tbuckley/cabot-search huggingface dataset:
Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes
Authors: M. Mino-Kenudson, C. Fernandez-del Castillo, Y. Baba, N. P. Valsangkar, A. S. Liss, M. Hsu, C. Correa-Gallego, T. Ingkakul, R. Perez Johnston, B. G. Turner, V. Androutsopoulos, V. Deshpande, D. McGrath, D. V. Sahani, W. R. Brugge, S. Ogino, M. B. Pitman, A. L. Warshaw, S. P. Thayer
Journal: Gut (2011)

<h3>Objective</h3> Invasive cancers arising from intraductal papillary mucinous neoplasm (IPMN) are recognised as a morphologically and biologically heterogeneous group of neoplasms. Less is known about the epithelial subtypes of the precursor IPMN from which these lesions arise. The authors investigate the clinicopathological characteristics and the impact on survival of both the invasive component and its background IPMN. <h3>Design and patients</h3> The study cohort comprised 61 patients with invasive IPMN (study group) and 570 patients with pancreatic ductal adenocarcinoma (PDAC, control group) resected at a single institution. Multivariate analyses were performed using a stage-matched Cox proportional hazard model. <h3>Results</h3> The histology of invasive components of the IPMN cohort was tubular in 38 (62%), colloid in 16 (26%), and oncocytic in seven (12%). Compared with PDAC, invasive IPMNs were associated with a lower incidence of adverse pathological features and improved mortality by multivariate analysis (HR 0.58; 95% CI 0.39 to 0.86). In subtype analysis, this favourable outcome remained only for colloid and oncocytic carcinomas, while tubular adenocarcinoma was associated with worse overall survival, not significantly different from that of PDAC (HR 0.85; 95% CI 0.53 to 1.36). Colloid and oncocytic carcinomas arose only from intestinal- and oncocytic-type IPMNs, respectively, and were mostly of the main-duct type, whereas tubular adenocarcinomas primarily originated in the gastric background, which was often associated with branch-duct IPMN. Overall survival of patients with invasive adenocarcinomas arising from gastric-type IPMN was significantly worse than that of patients with non-gastric-type IPMN (p=0.016). <h3>Conclusions</h3> Tubular, colloid and oncocytic invasive IPMNs have varying prognosis, and arise from different epithelial subtypes. Colloid and oncocytic types have markedly improved biology, whereas the tubular type has a course that resembles PDAC. Analysis of these subtypes indicates that the background epithelium plays an equally, if not more, important role in defining the biology and prognosis of invasive IPMNs.
Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes
Authors: Arianna Calcinotto, Paola Filipazzi, Matteo Grioni, Manuela Iero, Angelo De Milito, Alessia Ricupito, Agata Cova, Rossella Canese, Elena Jachetti, Monica Rossetti, Veronica Huber, Giorgio Parmiani, Luca Generoso, Mario Santinami, Martina Borghi, Stefano Fais, Matteo Bellone, Licia Rivoltini
Journal: Cancer Research (2012)

Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra-extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6-6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8(+) T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal-regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA-bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell-based cancer treatments.
Negative predictive value of TST and IGRA in anti-TNF treated patients
Authors: Sergio Campainha, Teresa Gomes, Aurora Carvalho, Raquel Duarte
Journal: European Respiratory Journal (2012)

detected sequences have a biological function.Here, the main question is whether or not TEs within or in the vicinity of asthma susceptible genes modulate the gene expression of these genes.This can be performed using cap-analysis gene expression, a method that specifically and unequivocally identifies the exact transcription start sites of genes [6].Once the regulated retrotransposon transcriptome of healthy tissue is known, it can be compared with that of asthma patients or additional complex diseases.This will provide unprecedented details about genes and gene expression patterns, and how they relate to the development and/or establishment of complex diseases.The impact of TEs on phenotype (variation) and disease are depicted in figure 1.With the advent of next generation sequencing and rapid genome and transcriptome analyses, the dynamic nature of TEs and their role in shaping intra-and inter-individual variation may soon be resolved.Because these developments will dissect TE-induced variation at ever increasing resolution, they will lead to a better understanding of TEs and their overall impact on gene expression, human health and the (epi)genetic constitution that underlies complex lung diseases, including asthma.We have already identified the number, position and type of TEs present in the 12 aforementioned asthma-associated genes and we are in the process of screening the same panel of genes in asthma patients.It may well be that some phenotypes of asthma are predominantly associated with TE-regulated genes of the immunological compartment, whereas other phenotypes of asthma are linked to a specific set of TE-regulated genes in lung tissue cells.Therefore, cell-and phenotype-specific understanding of the healthy and diseased transcriptomes may lead to better treatment and to personalised medicine.We would like to encourage pulmonary scientists to further examine the almost entirely unexplored TE field, which integrates clinics, the laboratory and bioinformatics.
Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab
Authors: Stefania Napolitano, Giulia Martini, Barbara Rinaldi, Erika Martinelli, Maria Donniacuo, Liberato Berrino, Donata Vitagliano, Floriana Morgillo, Giusy Barra, Raffaele De Palma, Francesco Merolla, Fortunato Ciardiello, Teresa Troiani
Journal: Clinical Cancer Research (2015)

