tbuckley/cabot-search huggingface dataset:
Transcriptional control of HLA-A,B,C antigen in human placental cytotrophoblast isolated using trophoblast- and HLA-specific monoclonal antibodies and the fluorescence-activated cell sorter.
Authors: M Kawata, J R Parnes, L A Herzenberg
Journal: The Journal of Experimental Medicine (1984)

Human placental cell suspensions prepared by trypsin digestion were analyzed with several monoclonal antibodies on a multiparameter fluorescence-activated cell sorter (FACS). Five distinct cell populations were isolated on the basis of size and quantitative differences in the coordinate expression of cell surface antigens detected by monoclonal antibodies against an HLA-A,B,C monomorphic determinant (MB40.5) and against human trophoblasts (anti-Trop-2). By FACS analysis and after sorting we clearly identified the major cell population as cytotrophoblasts based on several independent criteria, including presence of trophoblast-specific surface antigens, Trop-1, and Trop-2; absence of all HLA class I, class II, and beta 2-microglobulin (beta 2m) antigens; absence of the pan-leucocyte and monocyte antigens, HLe1 and LeuM1, respectively; presence of Y-chromatin in a male placenta; presence of placental and not liver alkaline phosphatase; and a large, mononuclear morphology. These procedures provide a reproducible method for obtaining highly purified human cytotrophoblast populations for further studies. We measured by molecular hybridization (RNA or Northern blots) the HLA-A,B,C and beta 2m mRNA in total RNA extracted from sorted cytotrophoblasts. We find that normal human cytotrophoblasts have extremely small amounts of HLA-A,B,C mRNA: approximately 300 times less than that in the lymphoid cell line LCL-721 or normal lymphocytes. In contrast, they have approximately 11% the level of beta 2m mRNA present in LCL-721 cells. Thus, HLA-A,B,C antigen expression on human cytotrophoblasts is limited by the level of HLA heavy chain mRNA.
PWE-054 The management of cyclic vomiting syndrome: a systematic review of 1141 cases: Abstract PWE-054 Table 1
Authors: L Lee, L Abbott, B Mahlangu, S Moodie
Journal: Gut (2012)

<h3>Introduction</h3> Cyclic Vomiting syndrome (CVS) is characterised by recurrent attacks of intractable vomiting with no identifiable organic cause. It can take years before CVS is diagnosed, furthermore there have only been a handful of case studies looking at management strategies to reduce the duration/frequency or intensity of cyclic vomiting attacks. The objectives of this review were to identify associated clinical features that would help suggest a diagnosis of CVS and to review the literature to identify management strategies with the highest efficacy. <h3>Methods</h3> A literature search was performed using the databases MEDLINE via Ovid (1948 to October 2011) and EMBASE (1980 to October 2011). The search terms included "Cyclic" and "Vomiting". Data from adult-onset to paediatric-onset CVS were included. Data were extracted into a standardised form. <h3>Results</h3> The systematic search yielded 33 papers with 1141 cases of cyclic vomiting syndrome. All but one paper were retrospective studies. Both adult-onset and paediatric-onset CVS had a high association with headaches/migraines and psychiatric conditions such as anxiety/depression. Furthermore, in children travel sickness was noted in 28.3%. The mean duration and frequency of attacks were higher in adult-onset CVS compared to paediatric-CVS. Overall remission was achieved in 73.2% of cases. When tricyclic antidepressants were used, 75.5% of adult-onset CVS patients had a response (n=237) and 67.6% of paediatric onset-CVS patients (n=244). In adult-onset CVS, 37 patients had been treated with sumatriptan with a response rate of 56.8%. In paediatric-onset CVS, 91 patients had been treated with propranolol and amitriptyline resulting in a response rate of 86.8%. There were no studies focusing on the acute management of CVS. <h3>Conclusion</h3> CVS is an intractable illness with a major impact on patient9s quality of life. There is a long duration between symptom onset and diagnosis of the condition. There is a high association with headaches/migraines and anxiety/depression. Symptoms are more severe in adult-onset CVS. Tricyclic antidepressants have the most evidence and have high efficacy at reducing the frequency/duration or intensity of attacks. There is limited evidence on the acute management of CVS. <h3>Competing interests</h3> None declared.
Habit formation in Tourette Syndrome with associated obsessive-compulsive behavior: At the crossroads of neurobiological modelling
Authors: Aribert Rothenberger, Veit Roessner, Tobias Banaschewski
Journal: Behavioral and Brain Sciences (2006)

