tbuckley/cabot-search huggingface dataset:
Stimulation of CD28 triggers an association between CD28 and phosphatidylinositol 3-kinase in Jurkat T cells.
Authors: K E Truitt, C M Hicks, J B Imboden
Journal: The Journal of Experimental Medicine (1994)

The T cell surface molecule CD28 can provide costimulatory signals that permit the full activation of T cells. Here we demonstrate that stimulation of CD28, either by B7, its natural ligand, or by the anti-CD28 monoclonal antibody 9.3, induces an association between CD28 and phosphatidylinositol 3-kinase (PI3-K) in Jurkat T cells, raising the possibility that an interaction with PI3-K contributes to CD28-mediated signaling. To examine the mechanism of the association, we synthesized tyrosine-phosphorylated oligopeptides corresponding to each of the four tyrosines in the CD28 cytoplasmic domain. When added to lysates of B7-stimulated Jurkat cells, the oligopeptide corresponding to Tyr 173 inhibits the coimmunoprecipitation of PI3-K with CD28; the other oligopeptides have no effect. Tyr 173 is contained within the sequence YMNM, a motif that is also found in the platelet-derived growth factor receptor and that, when phosphorylated, forms a high affinity binding site for the p85 subunit of PI3-K. These observations suggest that phosphorylation of Tyr 173 may mediate the interaction between CD28 and PI3-K. However, because CD28 is not known to be phosphorylated, it remains possible that CD28 interacts with PI3-K through a mechanism independent of tyrosine phosphorylation.
Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.
Authors: D E Hammerschmidt, J G White, P R Craddock, H S Jacob
Journal: Journal of Clinical Investigation (1979)

Granulocyte (PMN) aggregation and embolization may underlie complement (C)-mediated organ dysfunction in such syndromes as hemodialysis neutropenia and Purtscher's ischem;c retinopathy. Because of clinical and pathologic parallels, we have further suggested a role for this phenomenon in the genesis of the adult respiratory distress syndrome (ARDS). Because corticosteroids are commonly used in immune diseases, and have particularly been claimed efficacious in shock and ARDS, we tested the capability of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) to inhibit PMN aggregation. Aggregation engendered in vitro by zymosan-activated plasma (ZAP) was inhibited by MP and HC at concentrations approximating plasma levels achieved with the large bolus (30 mg/kg i.v) therapy advocated in shock states; DEX was almost without effect. Using intravital fluorescence microscopy, we observed PMN aggregation and embolization in the mesenteric vessels of rats given intra-arterial infusions of ZAP; this was also prevented by pretreatment with 30 mg/kg MP. Steroid inhibition of aggregation seemed not to involve disruption of receptor function, because aggregation induced by alternative agents, n-formyl-Met-Leu-Phe and the ionophore A23187, was also inhibited by MP. Moreover, corticosteroid inhibition of PMN prostaglandin synthesis is also an unlikely explanation for our results, since aspirin and ibuprofen failed to block aggregation and arachidonic acid neither effected aggregation itself nor ameliorated the steroid effect. Our studies provide a plausible rationale for the empiric observation that high-dose corticosteroids may benefit patients with syndromes associated with microvascular leukostasis.
Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study
Authors: Marije F Bakker, Guy Cavet, Johannes WG Jacobs, Johannes W J Bijlsma, Douglas J Haney, Yijing Shen, Lyndal K Hesterberg, Dustin R Smith, Michael Centola, Joel A G van Roon, Floris P J G Lafeber, Paco M J Welsing
Journal: Annals of the Rheumatic Diseases (2012)

To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
BRCA2 Suppresses Cell Proliferation via Stabilizing MAGE-D1
Authors: Xin-xia Tian, Deepak Rai, Jun Li, Chaozhong Zou, Yujie Bai, David Wazer, Vimla Band, Qingshen Gao
Journal: Cancer Research (2005)

