tbuckley/cabot-search huggingface dataset:
Chronic Stress and Susceptibility to Skin Cancer
Authors: Alison N. Saul, Tatiana M. Oberyszyn, Christine Daugherty, Donna Kusewitt, Susie Jones, Scott Jewell, William B. Malarkey, Amy Lehman, Stanley Lemeshow, Firdaus S. Dhabhar
Journal: JNCI Journal of the National Cancer Institute (2005)

Studies have shown that chronic stress or UV radiation independently suppress immunity. Given their increasing prevalence, it is important to understand whether and how chronic stress and UV radiation may act together to increase susceptibility to disease. Therefore, we investigated potential mediators of a stress-induced increase in emergence and progression of UV-induced squamous cell carcinoma.SKH1 mice susceptible to UV-induced tumors were unexposed (naïve, n = 4) or exposed (n = 16) to 2240 J/m2 of UVB radiation three times a week for 10 weeks. Half of the UVB-exposed mice were left nonstressed (i.e., they remained in their home cages) and the other half were chronically stressed (i.e., restrained during weeks 4-6). UV-induced tumors were measured weekly from week 11 through week 34, blood was collected at week 34, and tissues were collected at week 35. mRNA expression of interleukin (IL)-12p40, interferon (IFN)-gamma, IL-4, IL-10, CD3epsilon, and CCL27/CTACK, the skin T cell-homing chemokine, in dorsal skin was quantified using real-time polymerase chain reaction. CD4+, CD8+, and CD25+ leukocytes were counted using immunohistochemistry and flow cytometry. All statistical tests were two-sided.Stressed mice had a shorter median time to first tumor (15 versus 16.5 weeks, difference = 1.5 weeks, 95% confidence interval [CI] = -3.0 to 3.3 weeks; P = .03) and reached 50% incidence earlier than controls (15 weeks versus 21 weeks). Stressed mice also had lower IFN-gamma ( mean = 0.03 versus mean = 0.07, difference = 0.04, 95% CI = 0.004 to 0.073; P = .02), CCL27/CTACK (mean = 101 versus mean = 142, difference = 41, 95% CI = 8.1 to 74.4; P = .03), and CD3epsilon (mean = 0.18 versus mean = 0.36, difference = 0.18, 95% CI = 0.06 to 0.30; P = .007) gene expression and lower numbers of infiltrating CD4+ cells (mean = 9.40 versus mean = 13.7, difference = 4.3, 95% CI = 2.36 to 6.32; P = .008) than nonstressed mice. In addition, stressed mice had more regulatory/suppressor CD25+ cells infiltrating tumors and more CD4+ CD25+ cells in circulation (mean = 0.36 versus mean = 0.17, difference = 0.19, 95% CI = 0.005 to 0.38; P = .03) than nonstressed mice.Chronic stress increased susceptibility to UV-induced squamous cell carcinoma in this mouse model by suppressing type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell numbers.
Mid Staffordshire trust pleads guilty to health and safety breaches
Authors: Clare Dyer
Journal: BMJ (2015)

Mid Staffordshire NHS Trust, which was at the centre of one of the biggest scandals to hit the health service, has pleaded guilty to “very significant” health and safety breaches in relation to the deaths of four elderly patients at Stafford Hospital between 2005 and 2014.

Stafford Magistrates’ Court heard that three of the patients died after having fallen and that the fourth was given penicillin even though hospital staff had been told that she was allergic to the antibiotic.

Bernard Thorogood, prosecuting for the Health and Safety Executive, told the court, “Three of the individuals concerned arrived at hospital vulnerable …
Imiquimod 5% cream for the treatment of actinic keratosis: Results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology
Authors: Rolf-Markus Szeimies, Marie-Jeanne P. Gerritsen, Girish Gupta, Jean Paul Ortonne, Stefano Serresi, Jens Bichel, James H. Lee, Terry L. Fox, Agustı́n Alomar
Journal: Journal of the American Academy of Dermatology (2004)
Progression From Newly Acquired Impaired Fasting Glusose to Type 2 Diabetes
Authors: Gregory A. Nichols, Teresa A. Hillier, Jonathan B. Brown
Journal: Diabetes Care (2007)

