tbuckley/cabot-search huggingface dataset:
Tumor-Initiated Inflammation Overrides Protective Adaptive Immunity in an Induced Melanoma Model in Mice
Authors: Saïdi M. Soudja, Maria Wehbe, Amandine Mas, Lionel Chasson, Céline Powis de Tenbossche, Ivo Huijbers, Benoît Van den Eynde, Anne-Marie Schmitt-Verhulst
Journal: Cancer Research (2010)

Abstract We studied the effect of the immune system on two differentially aggressive melanomas developing in mice on conditional deletion of the INK4A/ARF tumor suppressor gene, with concomitant expression of oncogene H-RasG12V and a natural cancer-germline tumor antigen (TA). “Slow progressor” melanomas contained no activated T lymphocytes (TL). In contrast, “aggressive” melanomas were infiltrated by activated TLs lacking effector molecules and expressing high levels of PD-1, indicating an exhausted phenotype. Aggressive melanomas were also infiltrated by immature myeloid cells (IMC). Infiltration was associated with local inflammation and systemic Th2/Th17-oriented chronic inflammation that seemed to impair further activation of TLs, as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate the melanoma. This immunosuppression also led to the incapacity of these mice to reject inoculated TA-positive tumors, in contrast to slow-progressing melanoma-bearing mice, which were responsive. To test the role of adaptive immunity in tumor progression, we induced melanomas in immunodeficient RagKO compound mice. These mice developed aggressive but not slow-progressing melanomas at a higher frequency and with a shorter latency than immunocompetent mice. Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice, indicating that this phenotype was not dependent on adaptive immunity. Therefore, tumor-intrinsic factors distinguishing the two melanoma types control the initiation of inflammation, which was independent of adaptive immunity. The latter delayed development of aggressive melanomas but was overridden by inflammation. Cancer Res; 70(9); 3515–25. ©2010 AACR.
In Cardiomyocytes, Binding of Unzipping Peptide Activates Ryanodine Receptor 2 and Reciprocally Inhibits Calmodulin Binding
Authors: Tetsuro Oda, Yi Yang, Florentin R. Nitu, Bengt Svensson, Xiyuan Lu, Bradley R. Fruen, Razvan L. Cornea, Donald M. Bers
Journal: Circulation Research (2012)