Abstract Germ line mutations in BRCA2 gene predispose women to early-onset familial breast and ovarian cancer. BRCA2 is a protein of multiple functions. In addition to its role in DNA double-strand break repair, BRCA2 also plays a role in stabilization of stalled DNA replication forks, cytokinesis, transcription regulation, mammalian gametogenesis, centrosome duplication, and suppression of cell proliferation. However, how BRCA2 mutations predispose women specifically to breast and ovarian cancer remains undefined. Here we found that BRCA2 binds and stabilizes MAGE-D1, a member of the MAGE gene family of proteins. Expression of BRCA2 and MAGE-D1 synergistically suppresses cell proliferation independently of the p53 pathway. Using two MAGE-D1 RNA interferences and two cell lines expressing low or undetectable levels of MAGE-D1, we further showed that the expression of MAGE-D1 is required for BRCA2-mediated suppression of cell proliferation, indicating that MAGE-D1 is a downstream target of BRCA2 and that BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. Importantly, MAGE-D1 protein expression was reduced in 6 of 16 breast carcinoma cell lines tested as compared with untransformed immortal mammary epithelial cell lines, suggesting that suppression of MAGE-D1 expression may be involved in the tumorigenesis of a subset of sporadic breast cancers.
Corrigendum to “What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications” [Sleep Med Rev 18 (2014) 153–164]
Authors: Magdolna Hornyak, Hanna Scholz, Ralf Kohnen, Juergen Bengel, Jan Kassubek, Claudia Trenkwalder
Journal: Sleep Medicine Reviews (2014)
Autologous Dendritic Cell Vaccines for Non–Small-Cell Lung Cancer
Authors: Edward A. Hirschowitz, Terry Foody, Richard Kryscio, Larry Dickson, Jamie Sturgill, John Yannelli
Journal: Journal of Clinical Oncology (2004)

Therapeutic outcomes of definitively treated non-small-cell lung cancer (NSCLC) are unacceptably poor. A wealth of preclinical information, and a modest amount of clinical information indicate that dendritic cell (DC) vaccines have therapeutic potential. Only a handful of NSCLC patients have been included in DC clinical trials. We delivered autologous DC vaccines to 16 individuals with stage IA to IIIB NSCLC treated with surgery, chemoradiation, or multimodality therapy. The objectives of the study were to evaluate tolerability and measure immunologic responses to DC vaccines in a heterogeneous group of NSCLC patients.DC vaccines were generated from CD14+ precursors, pulsed with apoptotic bodies of an allogeneic NSCLC cell line that overexpressed Her2/neu, CEA, WT1, Mage2, and survivin. DCs were partially matured with a factor that induced surface molecule expression but minimal cytokine production. Individuals were immunized intradermally two times, 1 month apart. Peripheral blood was drawn serially over 16 weeks, and immune responses were measured by interferon-gamma ELISPOT.There were no unanticipated or serious adverse events. Immunologic responses followed three distinct patterns of reactivity: (1) five of 16 patients showed no clear immunologic response, (2) five of 16 patients showed a tumor-antigen independent response, and (3) six of 16 show an antigen specific response. Immunologic responses were independent of stage and prior therapy. Favorable and unfavorable clinical outcomes were independent of measured immunologic responses.Vaccines were well tolerated and had biologic activity in a variety of NSCLC patients. Establishing an optimal approach will require comparative studies in well-defined NSCLC patient groups.
The polymorphisms of interleukin 17A (<i>IL17A</i>) gene and its association with pediatric asthma in Taiwanese population
Authors: J. Y. Wang, S. D. Shyur, W. H. Wang, Y. H. Liou, C. G. J. Lin, Y. J. Wu, L. S. H. Wu
Journal: Allergy (2009)

