tbuckley/cabot-search huggingface dataset:
Progress report. Familial inflammatory bowel disease--heredity or environment?
Authors: R M Lewkonia, R B McConnell
Journal: Gut (1976)

Progress reportFamilial inflammatory bowel diseaseheredity or environment?Soon after ulcerative colitis was first recognized as a disease entity distinct from epidemic dysentery, occasional instances of familial cases were reported but, early in the twentieth century, these were regarded as being merely coin- cidental'.Some years later, the man in whom Crohn made his initial observa- tions of ileitis was found to have a sister similarly affected and Crohn sug- gested the name 'familial ileitis' for the condition2.It has become generally accepted that both of these inflammatory bowel diseases (IBD) are sometimes familial.When this subject was reviewed in the first volume of Gut3 the significance of familial cases was uncertain.Despite advances in the intervening years the cause, or causes, of IBD remains unknown4, and the significance of familial involvement is still conjectural. EpidemiologyMost of the population surveys of the incidence of IBD have been carried out in Western Europe and North America5'6'7'8' 9.The differences that have been found are not striking and may represent variations in ascertainment of cases and diagnostic standards rather than differing racial propensities or the differing local environment.Little is known of the incidence of IBD in other parts of the world, especially in those parts where ulcerative colitis and Crohn's disease may be overshadowed by endemic dysenteries and intestinal tuberculosis.There have, for example, been few reports of IBD in Asians or Africans, a fact which has led to the suggestion that the low fibre content of the modern Western diet might be an important environmental factor in IBD10.
The Chrispin-Norman score in cystic fibrosis: doing away with the lateral view
Authors: C. Benden, C. Wallis, C. M. Owens, D. A. Ridout, R. Dinwiddie
Journal: European Respiratory Journal (2005)

The Chrispin–Norman chest radiograph scoring (CNS) system is widely used to assess respiratory disease progression in cystic fibrosis (CF). Frontal and lateral chest radiographs were performed. The present authors developed a modified CNS, which obviates the need for the lateral film. This study compares the original and the current authors' modified scoring system. A total of 50 chest radiographs from CF children, taken between August and December 2003, were scored according to the original and modified CNS. Two observers scored all 50 chest radiographs, scoring in random order the frontal radiographs, and separately the frontal and lateral radiographs together. There was no evidence of a difference between the methods for either observer, using the Bland and Altman 95% limits of agreement as follows: observer 1 (−2.0–1.9), and observer 2 (−1.77–2.2). No evidence of a difference between the observers for either method was found, comparing the 95% limits of agreement (−5.5–5.7) with the modified CNS (−5.6–6.4). In conclusion, in terms of the final score, good agreement was found between the use of the original and modified Chrispin–Norman score. In addition, low inter-observer variability was shown for both methods. The use of the modified Chrispin–Norman chest radiograph scoring system to stage disease severity in cystic fibrosis removes the need for a lateral chest radiograph.
Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection
Authors: Hanna Sjölin, Elena Tomasello, Mehrdad Mousavi-Jazi, Armando Bartolazzi, Klas Kärre, Eric Vivier, Cristina Cerboni
Journal: The Journal of Experimental Medicine (2002)

Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30–40-fold) and in the liver (2–5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon γ was reduced by 56 ± 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell–mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H.
Immunochemotherapy As Induction (R-CHOP and R-HyperC-VAD/R-MA) in Mantle Cell Lymphoma, a Hungarian Multicenter Open Label Phase II Study (Rituximab [MabThera®] in Mantle Cell Lymphoma, REMENY)
Authors: Miklos Udvardy, Andras Rosta, Zoltan Gasztonyi, Zita Borbenyi, Gaspar Radvanyi, Miklos Egyed, Beata Gasztonyi, Hajna Losonczy, Andras Matolcsy, Agnes H. Andrasfalvy, Tamas J. Schneider
Journal: Blood (2012)
Predictive value of FIB-4 versus fibrotest, APRI, FIBROINDEX and FORNS to noninvasively estimate fibrosis in hepatitis C
Authors: Anais Vallet-Pichard, Vincent Mallet, Stanislas Pol
Journal: Hepatology (2008)