Tourette Syndrome (TS) and Obsessive-Compulsive Disorder (OCD) are highly associated and often it is difficult to differentiate their symptomatology. In TS, habit forming neuronal systems may form habits of their own – sometimes similar to ritualized behavior. However, whereas in OCD merely the “affect-loop” is touched, in TS the “sensorimotor-loop” plays the major role, although some overlap can be seen in the clinical spectrum between TS and OCD. The latter is mainly related to the “just-right” phenomenon which shows a clear developmental course. An analogous behavioral model for TS and OCD with reference to “just-right” is suggested.
Definition of microRNAs That Repress Expression of the Tumor Suppressor Gene <i>FOXO1</i> in Endometrial Cancer
Authors: Stephen S. Myatt, Jun Wang, Lara J. Monteiro, Mark Christian, Ka-Kei Ho, Luca Fusi, Roberto E. Dina, Jan J. Brosens, Sadaf Ghaem-Maghami, Eric W-F. Lam
Journal: Cancer Research (2009)

Endometrial cancer is the most common malignancy of the lower female reproductive tract. The tumor suppressor FOXO1 is downregulated in endometrial cancer compared with normal endometrium but the underlying mechanisms are not well understood. Using microRNA (miR) target prediction algorithms, we identified several miRs that potentially bind the 3'-untranslated region of FOXO1 transcripts. Expression profiling of normal and malignant endometrial samples by quantitative real-time PCR and Northern blot analysis revealed an inverse correlation between the levels of FOXO1 protein and the abundance of several of the in silico-predicted miRs, suggesting that loss of FOXO1 expression in endometrial cancer may be mediated by miRs. To determine the role of candidate miRs, we used the endometrial cancer cell lines HEC-1B and Ishikawa, which express FOXO1 at high and low levels, respectively. Expression of miR-9, miR-27, miR-96, miR-153, miR-182, miR-183, or miR-186, but not miR-29a, miR-128, miR-152, or miR-486 mimetics in HEC-1B cells was sufficient to significantly reduce the abundance of FOXO1. Conversely, FOXO1 expression was efficiently restored in the Ishikawa cell line upon simultaneous inhibition of miR-9, miR-27, miR-96, miR-153, miR-183, and miR-186. Moreover, induction of FOXO1 in Ishikawa cells by miR inhibitors was accompanied by G1 cell cycle arrest and cell death, and was attenuated by the small interfering RNA-mediated downregulation of FOXO1 expression. Our findings identify several miRs overexpressed in endometrial cancer that function in concert to repress FOXO1 expression. Further, aberrant miR expression results in deregulated cell cycle control and impaired apoptotic responses, and thus, may be central to endometrial tumorigenesis.
Screening Mammography — A Long Run for a Short Slide?
Authors: H. Gilbert Welch
Journal: New England Journal of Medicine (2010)

No screening test has ever been more carefully studied than screening mammography. In the past 50 years, more than 600,000 women have participated in 10 randomized trials, each involving approximately 10 years of follow-up. Given this extraordinary research effort, it is ironic that screening mammography continues to be one of the most contentious issues within the medical community.The juxtaposition of such a charged medical debate in the face of such an exhaustive scientific investigation is in itself instructive. For context, one trial involving fewer than 150 men who were followed for less than 2 years was sufficient to convince . . .
Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation
Authors: Matt J Barter, Wang Hui, Rachel L Lakey, John B Catterall, Tim E Cawston, David A Young
Journal: Annals of the Rheumatic Diseases (2010)

Objective To investigate if statins prevent cartilage degradation and the production of collagenases and gelatinases in bovine nasal and human articular cartilage after proinflammatory cytokine stimulation. Methods In a cartilage degradation model, the effects of several statins were assessed by measuring proteoglycan degradation and collagen degradation, while collagenolytic and gelatinolytic activity in culture supernatants were determined by collagen bioassay and gelatin zymography. The production of matrix metalloproteinases (MMPs) in cartilage and chondrocytes were analysed by real-time reverse transcriptase PCR and immunoassay. Cytokine-induced signalling pathway activation was studied by immunoblotting. Results Simvastatin and mevastatin significantly inhibited interleukin 1 (IL-1)+oncostatin M (OSM)-induced collagen degradation; this was accompanied with a marked decrease in collagenase and gelatinase activity from bovine nasal cartilage. The cholesterol pathway intermediate mevalonic acid reversed the simvastatin-mediated protection of cartilage degradation, and the expression and production of collagenase (MMP-1 and MMP-13) and gelatinase (MMP-2 and MMP-9). Statins also significantly decreased MMP-1 and MMP-13 expression in human articular cartilage and chondrocytes stimulated with IL-1+OSM, and blocked the activation of critical proinflammatory signalling pathways required for MMP expression. The loss of the isoprenoid intermediate geranylgeranyl pyrophosphate due to statin treatment accounted for the inhibition of MMP expression and signalling pathway activation. Conclusions This study shows, for the first time, that lipophilic statins are able to block cartilage collagen breakdown induced by proinflammatory cytokines, by downregulating key cartilage-degrading enzymes. This demonstrates a possible therapeutic role for statins in acting as anti-inflammatory agents and in protecting cartilage from damage in joint diseases.
Pulmonic regurgitation due to valvular tophi.
Authors: E I Curtiss, T R Miller, L S Shapiro
Journal: Circulation (1983)