One hypothesis for elevated Ca(2+) leak through cardiac ryanodine receptors (ryanodine receptor 2 [RyR2]) in heart failure is interdomain unzipping that can enhance aberrant channel activation. A peptide (domain peptide corresponding to RyR2 residues 2460-2495 [DPc10]) corresponding to RyR2 central domain residues 2460-2495 recapitulates this arrhythmogenic RyR2 leakiness by unzipping N-terminal and central domains. Calmodulin (CaM) and FK506-binding protein (FKBP12.6) bind to RyR2 and stabilize the closed channel. Little is known about DPc10 binding to the RyR2 and how that may interact with binding (and effects) of CaM and FKBP12.6 to RyR2.To measure, directly in cardiac myocytes, the kinetics and binding affinity of DPc10 to RyR2 and how that affects RyR2 interaction with FKBP12.6 and CaM.We used permeabilized rat ventricular myocytes and fluorescently labeled DPc10, FKBP12.6, and CaM. DPc10 access to its binding site is extremely slow in resting RyR2 but is accelerated by promoting RyR opening or unzipping (by unlabeled DPc10). RyR2-bound CaM (but not FKBP12.6) drastically slowed DPc10 binding. Conversely, DPc10 binding significantly reduced CaM (but not FKBP12.6) binding to the RyR2. Fluorescence resonance energy transfer measurements indicate that DPc10-binding and CaM-binding sites are separate and allow triangulation of the structural DPc10 binding locus on RyR2 vs FKBP12.6-binding and CaM-binding sites.DPc10-RyR2 binding is sterically limited by the resting zipped RyR2 state. CaM binding to RyR2 stabilizes this zipped state, whereas RyR2 activation or prebound DPc10 enhances DPc10 access. DPc10-binding and CaM-binding sites are distinct but are allosterically interacting RyR2 sites. Neither DPc10 nor FKBP12.6 influences RyR2 binding of the other.
Cigarette Smoking in Renal Transplant Recipients
Authors: BERTRAM L. KASISKE, DAGMAR KLINGER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Cigarette smoking increases the risk for cancer and cardiovascular disease in the general population, but the effects of smoking in renal transplant recipients are unknown. The effects of smoking were investigated among patients transplanted at Hennepin County Medical Center between 1963 and 1997. Information on smoking was available in 1334 patients. The 24.7% prevalence of smoking at the time of transplantation was similar to that in the general population. After adjusting for multiple predictors of graft failure, smoking more than 25 pack-years at transplantation (compared to smoking less than 25 pack-years or never having smoked) was associated with a 30% higher risk of graft failure (relative risk 1.30; 95% confidence interval [CI], 1.04 to 1.63; P = 0.021). Having quit smoking more than 5 yr before transplantation reduced the relative risk of graft failure by 34% (relative risk 0.66; 95% CI, 0.52 to 0.85; P &lt; 0.001). The increase in graft failure was due to an increase in deaths (adjusted relative risk 1.42; 95% CI, 1.08 to 1.87; P = 0.012). The relative risk for major cardiovascular disease events with smoking 11 to 25 pack-years at transplant was 1.56 (95% CI, 1.06 to 2.31; P = 0.024), whereas that of smoking more than 25 pack-years was 2.14 (95% CI, 1.49 to 3.08; P &lt; 0.001). The relative risk of invasive malignancies was 1.91 (95% CI, 1.05 to 3.48; P = 0.032). Smoking had no discernible effect on the rate of return to dialysis or on serum creatinine during the first year after transplantation. Thus, cigarette smoking is associated with an increased risk of death after renal transplantation. The effects of smoking appear to dissipate 5 yr after quitting. These results indirectly suggest that greater efforts to encourage patients to quit smoking before transplantation may decrease morbidity and mortality.
Early‐onset acral basal cell carcinomas in Gorlin syndrome
Authors: A. Torrelo, A. Vicente, L. Navarro, M. Planaguma, E. Bueno, R. González‐Sarmiento, A. Hernández‐Martín, L. Noguera‐Morel, L. Requena, I. Colmenero, A. Parareda, M.A. González‐Enseñat, R. Happle
Journal: British Journal of Dermatology (2014)

Two patients are reported in whom early-onset, distal papules with a histopathological diagnosis of basal cell carcinoma were the first manifestation of Gorlin syndrome (GS). These lesions showed no progression and remained stable through follow-up. Two different PTCH1 gene mutations were detected in the two patients, and thus a phenotype-genotype correlation of this manifestation of GS was not possible.
Ten years’ experience of screening patients with Barrett’s oesophagus in a university teaching hospital
Authors: C E Macdonald, A C Wicks, R J Playford
Journal: Gut (1997)

Background —Barrett’s metaplasia is a premalignant condition for which screening is recommended. Aims/methods —Annual screening endoscopies have been performed on all subjects suitable for surgery for many years. To examine the benefits to patients of continuing this policy 10 years’ experience of screening for Barrett’s oesophagus was reviewed. Results —Of the 29 374 endoscopies performed over this period, Barrett’s metaplasia was present in 1.4%. There was an approximate equal sex distribution with the majority of cases being identified in patients over 50 years old. Thirty five per cent of these patients were suitable to enter a yearly screening programme. During screening, the length of oesophagus involved did not vary over time. As a result of 379 endoscopies performed for screening purposes, only one patient was identified as developing carcinoma solely as a result of the screening programme. Two further patients had carcinoma identified as a result of progressive dysphagia requiring additional endoscopies. All three patients who developed carcinoma while in the screening programme had “long segment” (&gt;8 cm) regions of Barrett’s metaplasia with a stricture present at the initial endoscopy. Conclusions —The poor yield from this screening programme suggests that the policy should be reconsidered. Resources may be better spent on focusing on patients who present with ulceration or stricture in addition to Barrett’s metaplasia.
S57 Gene expression profiling of endobronchial ultrasound-derived cytological aspirates from hilar and mediastinal lymph nodes in NSCLC
Authors: R. W. Lee, E. McClean, A. Quinn, R. Breen, D. Cousins, G. Santis
Journal: Thorax (2011)