We sought to estimate the rate of progression from newly acquired (incident) impaired fasting glucose (IFG) to diabetes under the old and new IFG criteria and to identify predictors of progression to diabetes.We identified 5,452 members of an HMO with no prior history of diabetes, with at least two elevated fasting glucose tests (100-125 mg/dl) measured between 1 January 1994 and 31 December 2003, and with a normal fasting glucose test before the two elevated tests. All data were obtained from electronic records of routine clinical care. Subjects were followed until they developed diabetes, died, left the health plan, or until 31 December 2005.Overall, 8.1% of subjects whose initial abnormal fasting glucose was 100-109 mg/dl (added IFG subjects) and 24.3% of subjects whose initial abnormal fasting glucose was 110-125 mg/dl (original IFG subjects) developed diabetes (P < 0.0001). Added IFG subjects who progressed to diabetes did so within a mean of 41.4 months, a rate of 1.34% per year. Original IFG subjects converted at a rate of 5.56% per year after an average of 29.0 months. A steeper rate of increasing fasting glucose; higher BMI, blood pressure, and triglycerides; and lower HDL cholesterol predicted diabetes development.To our knowledge, these are the first estimates of diabetes incidence from a clinical care setting when the date of IFG onset is approximately known under the new criterion for IFG. The older criterion was more predictive of diabetes development. Many newly identified IFG patients progress to diabetes in <3 years, which is the currently recommended screening interval.
Presence of Somatic Mutations within <i>PIK3CA</i>, <i>AKT</i>, <i>RAS</i>, and <i>FGFR3</i> but not <i>BRAF</i> in Cisplatin-Resistant Germ Cell Tumors
Authors: Darren R. Feldman, Gopa Iyer, Lindsay Van Alstine, Sujata Patil, Hikmat Al-Ahmadie, Victor E. Reuter, George J. Bosl, Raju S. Chaganti, David B. Solit
Journal: Clinical Cancer Research (2014)

A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center.Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom.Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS).BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors.
Two-dimensional echocardiographic features of right ventricular infarction.
Authors: B D'Arcy, N C Nanda
Journal: Circulation (1982)

Real-time, two-dimensional echocardiographic studies were performed in 10 patients with acute myocardial infarction who had clinical features suggestive of right ventricular involvement. All patients showed right ventricular wall motion abnormalities. In the four-chamber view, seven patients showed akinesis of the entire right ventricular diaphragmatic wall and three showed akinesis of segments of the diaphragmatic wall. Segmental dyskinetic areas involving the right ventricular free wall were identified in four patients. One patient showed a large right ventricular apical aneurysm. Other echocardiographic features included enlargement of the right ventricle in eight cases, paradoxical ventricular septal motion in seven cases, tricuspid incompetence in eight cases, dilatation of the stomach in four cases and localized pericardial effusion in two cases. Right ventricular infarction was confirmed by radionuclide in seven patients, at surgery in one patient and at autopsy in two patients.
What lies behind serum urate concentration? Insights from genetic and genomic studies
Authors: Kimiyoshi Ichida
Journal: Genome Medicine (2009)

Many factors, including genetic components and acquired factors such as obesity and alcohol consumption, influence serum uric acid (urate) concentrations. Since serum urate concentrations are determined by the balance between renal urate excretion and the volume of urate produced via purine metabolism, urate transporter genes as well as genes coding for enzymes involved in purine metabolism affect serum urate concentrations. URAT1 was the first transporter affecting serum urate concentrations to be identified. Using the characterization of this transporter as an indicator, several transporters have been shown to transport urate, allowing the construction of a synoptic renal urate transport model. Notable re-absorptive urate transporters are URAT1 at apical membranes and GLUT9 at basolateral membranes, while ABCG2, MRP4 (multidrug resistance protein 4) and NPT1 are secretive transporters at apical membranes. Recent genome-wide association studies have led to validation of the in vitro model constructed from each functional analysis of urate transporters, and identification of novel candidate genes related to urate metabolism and transport proteins, such as glucokinase regulatory protein (GKRP), PDZK1 and MCT9. However, the function and physiologic roles of several candidates, as well as the influence of acquired factors such as obesity, foods, or alcoholic beverages, remain unclear.
Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Authors: Chrystal M. Paulos, Claudia Wrzesinski, Andrew Kaiser,, Christian S. Hinrichs, Marcello Chieppa, Lydie Cassard, Douglas C. Palmer, Andrea Boni, Pawel Muranski, Zhiya Yu, Luca Gattinoni, Paul A. Antony, Steven A. Rosenberg, Nicholas P. Restifo
Journal: Journal of Clinical Investigation (2007)

Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8(+) T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8(+) T cells in mice genetically deficient in all lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand-containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8(+) T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
Age-related increase in visceral adipose tissue and body fat and the metabolic risk profile of premenopausal women.
Authors: A Pascot, S Lemieux, I Lemieux, D Prud'homme, A Tremblay, C Bouchard, A Nadeau, C Couillard, A Tchernof, J Bergeron, J P Després
Journal: Diabetes Care (1999)

OBJECTIVE: Age-related differences in body fat and, more specifically, in the accumulation of abdominal visceral adipose tissue (AT) were examined as potential covariates of the age-related difference in the metabolic profile predictive of cardiovascular disease (CVD) risk observed in young, as compared with middle-aged, premenopausal women. RESEARCH DESIGN AND METHODS: Body composition, AT distribution, plasma lipoprotein-lipid levels, glucose tolerance, and plasma insulin concentrations were assessed in a sample of 122 young women (27.4+/-7.5 years, mean +/- SD) and compared with a sample of 52 middle-aged premenopausal women (49.5+/-5.3 years) who still had a normal menstrual cycle. RESULTS: Middle-aged women were characterized by elevated levels of total abdominal and visceral AT and greater body fat mass and waist circumference, as well as by higher plasma levels of total cholesterol, LDL cholesterol, apolipoprotein (apo)B, and LDL-apoB compared with younger women. Furthermore, middle-aged women showed a greater glycemic response to a 75-g oral glucose load than young women (P &amp;lt; 0.01). In both young and middle-aged subjects, visceral AT accumulation was significantly correlated with plasma triglyceride, apoB, and LDL-apoB levels and with the cholesterol/HDL cholesterol ratio, as well as with plasma glucose, insulin, and C-peptide levels measured in the fasting state and after the oral glucose load, and negatively correlated with HDL cholesterol levels (-0.41 &amp;lt; or = r &amp;lt; or = 0.65, P &amp;lt; 0.05). When variables were adjusted for levels of visceral AT and fat mass, age-related differences that were initially found in plasma apoB and LDL-apoB levels, as well as in fasting glycemia and glucose tolerance, were eliminated. CONCLUSIONS: Results of the present study suggest that even before the onset of menopause there is an age-related deterioration in the metabolic risk profile and an increase in visceral AT deposition in middle-aged women compared with young control subjects. Furthermore, our results provide support for the notion that the age-related increase in visceral AT accumulation is a significant factor involved in the deterioration of the CVD risk profile noted in premenopausal women with age.
Human autoantibodies against the 230-kD bullous pemphigoid antigen (BPAG1) bind only to the intracellular domain of the hemidesmosome, whereas those against the 180-kD bullous pemphigoid antigen (BPAG2) bind along the plasma membrane of the hemidesmosome in normal human and swine skin.
Authors: A Ishiko, H Shimizu, A Kikuchi, T Ebihara, T Hashimoto, T Nishikawa
Journal: Journal of Clinical Investigation (1993)

