like stem cells (VSELs) that differentiate into cardiomyocytes in vitro. The clinical usefuln...
BCL6 Represses Smad Signaling in Transforming Growth Factor-β Resistance
Authors: Degang Wang, Jianyin Long, Fangyan Dai, Min Liang, Xin-Hua Feng, Xia Lin
Journal: Cancer Research (2008)

Abstract Transforming growth factor-β (TGF-β) controls a wide spectrum of cellular processes. Deregulation of TGF-β signaling contributes to the pathogenesis of many diseases including cancer and autoimmune diseases. TGF-β signaling is generally mediated through intracellular signal transducers and transcription factors called Smads. Herein, we have identified the oncoprotein BCL6 as a transcriptional corepressor of tumor suppressor Smad4. BCL6 physically interacts with Smad3 and Smad4, disrupts the Smad-p300 interaction, and represses the transcriptional activity of Smad4. In accordance, B-cell lymphoma cells with a high expression level of BCL6 were found to be refractory to TGF-β antiproliferative response, whereas knockdown of BCL6 expression in B-cell lymphoma cells partially restores the TGF-β responses. This study provides strong evidence that overexpression of BCL6 contributes to TGF-β resistance in B-cell lymphoma. [Cancer Res 2008;68(3):783–9]
Depth of morphologic skin damage and viability after one, two, and three passes of a high-energy, short-pulse CO 2 laser (Tru-Pulse) in pig skin
Authors: Kathleen J. Smith, Henry G. Skelton, John S. Graham, Tracey A. Hamilton, Brennie E. Hackley, Charles G. Hurst
Journal: Journal of the American Academy of Dermatology (1997)
Coffee and Plasma Lipid Levels
Authors: Katrina Kokjohn
Journal: JAMA (1992)

<h3>To the Editor.</h3> —Fried et al<sup>1</sup>should be commended for their well-designed clinical trial. However, several questions remain to be clarified. A total cholesterol level "greater than the 90th percentile for age" and "morbid obesity" were both listed as exclusion criteria. What were the reference standards for these criteria? All subjects in the coffee-drinking groups were instructed to prepare 1260 mL of coffee daily. However, they drank only 720 mL or 360 mL of coffee depending on the group to which they were allocated. Why was such a large quantity prepared? Could the availability of more than 500 mL of unnecessary coffee lead to higher consumption than the study design required? The compliance check using a 24-hour urine specimen was clever and innovative. However, it would be useful to know how often these checks were made and if they were taken at uniform time points for all subjects. Furthermore,
Dynamic Reconfiguration of Hippocampal Interneuron Circuits during Spatial Learning
Authors: David Dupret, Joseph O’Neill, Jozsef Csicsvari
Journal: Neuron (2013)

SummaryIn the hippocampus, cell assemblies forming mnemonic representations of space are thought to arise as a result of changes in functional connections of pyramidal cells. We have found that CA1 interneuron circuits are also reconfigured during goal-oriented spatial learning through modification of inputs from pyramidal cells. As learning progressed, new pyramidal assemblies expressed in theta cycles alternated with previously established ones, and eventually overtook them. The firing patterns of interneurons developed a relationship to new, learning-related assemblies: some interneurons associated their activity with new pyramidal assemblies while some others dissociated from them. These firing associations were explained by changes in the weight of monosynaptic inputs received by interneurons from new pyramidal assemblies, as these predicted the associational changes. Spatial learning thus engages circuit modifications in the hippocampus that incorporate a redistribution of inhibitory activity that might assist in the segregation of competing pyramidal cell assembly patterns in space and time.Highlights•Interneuron firing reorganizes as pyramidal assemblies flicker during spatial learning•Interneurons form dynamic firing associations to newly established assemblies•Changes in pyramidal cell connections to interneurons explain firing associations•Pyramidal cell-interneuron coupling changes are activity dependent and map specific
ABNORMALITIES OF IN VITRO LYMPHOCYTE RESPONSES DURING RUBELLA VIRUS INFECTIONS
Authors: George B. Olson, Peter B. Dent, William E. Rawls, Mary Ann South, J. R. Montgomery, Joseph L. Melnick, Robert A. Good
Journal: The Journal of Experimental Medicine (1968)