Reply: We thank Dr. Adler's group for their interesting results which confirm the accuracy of the FIB-4 index for delineating significant (requiring therapy) and nonsignificant fibrosis in chronic hepatitis C (HCV), in HCV monoinfection as well as in human immunodeficiency virus (HIV)-HCV coinfection.1 Adler et al. included in their analysis a broad population of patients, some of them with chronic hepatitis B (HBV) infection and alcoholic liver disease. Our results in chronic hepatitis B (work submitted) suggest that the FIB-4 index is robust to diagnose nil-to-moderate fibrosis, providing therefore an interesting first-line evaluation. The comparison of the FIB-4 index with liver biopsies performed the same day in 138 patients allowed the correct identification of patients with nil-to-moderate fibrosis (METAVIR F0-F2) with an area under the receiving operating characteristic curve of 0.81 (confidence interval 95% 0.74-0.88) (P < 0.001). Interestingly, the longer the length of the liver biopsy, the higher was the AUROC increasing from 0.81 to 0.91. The FIB-4 score was less accurate for assessing the diagnosis of severe fibrosis (METAVIR F3-F4). The high number of African patients included in our study could explain at least in part these results: most discordant patients with a high FIB-4 index and nil-to-moderate fibrosis had a low platelet count, possibly following chronic malarial infection. In alcohol-related liver disease (ALD), our analysis of the FIB-4 index in 160 patients is disappointing and confirmed the idea that existing diagnostic tests based on aminotransferase level and platelet count are not suitable for the determination of fibrosis stage in patients with ALD (work submitted). This point could receive several nonexclusive explanations: alcohol is well known to induce a higher AST/ALT ratio than other causes of liver diseases; the level of aminotransferases is classically lower in ALD and this has been related to pyridoxal phosphate deficiency; platelet count is affected by the acute toxicity of ethanol on thrombopoiesis and its correlation to portal hypertension is therefore poor in that context. All these alcohol-related variations clearly make an impact on the FIB-4 index which includes AST, ALT, GGT and the platelet count. The accuracy and the low cost of the FIB-4 index should make the FIB-4 index, with the fibroscan, a first line noninvasive biochemical marker and should be added to the recommendations of the Haute Autorité de Santé.2 Anais Vallet-Pichard M.D.*, Vincent Mallet M.D., Ph.D.*, Stanislas Pol M.D., Ph.D.*, * Université Paris Descartes; INSERM U.567; APHP, Hôpital Cochin, Unité d'hépatologie Paris, France.
Human natural killer cell committed thymocytes and their relation to the T cell lineage.
Authors: M J Sánchez, H Spits, L L Lanier, J H Phillips
Journal: The Journal of Experimental Medicine (1993)

Recent studies have demonstrated that mature natural killer (NK) cells can be grown from human triple negative (TN; CD3-, CD4-, CD8-) thymocytes, suggesting that a common NK/T cell precursor exists within the thymus that can give rise to both NK cells and T cells under appropriate conditions. In the present study, we have investigated human fetal and postnatal thymus to determine whether NK cells and their precursors exist within this tissue and whether NK cells can be distinguished from T cell progenitors. Based on the surface expression of CD56 (an NK cell-associated antigen) and CD5 (a T cell-associated antigen), three phenotypically distinctive populations of TN thymocytes were identified. CD56+, CD5-; CD56-, CD5-, and CD56-, CD5+. The CD56+, CD5- population of TN thymocytes, although displaying a low cytolytic function against NK sensitive tumor cell targets, were similar in antigenic phenotype to fetal liver NK cells, gave rise to NK cell clones, and were unable to generate T cells in mouse fetal thymic organ cultures (mFTOC). This population of thymocytes represents a relatively mature population of lineage-committed NK cells. The CD56-, CD5- population of TN thymocytes were similar to thymic NK cells in antigenic phenotype and NK cell clonogenic potential. Clones derived from this population of TN thymocytes acquired CD56 surface expression and NK cell cytolytic function. CD56-, CD5- TN thymocytes thus contain a novel population of NK cell-committed precursors. The CD56-, CD5- population of TN thymocytes also contains a small percentage of CD34+ cells, which demonstrate no in vitro clonogenic potential, but possess T cell reconstituting capabilities in mFTOC. The majority of TN thymocytes do not express CD56, but coexpress CD34 and CD5. These CD56-, CD5+, CD34+ cells demonstrate no NK or T cell clonogenic potential, but are extremely efficient in repopulating mFTOC and differentiating into CD3+, CD4+, CD8+ T cells. The results of this investigation have identified NK cells and NK cell precursors in the human thymus and have shown that these cell types are unable to differentiate along the T cell lineage pathway. Thus, while a common NK/T cell progenitor likely exists, once committed to the NK cell lineage these cells no longer have the capacity to develop along the T cell developmental pathway.
Methodological issues in therapeutic trials of COPD
Authors: S. Suissa, P. Ernst, K. L. Vandemheen, S. D. Aaron
Journal: European Respiratory Journal (2008)