The interleukin 17A (IL17A) gene, located on chromosome 6p and linked to asthma phenotype, is a highly potential candidate gene conferring asthma susceptibility. The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL17A and asthma in Taiwanese children.We selected and performed genotyping on nine SNPs that encompass the genomic region of IL17A in Taiwanese children with or without asthma. A total of 1939 subjects containing 1027 subjects in testing group and 931 subjects in validation group were recruited in this study.After Bonferroni correction, SNP rs8193036 was found to have a weak association (P = 0.0074 x 9 = 0.066) in genotype frequency test. This association was confirmed by validation group. Logistic regression adjusted allergy comorbidity and gender showed a slightly weaker association.The results indicated an independent role of IL17A promoter polymorphism rs8193036 in the association with pediatric asthma in Taiwanese population.
Phase I study of combined radiation, hyperthermia andintra-arterial carboplatin for local recurrence of cervical cancer
Authors: H. Tsuda, M. Tanaka, T. Manabe, H. Ikeda, S. Negoro, O. Ishiko, K. Yamamoto
Journal: Annals of Oncology (2003)

Background:Patients with cervical cancer who develop pelvic recurrence after primary surgery are usually treated with radiation-based therapy. However, their prognoses are dismal. We conducted a phase I study of combined radiation, hyperthermia and intra-arterial (IA) carboplatin for local recurrence of cervical cancer.Patients and methods:Patients with local recurrence of cervical cancer without extrapelvic recurrence were included in this study. Carboplatin was given as a 5-min IA infusion without hydration just before pelvic radiation every day. External pelvic irradiation (1.8 Gy/day for 28 days) was performed according to local standard schedules. After 20 Gy had been administered, hyperthermia was performed once a week with a radio frequency heating system for four cycles.Results:Fifteen patients were entered through the four dose levels of carboplatin. The maximum tolerated dose was determined to be 25 mg/m2 and the dose-limiting toxicities were leukocytopenia, neutrocytopenia and diarrhea. Grade 3/4 leukocytopenia and diarrhea were observed in nine (60%) and three (20%) of 15 patients. Tumor responses included five complete responses and nine partial responses, and the overall response rate was 93.3% (14 of 15) (95% confidence interval 59.4% to 100%). Tumor reductions were observed only at 20 Gy in 10 cases of 14 responders (71.4%).Conclusion:The combination therapy of radiation, hyperthermia and IA carboplatin is safe and well-tolerated for locally recurrent cervical cancer.
Effect of Addition and Removal of a Kidney Transplant in Renal and Adrenocortical Hypertensive Rats
Authors: A. H. GOMEZ, S. W. HOOBLER, P. BLAQUIER
Journal: Circulation Research (1960)

A method is described for preparing and studying the acute effect of renal transplants on the blood pressure of the rat. In such a preparation, renal blood flow, urine flow, and blood pressure are well maintained over a period of several hours. In hypertension of less than 6 months' duration following renal ligation or desoxycorticosterone administration, the transplant consistently reduced the blood pressure and in 36 out of 44 experiments normotensive levels were achieved in 30 to 40 minutes. Exclusion of the kidney permitted a gradual restoration of the hypertension. When the blood pressure was elevated by infusions of renin or angiotensin, the blood pressure did not fall after the transplantation procedure. Introduction of kidney tissue after the hypertension had lasted for 6 months or more reduced the blood pressure in only 10 of 23 experiments, suggesting that after the passage of time irreversible vascular changes had occurred. The mechanism by which the transplant lowers the blood pressure is unknown, but such factors as the creation of an area of low vascular resistance, the release of non-specific depressor substances into the circulation, and the external loss of a pressor substance into the urine seem to be excluded. Reasons are given for suspecting that the antihypertensive action of normal kidney tissue is a specific metabolic or incretory effect, rather than an excretory action related to urine formation.
Prevention of Chronic Diseases by Tea: Possible Mechanisms and Human Relevance
Authors: Chung S. Yang, Jungil Hong
Journal: Annual Review of Nutrition (2013)