Abstract Purpose: In colorectal cancer, the activation of the intracellular RAS–RAF and PIK3CA–AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance. Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR). Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation. Conclusions: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. Clin Cancer Res; 21(13); 2975–83. ©2015 AACR.
STUDIES ON IMMUNOLOGICAL RELATIONSHIPS AMONG THE PNEUMOCOCCI
Authors: Annie Luverne Harris, John Y. Sugg, James M. Neill
Journal: The Journal of Experimental Medicine (1928)

The paper reports an experimental comparison of the antibody responses of mice and of rabbits to immunization with typical Type III pneumococci and a strain related to Type III. The results as a whole show that the relative antigenic effectiveness of these two kinds of related pneumococci, is different in different animals. In rabbits the strain related to but not identical with Type III elicits the better response; in mice, the typical Type III strain is more effective. These relationships furnish an example of the influence of the species of animal upon the effectiveness of even closely related bacterial antigens.
Hypoglycemia Associated With Hospitalization and Adverse Events in Older People
Authors: Sumit R. Majumdar, Brenda R. Hemmelgarn, Meng Lin, Kerry McBrien, Braden J. Manns, Marcello Tonelli
Journal: Diabetes Care (2013)

Little is known about the prognostic impact of hypoglycemia associated with hospitalization. We hypothesized that hospitalized hypoglycemia would be associated with increased long-term morbidity and mortality, irrespective of diabetes status.We undertook a cohort study using linked administrative health care and laboratory databases in Alberta, Canada. From 1 January 2004 to 31 March 2009, we included all outpatients 66 years of age and older who had at least one serum creatinine and one A1C measured. To examine the independent association between hospitalized hypoglycemia and all-cause mortality, we used time-varying Cox proportional hazards (adjusted hazard ratio [aHR]), and for all-cause hospitalizations, we used Poisson regression (adjusted incidence rate ratio [aIRR]).The cohort included 85,810 patients: mean age 75 years, 51% female, and 50% had diabetes defined by administrative data. Overall, 440 patients (0.5%) had severe hypoglycemia associated with hospitalization and most (93%) had diabetes. During 4 years of follow-up, 16,320 (19%) patients died. Hospitalized hypoglycemia was independently associated with increased mortality (60 vs. 19% mortality for no hypoglycemia; aHR 2.55 [95% CI 2.25-2.88]), and this increased in a dose-dependent manner (aHR no hypoglycemia = 1.0 vs. one episode = 2.49 vs. one or more = 3.78, P trend <0.001). Hospitalized hypoglycemia was also independently associated with subsequent hospitalizations (aIRR no hypoglycemia = 1.0 vs. one episode = 1.90 vs. one or more = 2.61, P trend <0.001) and recurrent hypoglycemia (aHR no hypoglycemia = 1.0 vs. one episode = 2.45 vs. one or more = 9.66, P trend <0.001).Older people who have an episode of hospitalized hypoglycemia are easily identified and at substantially increased risk of morbidity and mortality.
Benign Breast Disease, Mammographic Breast Density, and the Risk of Breast Cancer
Authors: Jeffrey A. Tice, Ellen S. O’Meara, Donald L. Weaver, Celine Vachon, Rachel Ballard-Barbash, Karla Kerlikowske
Journal: JNCI Journal of the National Cancer Institute (2013)

Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk.We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided.Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses.Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.
Tissue Selectivity in Multiple Endocrine Neoplasia Type 1-Associated Tumorigenesis
Authors: Ana Gracanin, Koen M. A. Dreijerink, Rob B. van der Luijt, Cornelis J. M. Lips, Jo W. M. Höppener
Journal: Cancer Research (2009)