The recent Towards a Revolution in COPD Health (TORCH) randomised trial replicated the findings of previous trials in chronic obstructive pulmonary disease (COPD) on the apparent effectiveness of inhaled corticosteroids (ICS) in reducing exacerbation rates, but not so for mortality. In the present article, the authors review methodological issues in the TORCH and previous trials, such as patients already receiving ICS before randomisation and the absence of follow-up after study drug discontinuation, using data from two trials. First, among previous ICS users in the Canadian Optimal Therapy of COPD Trial, the hazard ratio of the first exacerbation with ICS relative to bronchodilators was 0.71 (95% confidence interval (CI) 0.53–0.96), while among those not using ICS prior to randomisation, it was 1.11 (95% CI 0.69–1.79). Secondly, the rate ratio of exacerbations with ICS was 0.78 (95% CI 0.61–0.99) prior to drug discontinuation during follow-up and 1.23 (95% CI 0.78–1.95) thereafter. Finally, a 2×2 factorial analysis of the TORCH data found a rate ratio of mortality for the salmeterol component to be 0.83 (95% CI 0.74–0.95), while for the fluticasone component it was 1.00 (95% CI 0.89–1.13). In conclusion, after proper consideration of the various methodological shortcomings in the design and analysis of randomised trials, the effectiveness of inhaled corticosteroids in treating chronic obstructive pulmonary disease remains doubtful, while the benefit observed with combination therapy may be due exclusively to the beneficial effects of the long-acting bronchodilator alone.
Traumatic Brain Injury and Its Neuropsychiatric Sequelae in War Veterans
Authors: Nina A. Sayer
Journal: Annual Review of Medicine (2012)

The post–September 11, 2001 wars in and around Afghanistan and Iraq have increased awareness of traumatic brain injury (TBI), particularly blast-induced mild TBI. This article provides an overview of TBI and its neuropsychiatric sequelae in U.S. war veterans who participated in the current operations in and around Afghanistan and Iraq, with particular emphasis on blast-related mild TBI. Psychiatric disorders, particularly posttraumatic stress disorder, pain, and sensory impairments are prevalent in war veterans with TBI. Research is needed to more definitively characterize the epidemiology of TBI-related functional difficulties, the effects of blasts compared with other mechanisms of injury, recovery trajectories, and treatment outcomes in this population.
Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma
Authors: Antoon Dijkstra, Timothy D. Howard, Judith M. Vonk, Elizabeth J. Ampleford, Leslie A. Lange, Eugene R. Bleecker, Deborah A. Meyers, Dirkje S. Postma
Journal: Journal of Allergy and Clinical Immunology (2006)
High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis
Authors: P R Fleshner
Journal: Gut (2001)

<h3>BACKGROUND</h3> The reported cumulative risk of developing pouchitis in ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA) approaches 50% after 10 years. To date, no preoperative serological predictor of pouchitis has been found. <h3>AIMS</h3> To assess whether preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) expression was associated with acute and/or chronic pouchitis after IPAA. <h3>METHODS</h3> Patients were prospectively assessed for the development of clinically and endoscopically proved pouchitis. Serum obtained at the time of colectomy in 95 UC patients undergoing IPAA was analysed for pANCA by ELISA and indirect immunofluorescence. pANCA+ patients were stratified into high level (&gt;100 ELISA units (EU)/ml) (n=9), moderate level (40–100 EU/ml) (n=32), and low level (&lt;40 EU/ml) (n=19) subgroups. <h3>RESULTS</h3> Sixty of the 95 patients (63%) expressed pANCA. After a median follow up of 32 months (range 1–89), 32 patients (34%) developed either acute (n=14) or chronic (n=18) pouchitis. Pouchitis was seen in 42% of pANCA+ patients compared with 20% of pANCA− patients (p=0.09). There was no significant difference in the incidence of acute pouchitis between the three pANCA+ patient subgroups. The cumulative risk of developing chronic pouchitis among patients with high level pANCA (56%) before colectomy was significantly higher than in patients with medium level (22%), low level (16%), and those who were pANCA− (20%) (p<i>=</i>0.005). Multivariate analysis revealed that the sole parameter significantly associated with the development of chronic pouchitis after IPAA was the presence of high level pANCA before colectomy (p=0.005). <h3>CONCLUSION</h3> High level pANCA before colectomy is significantly associated with the development of chronic pouchitis after IPAA.
Clinical Acquired Resistance to RAF Inhibitor Combinations in <i>BRAF</i>-Mutant Colorectal Cancer through MAPK Pathway Alterations
Authors: Leanne G. Ahronian, Erin M. Sennott, Eliezer M. Van Allen, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, Jason T. Godfrey, Koki Nishimura, Kerry D. Lynch, Craig H. Mermel, Elizabeth L. Lockerman, Anuj Kalsy, Joseph M. Gurski, Samira Bahl, Kristin Anderka, Lisa M. Green, Niall J. Lennon, Tiffany G. Huynh, Mari Mino-Kenudson, Gad Getz, Dora Dias-Santagata, A. John Iafrate, Jeffrey A. Engelman, Levi A. Garraway, Ryan B. Corcoran
Journal: Cancer Discovery (2015)

BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance.
Molecular Cytogenetic Identification of Subgroups of Grade III Invasive Ductal Breast Carcinomas with Different Clinical Outcomes
Authors: Chris Jones, Emily Ford, Cheryl Gillett, Ken Ryder, Samantha Merrett, Jorge S. Reis-Filho, Laura G. Fulford, Andrew Hanby, Sunil R. Lakhani
Journal: Clinical Cancer Research (2004)

Abstract Tumor grade is an established indicator of breast cancer outcome, although considerable heterogeneity exists even within-grade. Around 25% of grade III invasive ductal breast carcinomas are associated with a “basal” phenotype, and these tumors are reported to be a distinct subgroup. We have investigated whether this group of breast cancers has a distinguishing pattern of genetic alterations and which of these may relate to the different clinical outcome of these patients. We performed comparative genomic hybridization (CGH) analysis on 43 grade III invasive ductal breast carcinomas positive for basal cytokeratin 14, as well as 43 grade- and age-matched CK14-negative controls, all with up to 25 years (median, 7 years) of clinical follow-up. Significant differences in CGH alterations were seen between the two groups in terms of mean number of changes (CK14+ve − 6.5, CK14−ve − 10.3; P = 0.0012) and types of alterations at chromosomes 4q, 7q, 8q, 9p, 13q, 16p, 17p, 17q, 19p, 19q, 20p, 20q and Xp. Supervised and unsupervised algorithms separated the two groups on CGH data alone with 76% and 74% accuracy, respectively. Hierarchical clustering revealed distinct subgroups, one of which contained 18 (42%) of the CK14+ve tumors. This subgroup had significantly shorter overall survival (P = 0.0414) than other grade III tumors, regardless of CK14 status, and was an independent prognostic marker (P = 0.031). These data provide evidence that the “basal” phenotype on its own does not convey a poor prognosis. Basal tumors are also heterogeneous with only a subset, identifiable by pattern of genetic alterations, exhibiting a shorter overall survival. Robust characterization of this basal group is necessary if it is to have a major impact on management of patients with breast cancer.
NADPH Oxidase-Mediated Redox Signaling: Roles in Cellular Stress Response, Stress Tolerance, and Tissue Repair
Authors: Fan Jiang, Yun Zhang, Gregory J. Dusting
Journal: Pharmacological Reviews (2011)

NADPH oxidase (Nox) has a dedicated function of generating reactive oxygen species (ROS). Accumulating evidence suggests that Nox has an important role in signal transduction in cellular stress responses. We have reviewed the current evidence showing that the Nox system can be activated by a collection of chemical, physical, and biological cellular stresses. In many circumstances, Nox activation fits to the cellular stress response paradigm, in that (1) the response can be initiated by various forms of cellular stresses; (2) Nox-derived ROS may activate mitogen-activated protein kinases (extracellular signal-regulated kinase, p38) and c-Jun NH<sub>2</sub>-terminal kinase, which are the core of the cell stress-response signaling network; and (3) Nox is involved in the development of stress cross-tolerance. Activation of the cell survival pathway by Nox may promote cell adaptation to stresses, whereas Nox may also convey signals toward apoptosis in irreversibly injured cells. At later stage after injury, Nox is involved in tissue repair by modulating cell proliferation, angiogenesis, and fibrosis. We suggest that Nox may have an integral role in cell stress responses and the subsequent tissue repair process. Understanding Nox-mediated redox signaling mechanisms may be of prominent significance at the crossroads of directing cellular responses to stress, aiming at either enhancing the stress resistance (in such situations as preventing ischemia-reperfusion injuries and accelerating wound healing) or sensitizing the stress-induced cytotoxicity for proliferative diseases such as cancer. Therefore, an optimal outcome of interventions on Nox will only be achieved when this is dealt with in a timely and disease-and stage-specific manner.
Treatment of Sexual Precocity by Removal of a Luteinizing Hormone—Releasing Hormone Secreting Hamartoma
Authors: R. A. Price, P. A. Lee, A. L. Albright, Oline Ronnekleiv, J. P. Gutai
Journal: JAMA (1984)

A 1-year-old infant was initially seen with precocious puberty that progressed rapidly and was associated with episodic gonadotropin release. A computed tomographic metrizamide cisternogram showed a pedunculated mass below the tuber cinereum; the mass was resected. His pubertal development regressed, his accelerated growth ceased, and his hormone levels returned to the normal prepubertal range. Immunocytochemical studies of the tissue demonstrated luteinizing hormone—releasing hormone (LHRH) granules in the perikaryon of neurons and axons in the hamartoma and axons connecting the hamartoma to the tuber cinereum. These data suggest that such lesions cause pubertal development by stimulating gonadotropin secretion via episodic release of LHRH. If such lesions are pedunculated, operative resection may be the treatment of choice. (<i>JAMA</i>1984;251:2247-2249)