Tea, made from leaves of the plant Camellia sinensis, Theaceae, has been used by humans for thousands of years, first as a medicinal herb and then as a beverage that is consumed widely. For the past 25 years, tea has been studied extensively for its beneficial health effects, including prevention of cancer, reduction of body weight, alleviation of metabolic syndrome, prevention of cardiovascular diseases, and protection against neurodegenerative diseases. Whether these effects can be produced by tea at the levels commonly consumed by humans is an open question. This review examines these topics and elucidates the common mechanisms for these beneficial health effects. It also discusses other health effects and possible side effects of tea consumption. This article provides a critical assessment of the health effects of tea consumption and suggests new directions for research in this area.
Discovery of new hazimycin congeners from Kitasatospora sp. P07101
Authors: Nobuhiro Koyama, Hirofumi Sato, Hiroshi Tomoda
Journal: Acta Pharmaceutica Sinica B (2015)

In an analytical study of microbial broths, the actinomycete strain Kitasatospora sp. P07101 was found to produce three new congeners, which were designated hazimycins B (1), C (2), and D (3), together with the previously reported hazimycin (renamed hazimycin A (4)). The structures of these hazimycins were examined using various spectroscopic methods including nuclear magnetic resonance (NMR), and the results revealed that 1-3 were analogues of hazimycin with the replacement of one of the two isonitrile groups in 4 by an NH-formyl group in 1, the two isonitrile groups and an amide group by two NH-formyl groups and a nitrile group in 2, and the two isonitrile groups and two amide groups by two NH-formyl groups and two nitrile groups in 3. Only hazimycin A exhibited moderate antimicrobial activities against Gram-positive bacteria and Candida albicans. These results indicated that the presence of two isonitrile groups in the hazimycin structure is essential for antimicrobial activity.
Setting performance targets in pay for performance programmes: what can we learn from QOF?
Authors: T. Doran, E. Kontopantelis, D. Reeves, M. Sutton, A. M. Ryan
Journal: BMJ (2014)

The UK’s Quality and Outcomes Framework, which was introduced in 2004 to reward general practitioners for meeting performance targets, has been controversial. <b>Tim Doran and colleagues</b> reflect on the difficulties of setting and adjusting targets and the missed opportunities for improving the evidence base
Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement
Authors: F Tubach
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> In clinical trials, at the group level, results are usually reported as mean and standard deviation of the change in score, which is not meaningful for most readers. <b>Objective:</b> To determine the minimal clinically important improvement (MCII) of pain, patient's global assessment of disease activity, and functional impairment in patients with knee and hip osteoarthritis (OA). <b>Methods:</b> A prospective multicentre 4 week cohort study involving 1362 outpatients with knee or hip OA was carried out. Data on assessment of pain and patient's global assessment, measured on visual analogue scales, and functional impairment, measured on the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) function subscale, were collected at baseline and final visits. Patients assessed their response to treatment on a five point Likert scale at the final visit. An anchoring method based on the patient's opinion was used. The MCII was estimated in a subgroup of 814 patients (603 with knee OA, 211 with hip OA). <b>Results:</b> For knee and hip OA, MCII for absolute (and relative) changes were, respectively, (<i>a</i>) −19.9 mm (−40.8%) and −15.3 mm (−32.0%) for pain; (<i>b</i>) −18.3 mm (–39.0%) and −15.2 mm (−32.6%) for patient's global assessment; (<i>c</i>) −9.1 (−26.0%) and −7.9 (−21.1%) for WOMAC function subscale score. The MCII is affected by the initial degree of severity of the symptoms but not by age, disease duration, or sex. <b>Conclusion:</b> Using criteria such as MCII in clinical trials would provide meaningful information which would help in interpreting the results by expressing them as a proportion of improved patients.
TGF-β1–induced expression of human Mdm2 correlates with late-stage metastatic breast cancer
Authors: Shinako Araki, Jacob A. Eitel, Christopher N. Batuello, Khadijeh Bijangi-Vishehsaraei, Xian-Jin Xie, David Danielpour, Karen E. Pollok, David A. Boothman, Lindsey D. Mayo
Journal: Journal of Clinical Investigation (2009)