<h3>Introduction</h3> Endobronchial Ultrasound (EBUS) allows minimally-invasive hilar and mediastinal lymph node sampling and has an established role in the diagnosis and staging of lung cancer. Molecular biomarker development is becoming increasingly relevant in lung cancer management, however the suitability of EBUS-derived aspirates for detailed molecular analysis is not fully defined. Gene expression profiling (GEP), a powerful micro-array technology, which assesses genome-wide changes in gene expression, can generate individual-specific molecular signatures that can provide prognostic information and predict treatment responsiveness. Here we demonstrate the feasibility of using EBUS-derived cytological aspirates from benign and tumour infiltrated lymph nodes in patients with NSCLC for GEP. <h3>Methods</h3> Cytological aspirates from six patients with known NSCLC that had been referred for EBUS to stage the mediastinum were selected for GEP. Three patient samples were infiltrated by NSCLC and three were benign. NSCLC-infiltrated and benign lymph nodes were compared for differences in gene expression. <h3>Results</h3> RNA was available at a yield (median 17.5 μg, range 0.7–62.3 μg) and integrity (RIN Median 7.1, range 5.3–8.0) suitable for amplification and GEP. Reactive and malignant nodes were differentiated by principal component analysis and hierarchical clustering with ability to identify upregulation of cancer specific genes in malignant relative to benign nodes (notably EGFR, HGFR/c-met and HER2 were among genes most upregulated). <h3>Conclusion</h3> We demonstrate the feasibility of RNA extraction and GEP on EBUS-derived lymph node cytological aspirates and show differences in gene expression profiles between benign and tumour-infiltrated lymph node mRNA. Further studies on larger patient cohorts are necessary to identify expression profiles that can robustly differentiate benign from malignant lymph nodes in NSCLC.
Doctors who considered but did not pursue specific clinical specialties as careers: questionnaire surveys
Authors: Michael J Goldacre, Raph Goldacre, Trevor W Lambert
Journal: Journal of the Royal Society of Medicine (2012)

Objectives To report doctors' rejection of specialties as long-term careers and reasons for rejection. Design Postal questionnaires. Setting United Kingdom. Participants Graduates of 2002, 2005 and 2008 from all UK medical schools, surveyed one year after qualification. Main outcome measures Current specialty choice; any choice that had been seriously considered but not pursued (termed ‘rejected’ choices) with reasons for rejection. Results 2573 of 9155 respondents (28%) had seriously considered but then not pursued a specialty choice. By comparison with positive choices, general practice was under-represented among rejected choices: it was the actual choice of 27% of respondents and the rejected choice of only 6% of those who had rejected a specialty. Consideration of ‘job content’ was important in not pursuing general practice (cited by 78% of those who considered but rejected a career in general practice), psychiatry (72%), radiology (69%) and pathology (68%). The surgical specialties were the current choice of 20% of respondents and had been considered but rejected by 32% of doctors who rejected a specialty. Issues of work-life balance were the single most common factor, particularly for women, in not pursuing the surgical specialties, emergency medicine, the medical hospital specialties, paediatrics, and obstetrics and gynaecology. Competition for posts, difficult examinations, stressful working conditions, and poor training were mentioned but were mainly minority concerns. Conclusions There is considerable diversity between doctors in their reasons for finding specialties attractive or unattractive. This underlines the importance of recruitment strategies to medical school that recognize diversity of students' interests and aptitudes.
Noninvasive ventilatory support does not facilitate recovery from acute respiratory failure in chronic obstructive pulmonary disease
Authors: F Barbe, B Togores, M Rubi, S Pons, A Maimo, AG Agusti
Journal: European Respiratory Journal (1996)