In vitro rubella virus infections of lymphocytes from normal adult humans impaired their responsiveness to phytohemagglutinin (PHA) stimulations; a situation which seemed analogous to the PHA unresponsiveness of peripheral lymphocytes from babies with the congenital rubella syndrome. Such in vitro viral infection of normal cells also decreased the synthesis of normal nucleic acids and structural proteins, and abrogated the enhanced DNA synthesis induced by pokeweed and specific antigen stimulations. Furthermore, it was shown that live rubella virus, but not ultraviolet-irradiated virus, was necessary for the impaired mitogenic responses of normal leukocytes. These observations are interpreted to favor the view that the virus achieves its inhibitory effect on the action of mitogens by interference either directly or indirectly at an intracellular site. Such an action could reduce the functional potential of lymphocytes and impair their effectiveness as immunologically competent cells or as effectors in immunologic reactions.
Selective suppression of retroviral gp70-anti-gp70 immune complex formation by prostaglandin E1 in murine systemic lupus erythematosus.
Authors: S Izui, V E Kelley, P J McConahey, F J Dixon
Journal: The Journal of Experimental Medicine (1980)

The effect of pharmacologic quantities of prostaglandin E1 (PGE) was investigated in three strains of mice (NZB X NZW, MRL/1, and BXSB) that spontaneously develop lupus-like glomerulonephritis. PGE-treatment prolonged survival and retarded the glomerular deposition of immune complex (IC) and the development of glomerulonephritis in NZB X NZW and MRL/1 mice, but did not similarly protect BXSB mice. Changes in the responsive strains correlated well with reduced amounts of circulating gp70 complexed with anti-gp70 antibodies compared with untreated controls, although total concentrations of gp70 (free and complexed) detectable in sera were similar in both groups of mice. The results strongly suggest that: (a) PGE selectively suppressed the immune response to retroviral gp70, (b) PGe had little effect on the quantity or quality of anti-DNA antibodies but did reduce the deposition of anti-DNA containing IC in the kidneys, and (c) gp70 IC appear to play an important role in the pathogenesis of glomerulonephritis in murine systemic lupus erythematosus.
Osteonecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment
Authors: K Oinuma
Journal: Annals of the Rheumatic Diseases (2001)

To investigate the actual time of onset of osteonecrosis (ON) after high dose corticosteroid treatment in systemic lupus erythematosus (SLE).72 patients with active SLE, who received high dose corticosteroid for the first time, for the development of ON at hips and knees were monitored by magnetic resonance imaging for at least 12 months.ON lesions were detected in 32/72 patients (44%) between one and five months (3.1 months on average) after starting high dose corticosteroid treatment. No osteonecrotic lesion was newly detected from the sixth month of treatment until the end of the follow up period.The findings suggested that the actual time of onset of ON in SLE is within the first month of high dose corticosteroid treatment.
Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma
Authors: Aarif Y. Khakoo, Shibani Pati, Stasia A. Anderson, William Reid, Mohamed F. Elshal, Ilsa I. Rovira, Ahn T. Nguyen, Daniela Malide, Christian A. Combs, Gentzon Hall, Jianhu Zhang, Mark Raffeld, Terry B. Rogers, William Stetler-Stevenson, Joseph A. Frank, Marvin Reitz, Toren Finkel
Journal: The Journal of Experimental Medicine (2006)

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.
Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists
Authors: Edwin Bremer, Bram ten Cate, Douwe F. Samplonius, Nicole Mueller, Harald Wajant, Alja J. Stel, Martine Chamuleau, Arjan A. van de Loosdrecht, Julia Stieglmaier, Georg H. Fey, Wijnand Helfrich
Journal: Cancer Research (2008)

The clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity-dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFasL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non-Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells.
Splanchnic insulin metabolism in obesity. Influence of body fat distribution.
Authors: A N Peiris, R A Mueller, G A Smith, M F Struve, A H Kissebah
Journal: Journal of Clinical Investigation (1986)

The effects of obesity and body fat distribution on splanchnic insulin metabolism and the relationship to peripheral insulin sensitivity were assessed in 6 nonobese and 16 obese premenopausal women. When compared with the nonobese women, obese women had significantly greater prehepatic production and portal vein levels of insulin both basally and following glucose stimulation. This increase correlated with the degree of adiposity but not with waist-to-hip girth ratio (WHR). WHR, however, correlated inversely with the hepatic extraction fraction and directly with the posthepatic delivery of insulin. The latter correlated with the degree of peripheral insulinemia. The decline in hepatic insulin extraction with increasing WHR also correlated with the accompanying diminution in peripheral insulin sensitivity. Increasing adiposity is thus associated with insulin hypersecretion. The pronounced hyperinsulinemia of upper body fat localization, however, is due to an additional defect in hepatic insulin extraction. This defect is closely allied with the decline in peripheral insulin sensitivity.
Dual-Energy X-Ray Absorptiometry Study of Body Composition in Patients With Lipodystrophy
Authors: Cynthia M. Valerio, Amélio Godoy-Matos, Rodrigo O. Moreira, Lucia Carraro, Érika P. Guedes, Regina S. Moises, Patricia B. Mory, Luciana Lopes de Souza, Luis Augusto Russo, Ana Cláudia Melazzi
Journal: Diabetes Care (2007)

Lipodystrophies are acquired or inherited disorders characterized by selective or generalized loss of adipose tissue. Affected patients are predisposed to insulin resistance and metabolic complications of insulin resistance (1). Noticeably, patients with acquired or hereditary generalized forms are extremely insulin resistant (2,3). On the other hand, in partial forms the ample phenotypic spectrum determines clinical presentations and metabolic profiles of variable degrees (4). Among diagnostic resources for fat distribution evaluation, dual-energy X-ray absorptiometry (DEXA) has been utilized because of its accuracy, reproducibility, and good correlation with computerized tomography (5,6). The purpose of this study was to evaluate body composition with DEXA in patients with different types of lipodystrophy and to determine the correlation between densitometric, clinical, and metabolic features.

Five female patients with lipodystrophy phenotype had been studied, selected from an outpatient clinic. Three patients had diabetes (patients 1, 4, and 5). Laboratory evaluation was performed. Patients signed an informed consent, and the ethical committee of the institution approved this study. Whole-body DEXA scans were obtained at DENSSO laboratory with GE Lunar Prodigy Advance software, version 9.5, LNR 41569 model.

The relevant results are depicted in Table 1. Plasma leptin was markedly diminished, consistent with body fat mass. All patients exhibited severe hepatic steatosis at ultrasound study.

### Case reports

#### Patient 1.

Patient 1 was a 42 year-old woman who first noticed fat redistribution after her first pregnancy. She was diagnosed for hypertension and type …
The Alpha Cell in Diabetic Ketoacidosis
Authors: Bill Bartle
Journal: JAMA (1973)

To the Editor.—  In a recent EDITORIAL, Function of the Alpha Cell in Diabetic Ketoacidosis (224:1643, 1973), you mentioned the work of Unger et al 1 and Muller et al 2 that demonstrated the hyperglucagonemia of ketoacidosis. It would be interesting to see what effect a hypoglycemic sulphonylurea had on these elevated levels of glucagon, since Samols and coworkers 3,4 have shown that these agents directly suppress plasma glucagon values, although this has been disputed. Tolbutamide, or similar agents, if effective, could reduce the requirement of large doses of insulin.
Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma
Authors: Lu Dai, Jimena Trillo-Tinoco, Yueyu Cao, Karlie Bonstaff, Lisa Doyle, Luis Del Valle, Denise Whitby, Chris Parsons, Krzysztof Reiss, Jovanny Zabaleta, Zhiqiang Qin
Journal: Blood (2015)