Bullous pemphigoid (BP) is a blistering skin disease in which autoantibodies develop to hemidesmosomal components of the epidermal basement membrane zone, including two major antigenic proteins of the 230-kD antigen (BPAG1) and the 180-kD antigen (BPAG2). The present study demonstrated the precise ultrastructural localization of the epitopes for autoantibodies against BPAG1 and BPAG2 in normal skin. Autoantibodies against either BPAG1 or BPAG2 were affinity-purified using nitrocellulose membrane, which was blotted with SDS-PAGE-fractionated antigens from human epidermal extract as the immunoabsorbent. Postembedding, immunogold electron microscopy was performed after skin was processed by rapid freezing and freeze substitution fixation without chemical fixatives. Purified autoantibodies against BPAG1 bound only to the intracellular domain of the hemidesmosome, and 80% of the gold labeling was within 40-140 nm from the plasma membrane (mean distance 91 nm inside). In contrast, the autoantibodies against BPAG2 bound along the plasma membrane of the hemidesmosome, and 80% of the gold labeling was within 10 nm outside to 50 nm inside the cells (mean distance 12 nm inside). These results suggest that the autoantibodies against BPAG1 and BPAG2 react with the epitopes localizing in distinct regions of the hemidesmosome complex, and may play different roles in the blister formation in patients with BP.
Skeletal stem cell physiology on functionally distinct titania nanotopographies
Authors: Laura E. McNamara, Terje Sjöström, Karl E.V. Burgess, Joseph J.W. Kim, Er Liu, Simon Gordonov, Prabhas V. Moghe, R.M. Dominic Meek, Richard O.C. Oreffo, Bo Su, Matthew J. Dalby
Journal: Biomaterials (2011)
Pivotal role for glycogen synthase kinase–3 in hematopoietic stem cell homeostasis in mice
Authors: Jian Huang, Yi Zhang, Alexey Bersenev, W. Timothy O’Brien, Wei Tong, Stephen G. Emerson, Peter S. Klein
Journal: Journal of Clinical Investigation (2009)

Hematopoietic stem cell (HSC) homeostasis depends on the balance between self renewal and lineage commitment, but what regulates this decision is not well understood. Using loss-of-function approaches in mice, we found that glycogen synthase kinase–3 (Gsk3) plays a pivotal role in controlling the decision between self renewal and differentiation of HSCs. Disruption of Gsk3 in BM transiently expanded phenotypic HSCs in a β-catenin–dependent manner, consistent with a role for Wnt signaling in HSC homeostasis. However, in assays of long-term HSC function, disruption of Gsk3 progressively depleted HSCs through activation of mammalian target of rapamycin (mTOR). This long-term HSC depletion was prevented by mTOR inhibition and exacerbated by β-catenin knockout. Thus, GSK-3 regulated both Wnt and mTOR signaling in mouse HSCs, with these pathways promoting HSC self renewal and lineage commitment, respectively, such that inhibition of Gsk3 in the presence of rapamycin expanded the HSC pool in vivo. These findings identify unexpected functions for GSK-3 in mouse HSC homeostasis, suggest a therapeutic approach to expand HSCs in vivo using currently available medications that target GSK-3 and mTOR, and provide a compelling explanation for the clinically prevalent hematopoietic effects observed in individuals prescribed the GSK-3 inhibitor lithium.
Analyses of Recombinant Vaccinia and Fowlpox Vaccine Vectors Expressing Transgenes for Two Human Tumor Antigens and Three Human Costimulatory Molecules
Authors: Kwong Y. Tsang, Claudia Palena, Junko Yokokawa, Philip M. Arlen, James L. Gulley, Gail P. Mazzara, Linda Gritz, Alicia Gómez Yafal, Sandra Ogueta, Patricia Greenhalgh, Kelledy Manson, Dennis Panicali, Jeffrey Schlom
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the construction and characterization of two viral vector vaccines to address these issues. Experimental Design: The two viral vectors analyzed are the replication-competent recombinant vaccinia virus (rV-) and the avipox vector, fowlpox (rF-), which is replication incompetent in mammalian cells. Each vector encodes the transgenes for three human costimulatory molecules (B7-1, ICAM-1, and LFA-3, designated TRICOM) and the CEA and MUC-1 transgenes (which also contain agonist epitopes). The vectors are designated rV-CEA/MUC/TRICOM and rF-CEA/MUC/TRICOM. Results: Each of the vectors is shown to be capable of faithfully expressing all five transgenes in human dendritic cells (DC). DCs infected with either vector are shown to activate both CEA- and MUC-1–specific T-cell lines to the same level as DCs infected with CEA-TRICOM or MUC-1-TRICOM vectors. Thus, no evidence of antigenic competition between CEA and MUC-1 was observed. Human DCs infected with rV-CEA/MUC/TRICOM or rF-CEA/MUC/TRICOM are also shown to be capable of generating both MUC-1- and CEA-specific T-cell lines; these T-cell lines are in turn shown to be capable of lysing targets pulsed with MUC-1 or CEA peptides as well as human tumor cells endogenously expressing MUC-1 and/or CEA. Conclusion: These studies provide the rationale for the clinical evaluation of these multigene vectors in patients with a range of carcinomas expressing MUC-1 and/or CEA.
Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration
Authors: Daher C. Chade, Shahrokh F. Shariat, Angel M. Cronin, Caroline J. Savage, R. Jeffrey Karnes, Michael L. Blute, Alberto Briganti, Francesco Montorsi, Henk G. van der Poel, Hendrik Van Poppel, Steven Joniau, Guilherme Godoy, Antonio Hurtado-Coll, Martin E. Gleave, Marcos Dall'Oglio, Miguel Srougi, Peter T. Scardino, James A. Eastham
Journal: European Urology (2011)
Para-amino-salicylic Acid (P.A.S.) and Streptomycin in the Surgical Treatment of Pulmonary Tuberculosis
Authors: G. Birath, T. Bruce, C. Crafoord, L. G. Uggla
Journal: Thorax (1950)