The phenotype of the multiple endocrine neoplasia type 1 (MEN1) syndrome cannot be explained solely by the expression pattern of the predisposing gene MEN1 and its encoded protein, menin. This review addresses putative factors determining MEN1-associated tissue-selective tumorigenesis. Menin's interaction with mixed-lineage leukemia protein-containing histone methyl transferase (MLL-HMT) complex mediates tissue-selective tumor-suppressing and tumor-promoting effects of menin, and as such could be decisive for the predisposition of individual tissues to MEN1-associated tumorigenesis. In tissues in which menin acts as a tumor suppressor, tumorigenesis could depend on the inability of such tissues to adequately compensate for MEN1 gene loss, whereas the variable clinical presentation of MEN1 in individual patients could be a reflection of additional epigenetic factors and/or modifier genes. Further research on this topic may facilitate development of novel therapeutic strategies that could prevent or delay the onset of MEN1-associated tumorigenesis.
The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles
Authors: P. Lacolley, V. Regnault, A. Nicoletti, Z. Li, J.-B. Michel
Journal: Cardiovascular Research (2012)

Vascular smooth muscle cells (VSMCs) are the stromal cells of the vascular wall, continually exposed to mechanical signals and biochemical components generated in the blood compartment. They are involved in all the physiological functions and the pathological changes taking place in the vascular wall. Owing to their contractile tonus, VSMCs of resistance vessels participate in the regulation of blood pressure and also in hypertension. VSMCs of conduit arteries respond to hypertension-induced increases in wall stress by an increase in cell protein synthesis (hypertrophy) and extracellular matrix secretion. These responses are mediated by complex signalling pathways, mainly involving RhoA and extracellular signal-regulated kinase1/2. Serum response factor and miRNA expression represent main mechanisms controlling the pattern of gene expression. Ageing also induces VSMC phenotypic modulation that could have influence on cell senescence and loss of plasticity and reprogramming. In the early stages of human atheroma, VSMCs support the lipid overload. Endocytosis/phagocytosis of modified low-density lipoproteins, free cholesterol, microvesicles, and apoptotic cells by VSMCs plays a major role in the progression of atheroma. Migration and proliferation of VSMCs in the intima also participate in plaque progression. The medial VSMC is the organizer of the inwardly directed angiogenic response arising from the adventitia by overexpressing vascular endothelial growth factor in response to lipid-stimulated peroxisome proliferator-activated receptor-γ, and probably also the organizer of the adventitial immune response by secreting chemokines. VSMCs are also involved in the response to proteolytic injury via their ability to activate blood-borne proteases, to secrete antiproteases, and to clear protease/antiprotease complexes.
Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases
Authors: G. Wennergren, S. Kristjánsson
Journal: European Respiratory Journal (2001)

Evidence from a large number of prospective case-control studies shows that respiratory syncytial virus (RSV) bronchiolitis in infancy is often associated with recurrent wheezing and asthma during subsequent years. However, wheezing tends to diminish and most studies show no significant increase in wheezing compared to controls by school age or adolescence. An unresolved question is whether severe RSV infection during infancy causes the respiratory sequelae or inherent abnormalities predispose an infant to develop severe respiratory infection and sequelae, i.e. RSV is associated with the development of pulmonary sequelae. Studies on long-term outcome of RSV bronchiolitis are reviewed from an evidence-based perspective. The majority of prospective placebo-controlled studies do not show any long-term beneficial effects of corticosteroid treatment, i.e. the risk of subsequent wheezing is not diminished by the treatment. The evidence for an increased risk of allergic sensitization after RSV bronchiolitis is not nearly as strong as the evidence for an increased risk of subsequent wheezing. In fact, most studies do not show any significant increase in atopy after RSV bronchiolitis. This suggests that the increased risk of wheezing after RSV is not linked to an increased risk of atopy. There are some indications that infants who develop severe RSV and subsequent wheezing may have aberrations that predate the RSV infection. To decide whether respiratory syncytial virus bronchiolitis causes, or is associated with the respiratory sequelae (or with subsequent allergy), it will be necessary to conduct prospective, randomized studies, where the cytokine profile prior to bronchiolitis onset is known. Such studies should preferably include some form of intervention against respiratory syncytial virus. A more complete understanding of the risk factors for severe respiratory syncytial virus infection and the role of respiratory syncytial virus infection in the initiation of asthma is needed as a basis for large-scale and cost-effective programmes to prevent respiratory syncytial virus-related morbidity.
Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma
Authors: Martin J.B. Taphoorn, Roger Henriksson, Andrew Bottomley, Timothy Cloughesy, Wolfgang Wick, Warren P. Mason, Frank Saran, Ryo Nishikawa, Magalie Hilton, Christina Theodore-Oklota, Arliene Ravelo, Olivier L. Chinot
Journal: Journal of Clinical Oncology (2015)