Documented cardiac tophi are rare and have not previously been reported to cause clinically manifest valvular disease. A 31-year-old male with complex cyanotic congenital heart disease (Taussig-Bing anomaly) and secondary tophaceous gouty arthritis is described. Terminally, he presented with clinical evidence of a brain abscess and a new semilunar regurgitant murmur. Two-dimensional echocardiography suggested vegetative lesions as the cause of the murmur. The patient was treated for infective endocarditis. At autopsy, the cause of the semilunar regurgitant murmur was shown to be sterile tophi located along the line of pulmonary valvular coaptation. Tophaceous deposits were also present in the mitral valve.
An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells
Authors: Silvia Gregori, Patrizia Mangia, Rosa Bacchetta, Eleonora Tresoldi, Frank Kolbinger, Catia Traversari, Josè M. Carballido, Jan E. de Vries, Ulf Korthäuer, Maria-Grazia Roncarolo
Journal: The Journal of Experimental Medicine (2005)

The effects of a chimeric monoclonal antibody (chA6 mAb) that recognizes both the RO and RB isoforms of the transmembrane protein tyrosine phosphatase CD45 on human T cells were investigated. Chimeric A6 (chA6) mAb potently inhibited antigen-specific and polyclonal T cell responses. ChA6 mAb induced activation-independent apoptosis in CD4+CD45RO/RBhigh T cells but not in CD8+ T cells. In addition, CD4+ T cell lines specific for tetanus toxoid (TT) generated in the presence of chA6 mAb were anergic and suppressed the proliferation and interferon (IFN)-γ production by TT-specific effector T cells by an interleukin-10–dependent mechanism, indicating that these cells were equivalent to type 1 regulatory T cells. Similarly, CD8+ T cell lines specific for the influenza A matrix protein-derived peptide (MP.58-66) generated in the presence of chA6 mAb were anergic and suppressed IFN-γ production by MP.58-66–specific effector CD8+ T cells. Furthermore, chA6 mAb significantly prolonged human pancreatic islet allograft survival in nonobese diabetic/severe combined immunodeficiency mice injected with human peripheral blood lymphocytes (hu-PBL-NOD/SCID). Together, these results demonstrate that the chA6 mAb is a new immunomodulatory agent with multiple modes of action, including deletion of preexisting memory and recently activated T cells and induction of anergic CD4+ and CD8+ regulatory T cells.
Gemtuzumab Ozogamicin: Time to Resurrect?
Authors: Farhad Ravandi, Elihu H. Estey, Frederick R. Appelbaum, Francesco Lo-Coco, Charles A. Schiffer, Richard A. Larson, Alan K. Burnett, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2012)

On May 17, 2000, the US Food and Drug Administration (FDA) granted accelerated approval for the use of gemtuzumab ozogamicin (GO) in older patients (age ≥ 60 years) with acute myeloid leukemia (AML) in first relapse who were not considered candidates for standard cytotoxic chemotherapy.1 Approval for this novel anti-CD33 immunoconjugate was based on a phase II trial demonstrating a 30% response rate (including complete response [CR] and CR with incomplete platelet recovery)2 and was conditional on future demonstration of benefit in treatment of AML. Over the past 10 years, several phase II and III trials have addressed this issue.
An essential role for stromal interaction molecule 1 in neointima formation following arterial injury
Authors: Rui-Wei Guo, Hong Wang, Pan Gao, Mao-Quan Li, Chun-Yu Zeng, Yang Yu, Jian-Fei Chen, Ming-Bao Song, Yan-Kun Shi, Lan Huang
Journal: Cardiovascular Research (2008)