This investigation evaluates, in a prospective, randomized and controlled manner, whether noninvasive ventilatory support (NIVS) with bilevel positive airway pressure (BiPAP) facilitates recovery from acute respiratory failure (ARF) in patients with chronic obstructive pulmonary disease (COPD). Twenty four patients (mean age (+/-SEM) 68 +/- 2 yrs) with COPD (forced expiratory volume in one second (FEV1) at discharge 33 +/- 2% predicted), who attended the emergency room because of ARF (pH 7.33 +/- 0.01; arterial oxygen tension (Pa,O2) 6.0 +/- 0.2 kPa; arterial carbon dioxide tension (Pa,CO2) 7.9 +/- 0.3 kPa), were initially randomized. Four out of the 14 patients (29%) allocated to received NIVS did not tolerate it. Of the remaining 20 patients, 10 received NIVS with BiPAP in a conventional hospital ward during the first 3 days of hospitalization (two daytime sessions of 3 h duration each). All 20 subjects were treated with oxygen, bronchodilators and steroids. On the first and third hospitalization days, before and 30 min after withdrawing oxygen therapy and/or BiPAP ventilatory support, we measured peak expiratory flow, arterial blood gas values, ventilatory pattern, occlusion pressure (P0.1), and maximal inspiratory (MIP) and maximal expiratory (MEP) pressures. All patients were discharged without requiring tracheal intubation and mechanical ventilation. Hospitalization time was similar in both groups (11.3 +/- 1.3 vs 10.6 +/- 0.9 days, control vs BiPAP, respectively). Arterial oxygenation, respiratory acidosis and airflow obstruction improved significantly throughout hospitalization in both groups. By contrast, the ventilatory pattern, P0.1, MIP and MEP did not change. NIVS with BiPAP did not cause any significant difference between groups. We conclude that noninvasive ventilatory support with bilevel positive airway pressure does not facilitate recovery from acute respiratory failure in patients with chronic obstructive pulmonary disease. Furthermore, a substantial proportion of patients (29%) do not tolerate noninvasive ventilatory support under these circumstances. From these results, we cannot recommend the use of noninvasive ventilatory support with bilevel positive airway pressure in the routine management of chronic obstructive pulmonary disease patients recovering from acute respiratory failure.
Socioeconomic inequalities in mortality and importance of perceived control: cohort study
Authors: H. Bosma, C. Schrijvers, J. P Mackenbach
Journal: BMJ (1999)

Perceived control has convincingly been suggested to be a key concept in explaining socioeconomic differences in health. 1 Some empirical evidence exists of a higher prevalence of low control beliefs (such as powerlessness or fatalism) in lower socioeconomic groups and that this is relevant to socioeconomic inequalities in general health. 2However, a systematic examination of the extent to which perceived control contributes to socioeconomic inequalities in mortality is lacking.This is important, as attention has recently shifted towards psychological and psychosocial explanations of socioeconomic inequalities in health.
Prognostic significance of the type and site of malignant melanoma
Authors: S.K. Jones, P. Pocock, J.C. Briggs
Journal: British Journal of Dermatology (1987)