Whenthevalue ofP.A.S. andstreptomycin began toberealized, there was atfirst anideathatthesurgical treatment ofpulmonary tuberculosis wouldglide intothebackground. Thenewdrugs, however, didnotrender collapse therapy superfluous, andbefore longitwasclear thatoneofthechief indications for thecombined useofP.A.S. andstreptomycin wasprecisely inthesurgical treatment oftuberculosis. Thus, in1947, opinions astothevalue ofstreptomycin usedin combination withtheoperative treatment ofpulmonary tuberculosis appeared in several American publications. InthesameyearGloverandhisco-workers described cases wherecombined surgical andantibiotic treatment hadgiven very promising results. In1948, Carstensen andSjolin announced thatpatients in poorgeneral condition, withsimultaneous pulmonary andintestinal tuberculosis could, after P.A.S. therapy, bemadefitforoperation sothatthelungdisease couldbetreated bycollapse therapy. An extensive investigation ofthevalue ofstreptomycin combined withoperation wascarried outbyMulvihill andhis co-workers in1949.Up till now,however, a comparison ofcases whereboth P.A.S. andstreptomycin havebeentried hasbeenlacking.
Clinical diagnosis of current asthma: predictive value of respiratory symptoms in the SAPALDIA study
Authors: D. Sistek, J-M. Tschopp, C. Schindler, M. Brutsche, U. Ackermann-Liebrich, A-P. Perruchoud, P. Leuenberger
Journal: European Respiratory Journal (2001)

Bronchial asthma is a very common disease which often remains underdiagnosed. The aim of this study was to determine the predictive value of the most common respiratory symptoms and to explore the best symptom combinations to predict diagnosis of asthma. A questionnaire comprising common respiratory symptoms was submitted to 9,651 subjects aged 18–60 yrs, randomly selected from the Swiss population, of whom 225 subjects (2.3%) had current asthma as confirmed by their general practitioner. Based on these data the authors calculated the predictive values of single symptoms and symptom combinations to diagnose asthma. Wheezing was the most sensitive single symptom (sensitivity 75%). Simple symptoms such as wheezing with dyspnoea, chronic phlegm or chronic cough had specificity greater than 95%. Wheezing with dyspnoea (WD) or nocturnal dyspnoea (ND) had the best positive predictive value (PPV) as isolated symptoms (24% and 21%, respectively). When combining symptoms, wheezing associated with daily dyspnoea at rest or nocturnal dyspnoea showed the best PPV (42% and 39%, respectively), almost double single symptoms such as WD or ND. Wheezing associated with at least two of the three nocturnal symptoms (nocturnal dyspnoea, nocturnal cough or nocturnal chest tightness) had a sensitivity of 80% to diagnose asthma. In conclusion, respiratory symptoms obtained by medical history are reliable predictors of asthma. The findings suggest that particular combinations of symptoms are clinically useful in the differential diagnosis of asthma.