The E3 ubiquitin ligase human murine double minute (HDM2) is overexpressed in 40%-80% of late-stage metastatic cancers in the absence of gene amplification. Hdm2 regulates p53 stability via ubiquitination and has also been implicated in altering the sensitivity of cells to TGF-beta1. Whether TGF-beta1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-beta1-activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-beta1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-beta1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-beta1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.
Stomach Bugs and Diabetes: An Astounding Observation or Just Confounding?
Authors: Christopher K. Rayner, Nicholas J. Talley, Michael Horowitz
Journal: Diabetes Care (2012)

The discovery that a Gram-negative spiral bacillus was responsible for most peptic ulcer disease (1) created a paradigm shift that culminated in Marshall and Warren being awarded the Nobel Prize in Physiology or Medicine for 2005. Helicobacter pylori induces inflammation that may be limited to the gastric antrum, or can involve the corpus with subsequent mucosal atrophy, and is characterized, particularly in those strains that are positive for cytotoxin-associated gene A, by induction of cytokines including interleukins (IL-) 1, 6, and 8, and tumor necrosis factor-α (2). H. pylori is an established risk factor for gastric adenocarcinoma and lymphoma arising from mucosa-associated lymphoid tissue (MALT).

H. pylori appears to be acquired mainly in childhood by the fecal-oral or gastro-oral route. In developing countries, 80% or more of the population are infected by 20 years of age, while in the developed world the prevalence of infection increases with age. In each subsequent cohort, improving socioeconomic conditions lead to lower rates of infection in childhood (3). In Australia, for example, seroprevalence was recently estimated at ∼30% for those ≥70 years of age, but only 5% for those <40 years of age (4).

Over the last 15–20 years, an increased prevalence of diverse diseases, including coronary artery (5) and cerebrovascular (6) disease, Alzheimer disease, migraine, Raynaud phenomenon, and chronic urticaria (7), has been reported in those with evidence of H. pylori infection. …
A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance: Part 46
Authors: P A Deuster, A B Hodgson, S J Stear, L M Burke, L M Castell
Journal: British Journal of Sports Medicine (2013)

The concluding alphabetical part of our series, part 46, deals with just two topics for the letter ‘Z’. One of these, zinc monomethionine aspartate (ZMA), is a derivative of the other well-known supplement, zinc (Zn). Zn is widely used by both athletes and the general population.

### PA Deuster

The essential trace mineral Zn serves multiple biological functions—catalytic, structural, regulatory and substrate1—in support of metabolic, endocrine, signal transduction, cellular control, protein stabilisation and immune networks/pathways.1 ,2 Overall, approximately 3000 Zn proteins are encoded in the human genome1 and Zn is a cofactor to more than 300 enzymes; these include superoxide dismutase, alkaline phosphatase and alcohol dehydrogenase, in the liver, and carbonic anhydrase III, AMP deaminase and the matrix metalloproteinases, in skeletal muscle. As one of the most widely distributed metals in the body, 85% of Zn resides in muscle and bones, 11% in skin and the liver and the remainder in all the other tissues.2 This clearly demonstrates the overall importance of Zn and would suggest that it may be important in physical performance. The best food sources of Zn are oysters, wheat germ, liver, beef, melon, squash seeds and cocoa.

Improvement in physical performance or aspects of physical performance by administration of Zn can be demonstrated in one of three ways: (1) showing that providing Zn to persons who are Zn deficient restores/improves performance, (2) demonstrating that providing Zn to healthy individuals with adequate Zn status improves some aspect of performance or (3) showing that Zn supplementation counters a particular health risk that could compromise performance. Performance improvement in …