It has been suggested that histopathological type and sometimes site influence the prognosis of malignant melanoma. For instance, lentigo maligna melanoma (LMM) possibly has a more favourable prognosis than other melanomas, and tumours in the BANS are (upper Back, posterior Arm, Neck and posterior Scalp) may have a worse prognosis. To see if these hold true in British patients, we followed up all melanomas treated at Frenchay Hospital, Bristol from 1967 to 1980, comprising SSM 630, NM 130, LMM 20 and acral lentiginous melanoma (ALM) five patients. Survival rates are ‘adjusted’ figures, representing melanoma deaths only. For head and neck tumours, 5-year survivals were, LMM 93%, SSM 73% and NM 69%, 10-year survivals being LMM 93%, SSM 58% and NM 38%. After Breslow thicknes corrections, however, these differences were not significant. With regard to BANS and non-BANS tumours (average Breslow thicknesses being similar in both), survivals were: 5 years 10 years SSM NM SSM NM BANS 54% 57% 33% 44% Non-BANS 81% 65% 63% 55% Our data, therefore, would suggest that LMM carries a similar prognosis to other melanomas of similar Breslow thickness. Treatment should therefore be dictated by thicknes and site constraints and not by histopathologica type. Also, tumours in BANS areas do seem to carry a worse prognosis than lesions of similar thickness elsewhere.
The left frontal convolution plays no special role in syntactic comprehension
Authors: Gregory Hickok
Journal: Behavioral and Brain Sciences (2000)

Grodzinsky's localization claim can be questioned on empirical grounds. The Trace Deletion Hypothesis fails to account for a number of comprehension facts in Broca's aphasia and conduction aphasics show similar comprehension patterns. Frontoparietal systems are recruited during sentence comprehension only under conditions of increased processing load and/or attentional demands.
A haplotype in the inducible T‐cell tyrosine kinase is a risk factor for seasonal allergic rhinitis
Authors: M. Benson, R. Mobini, F. Barrenäs, C. Halldén, Å. T. Naluai, T. Säll, L. O. Cardell
Journal: Allergy (2009)

Background: Identification of disease‐associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease‐associated pathway. Objective: To search for SNPs in genes that belong to the T‐cell receptor (TCR) pathway and that change in expression in allergen‐challenged CD4+ cells from patients with SAR. Methods: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. Results: Gene expression microarray analysis of allergen‐challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS , IL4 , IL5 , IL13 , CSF2 , CTLA4 , the inducible T‐cell tyrosine kinase ( ITK ) and CD3D . Significant chi‐squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK . The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen‐challenged CD4+ cells from patients, but not from controls. Conclusion: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.
Vascular Endothelial–Cadherin Tyrosine Phosphorylation in Angiogenic and Quiescent Adult Tissues
Authors: Nathalie Lambeng, Yann Wallez, Christine Rampon, Francine Cand, Georges Christé, Danielle Gulino-Debrac, Isabelle Vilgrain, Philippe Huber
Journal: Circulation Research (2005)

Vascular endothelial-cadherin (VE-cadherin) plays a key role in angiogenesis and in vascular permeability. The regulation of its biological activity may be a central mechanism in normal or pathological angiogenesis. VE-cadherin has been shown to be phosphorylated on tyrosine in vitro under various conditions, including stimulation by VEGF. In the present study, we addressed the question of the existence of a tyrosine phosphorylated form of VE-cadherin in vivo, in correlation with the quiescent versus angiogenic state of adult tissues. Phosphorylated VE-cadherin was detected in mouse lung, uterus, and ovary but not in other tissues unless mice were injected with peroxovanadate to block protein phosphatases. Remarkably, VE-cadherin tyrosine phosphorylation was dramatically increased in uterus and ovary, and not in other organs, during PMSG/hCG-induced angiogenesis. In parallel, we observed an increased association of VE-cadherin with Flk1 (VEGF receptor 2) during hormonal angiogenesis. Additionally, Src kinase was constitutively associated with VE-cadherin in both quiescent and angiogenic tissues and increased phosphorylation of VE-cadherin-associated Src was detected in uterus and ovary after hormonal treatment. Src-VE-cadherin association was detected in cultured endothelial cells, independent of VE-cadherin phosphorylation state and Src activation level. In this model, Src inhibition impaired VEGF-induced VE-cadherin phosphorylation, indicating that VE-cadherin phosphorylation was dependent on Src activation. We conclude that VE-cadherin is a substrate for tyrosine kinases in vivo and that its phosphorylation, together with that of associated Src, is increased by angiogenic stimulation. Physical association between Flk1, Src, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of VEGF-stimulated angiogenic processes.