Purpose As glioblastoma progresses, patients experience a decline in health-related quality of life (HRQoL). Delaying this decline is an important treatment goal. In newly diagnosed glioblastoma, progression-free survival was prolonged when bevacizumab was added to radiotherapy plus temozolomide (RT/TMZ) versus placebo plus RT/TMZ (phase III AVAglio study; hazard ratio, 0.64; 95% CI, 0.55 to 0.74; P &lt; .001). To ensure that addition of bevacizumab to standard-of-care therapy was not associated with HRQoL detriment, HRQoL assessment was a secondary objective. Patients and Methods Patients completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BN20 at each tumor assessment (Appendix Table A1 , online only). Raw scores were converted to a 100-point scale and mean changes from baseline scores were evaluated (stable: &lt; 10-point change; clinically relevant deterioration/improvement: ≥ 10-point change). Deterioration-free survival was the time to deterioration/progression/death; time to deterioration was the time to deterioration/death. Results Most evaluable patients who had not progressed (&gt; 74%) completed all HRQoL assessments for at least 1 year of treatment, and almost all completed at least one HRQoL assessment at baseline (98.3% and 97.6%, bevacizumab and placebo arms, respectively). Mean changes from baseline did not reach a clinically relevant difference between arms for most items. HRQoL declined at progression in both arms. The addition of bevacizumab to RT/TMZ resulted in statistically longer (P &lt; .001) deterioration-free survival across all items. Time to deterioration was not statistically longer in the placebo plus RT/TMZ arm (v bevacizumab) for any HRQoL item. Conclusion The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period.
Risk Perception for Diabetes Among Women With Histories of Gestational Diabetes Mellitus
Authors: Catherine Kim, Laura N. McEwen, John D. Piette, Jennifer Goewey, Assiamira Ferrara, Elizabeth A. Walker
Journal: Diabetes Care (2007)

OBJECTIVE—To examine risk perception for diabetes among women with histories of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS—We surveyed 217 women with histories of GDM who were enrolled in a managed-care plan and who did not currently have diabetes. In a cross-sectional design, we assessed the associations between risk perceptions and current lifestyle behavioral practices, plans to modify behaviors, and recent lifestyle behavior changes. Multivariable models included participant characteristics as well as potential modifiers of risk perception (knowledge of diabetes risk factors, optimistic bias, perceived personal control, and beliefs in the benefits and barriers of lifestyle modification). RESULTS—Ninety percent of women recognized that GDM was a risk factor for future diabetes, but only 16% believed that they themselves had a high chance of developing diabetes; perceived risk increased to 39% when women were asked to estimate their risk assuming they maintained their current lifestyle. Women who consumed three or more but less than five servings a day of fruits and vegetables reported lower odds of moderate/high risk perception (adjusted odds ratio [OR] 0.39 [95% CI 0.16–0.92]) than women who consumed less than three servings a day, although this association was not significant after further adjustment for income. Women who perceived themselves to be at moderate/high risk more often planned to modify their future lifestyle behaviors (9.1 [0.16–0.92]). CONCLUSIONS—Despite understanding the association between GDM and postpartum diabetes, women with histories of GDM usually do not perceive themselves to be at elevated risk.
Physeal injuries in children’s and youth sports: reasons for concern?
Authors: D Caine, J DiFiori, N Maffulli
Journal: British Journal of Sports Medicine (2006)

A systematic review of the literature on the frequency and characteristics of sports related growth plate injuries affecting children and youth in organised sport was carried out. Both acute and chronic physeal injuries related to participation in sports have been reported to occur, although injury incidence data are somewhat limited. Of particular concern is the growing number of stress related physeal injuries, including those affecting the lower extremities. Although most physeal injuries appeared to resolve with treatment and rest, there is also evidence of growth disturbance and deformity. Possible injury risk factors and countermeasures are discussed, and suggestions for directing future research provided.