There is evidence to suggest that stromal interaction molecule 1 (STIM1) functions as a Ca2+ sensor on the endoplasmic reticulum, leading to transduction of signals to the plasma membrane and opening of store-operated Ca2+ channels (SOC). SOC have been detected in vascular smooth muscle cells (VSMCs) and are thought to have an essential role in the regulation of contraction and cell proliferation. We hypothesized that knockdown of STIM1 inhibits VSMC proliferation and suppresses neointimal hyperplasia.We examined the effect of the knockdown of STIM1 using a rat balloon injury model and cultured rat aortic VSMCs. Interestingly, knockdown of rat STIM1 by adenovirus delivery of small interfering RNA (siRNA) significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model at 14 days after injury. The re-expression of human STIM1 to smooth muscle reversed the effect of STIM1 knockdown on neointimal formation. Rat aortic VSMCs were used for the in vitro assays. Knockdown of endogenous STIM1 significantly inhibited proliferation and migration of VSMCs. Moreover, STIM1 knockdown induced cell-cycle arrest in G0/G1 and resulted in a marked decrease in SOC. Replenishment with recombinant human STIM1 reversed the effect of siRNA knockdown. These results suggest STIM1 has a critical role in neointimal formation in a rat model of vascular injury.STIM1 may represent a novel therapeutic target in the prevention of restenosis after vascular interventions.
High Blood Pressure Before and During Early Pregnancy Is Associated With an Increased Risk of Gestational Diabetes Mellitus
Authors: Monique M. Hedderson, Assiamira Ferrara
Journal: Diabetes Care (2008)

While women with prior gestational diabetes mellitus (GDM) are more likely to display features of the metabolic syndrome, including hypertension, in the years after delivery, it is unclear whether these components are also present before pregnancy. We examined the relationship between blood pressure (BP) measured before and during early pregnancy (<20 weeks) and the risk of GDM in a nested case-control study.Case (n = 381) and control (n = 942) subjects were selected from a cohort of women delivering between 1996 and 1998 and screened for GDM between 24 and 28 weeks' gestation. GDM was defined by the National Diabetes Data Group criteria. BP and covariates data were obtained by review of the medical records. Women were categorized according to BP levels recommended by the American Heart Association outside of pregnancy: <120/80 mmHg (normal), 120-139/80-89 mmHg (prehypertension), and >or=140 and/or >or=90 mmHg or use of antihypertensive medications (hypertension).During early pregnancy, women with prehypertension had a small increased risk of GDM (odds ratio [OR] 1.56 [95% CI 1.16-2.10]), and women with hypertension had a twofold increased risk of GDM (2.04 [1.14-3.65]) compared with women with normal BP after adjusting for age, race/ethnicity, gestational week of BP, BMI, and parity. Similar results were seen among the subset of women with BP levels measured before pregnancy (1.44 [0.95-2.19] for prehypertension and 2.01 [1.01-3.99] for hypertension).Clinicians should be aware that women presenting with hypertension may warrant early screening or intervention to prevent GDM.
Norepinephrine: the next therapeutics frontier for Parkinson's disease
Authors: Peter A LeWitt
Journal: Translational Neurodegeneration (2012)

Tissue concentrations of norepinephrine (NE) are markedly decreased in various regions of the Parkinson's disease (PD) brain. As in the substantia nigra pars compacta, neuronal dropout and Lewy bodies are prominent changes affecting the locus coeruleus, which is the source of ascending NErgic projections. Despite the major roles of NE throughout the brain, there has been only minimal exploration of pharmacological intervention with NErgic neurotransmission. Cognitive operations, "freezing" of gait, tremor, dyskinesia, REM sleep regulation, and other aspects of brain function are tied into signaling by NE, and there is also evidence that it may have a role in the neurodegenerative process itself. This article reviews the reported pharmacological experience in PD therapeutics.
DNA Methylation Analysis Determines the High Frequency of Genic Hypomethylation and Low Frequency of Hypermethylation Events in Plasma Cell Tumors
Authors: Bodour Salhia, Angela Baker, Gregory Ahmann, Daniel Auclair, Rafael Fonseca, John Carpten
Journal: Cancer Research (2010)

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow, which evolves from a premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). In some patients, an intermediate stage referred to as smoldering multiple myeloma (SMM) is clinically recognized, with the full-bore malignancy termed MM. We conducted a study to assess differential CpG methylation at 1,500 genic loci during MM progression and profiled CD138(+) plasma cells from MGUS, SMM, and MM specimens; human myeloma cell lines; and normal plasma cell (NPC) samples. We showed that the number of differentially methylated loci (DML) increased with tumor grade, and the vast majority were due to hypomethylation. Hierarchical clustering analysis revealed samples that coclustered tightly with NPC. These cases, referred to as "normal-like," contained significantly fewer DML when compared with their non-normal-like counterparts and displayed overall methylation levels resembling NPC. This study represents one of the first methylome interrogation studies in MM and points toward global hypomethylation at genic CpG loci as an important and early mechanism driving myelomagenesis. Determining the set of critical genes and pathways based on the myeloma methylome is expected to lead to an improved understanding of biological mechanisms involved in myelomagenesis.
Association Between Use of β-Blockers and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Lars H. Lund, Lina Benson, Ulf Dahlström, Magnus Edner, Leif Friberg
Journal: JAMA (2014)

<h3>Importance</h3> Heart failure with preserved ejection fraction (HFPEF) may be as common and may have similar mortality as heart failure with reduced ejection fraction (HFREF). β-Blockers reduce mortality in HFREF but are inadequately studied in HFPEF. <h3>Objective</h3> To test the hypothesis that β-blockers are associated with reduced all-cause mortality in HFPEF. <h3>Design</h3> Propensity score–matched cohort study using the Swedish Heart Failure Registry. Propensity scores for β-blocker use were derived from 52 baseline clinical and socioeconomic variables. <h3>Setting</h3> Nationwide registry of 67 hospitals with inpatient and outpatient units and 95 outpatient primary care clinics in Sweden with patients entered into the registry between July 1, 2005, and December 30, 2012, and followed up until December 31, 2012. <h3>Participants</h3> From a consecutive sample of 41 976 patients, 19 083 patients with HFPEF (mean [SD] age, 76 [12] years; 46% women). Of these, 8244 were matched 2:1 based on age and propensity score for β-blocker use, yielding 5496 treated and 2748 untreated patients with HFPEF. Also we conducted a positive-control consistency analysis involving 22 893 patients with HFREF, of whom 6081 were matched yielding 4054 treated and 2027 untreated patients. <h3>Exposures</h3> β-Blockers prescribed at discharge from the hospital or during an outpatient visit, analyzed 2 ways: without consideration of crossover and per-protocol analysis with censoring at crossover, if applicable. <h3>Main Outcomes and Measures</h3> The prespecified primary outcome was all-cause mortality and the secondary outcome was combined all-cause mortality or heart failure hospitalization. <h3>Results</h3> Median follow-up in HFPEF was 755 days, overall; 709 days in the matched cohort; no patients were lost to follow-up. In the matched HFPEF cohort, 1-year survival was 80% vs 79% for treated vs untreated patients, and 5-year survival was 45% vs 42%, with 2279 (41%) vs 1244 (45%) total deaths and 177 vs 191 deaths per 1000 patient-years (hazard ratio [HR], 0.93; 95% CI, 0.86-0.996;<i>P</i> = .04). β-Blockers were not associated with reduced combined mortality or heart failure hospitalizations: 3368 (61%) vs 1753 (64%) total for first events, with 371 vs 378 first events per 1000 patient-years (HR, 0.98; 95% CI, 0.92-1.04;<i>P</i> = .46). In the matched HFREF cohort, β-blockers were associated with reduced mortality (HR, 0.89; 95% CI, 0.82-0.97,<i>P</i>=.005) and also with reduced combined mortality or heart failure hospitalization (HR, 0.89; 95% CI, 0.84-0.95;<i>P</i> = .001). <h3>Conclusions and Relevance</h3> In patients with HFPEF, use of β-blockers was associated with lower all-cause mortality but not with combined all-cause mortality or heart failure hospitalization. β-Blockers in HFPEF should be examined in a large randomized clinical trial.
Oral Contraceptives and Endometrial Cancer
Authors: E. Stanton Maxey
Journal: JAMA (1983)

To the Editor.—  This letter addresses Oral Contraceptive Use and the Risk of Endometrial Cancer (1983; 249:1600). The findings have already received wide television coverage. Whether the use of oral contraceptives influences the risk of endometrial cancer developing is examined. The integrity of the conclusions may be impugned.  First, of 1,318 controls (none of whom had endometrial cancer), we find that 540 (41%) never took oral contraceptives. Contrary to this, among 187 women with endometrial cancer, 99 (53%) never took oral contraceptives.  What do we conclude? First, we may conclude that among 1,318 women who had telephones (used to select controls), 59% use oral contraceptives. If you can pay a monthly telephone bill you can buy the pill. Second, we may conclude that among 187 women with endometrial cancer, only 47% used oral contraceptives. Some of these undoubtedly could not afford the pill.  Is an economic factor at play? The