tbuckley/cabot-search huggingface dataset:
Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5
Authors: Maria Buxadé, Giulia Lunazzi, Jordi Minguillón, Salvador Iborra, Rosa Berga-Bolaños, Margarita del Val, José Aramburu, Cristina López-Rodríguez
Journal: The Journal of Experimental Medicine (2012)

Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.
Private rare deletions in <i>SEC16A</i> and <i>MAMDC4</i> may represent novel pathogenic variants in familial axial spondyloarthritis
Authors: Darren D O'Rielly, Mohammed Uddin, Dianne Codner, Michael Hayley, Jiayi Zhou, Lourdes Pena-Castillo, Ahmed A Mostafa, S M Mahmudul Hasan, William Liu, Nigil Haroon, Robert Inman, Proton Rahman
Journal: Annals of the Rheumatic Diseases (2015)

Objective Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family. Methods HLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure. Results This is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4 . Conclusions The results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele.
Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study
Authors: Antonio H Madrid, Javier Ortega, Jose G Rebollo, Juan G Manzano, Javier G Segovia, Andrés Sánchez, Gonzalo Peña, Concepción Moro
Journal: Journal of the American College of Cardiology (2001)
Plasma gastrin:somatostatin ratio is decreased in gastrinomas
Authors: R. Ramachandran, P. Bech, K. G. Murphy, W. S. Dhillo, L. Marelli, M. A. Ghatei, S. R. Bloom, M. Caplin, N. M. Martin
Journal: Gut (2011)

<h3>Introduction</h3> Fasting gastrin alone is inadequate for diagnosis of gastrinoma because hypergastrinemia occurs in a number of non-gastrinoma conditions, including atrophic gastritis. Confirmation of diagnosis requires more invasive investigations to demonstrate low gastric pH. The density of somatostatin secreting D-cells and gastrin secreting G-cells is dependent on gastric pH. A low gastric pH is associated with a relative increase in D-cell density, resulting in a decrease in G-cell:D-cell ratio. We compared plasma somatostatin levels and the plasma gastrin:somatostatin ratios in patients with achlorhydria secondary to atrophic gastritis and in patients with gastrinoma. We also compared chromogranin A (CgA) levels in the two groups. <h3>Methods</h3> Plasma gastrin, somatostatin and CgA were measured in 21 patients with gastrinomas and 23 patients with atrophic gastritis referred to the Supra regional Assay and Advisory Service Laboratory at our centre. <h3>Results</h3> There was no significant difference between plasma gastrin in patients with gastrinomas and atrophic gastritis. Plasma somatostatin was significantly higher in patients with gastrinomas compared to patients with atrophic gastritis (p&lt;0.005). Gastrinoma patients had significantly lower plasma gastrin:somatostatin ratios compared to those with atrophic gastritis (p&lt;0.001). Patients with gastrinomas had significantly higher plasma Cg A compared to patients with atrophic gastritis (p&lt;0.005). No patients with atrophic gastritis had Cg A levels greater than100 pmol/L. The combination of plasma Cg A and plasma gastrin:somatostatin ratio has a predictive power of 76% and an area under ROC curve of 0.87. <h3>Conclusion</h3> The plasma gastrin:somatostatin ratio and measurement of plasma Cg A may be helpful in planning the diagnostic work-up for patients with raised fasting gastrin levels. Combining these biochemical tests could allow correct identification of gastrinoma patients requiring further assessment and significantly reduce unnecessary investigation of gastric pH in non-gastrinoma patients.
Phase I/II Study of Cetuximab in Combination With Cisplatin or Carboplatin and Fluorouracil in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Authors: Jean Bourhis, Fernando Rivera, Ricard Mesia, Ahmad Awada, Lionel Geoffrois, Christian Borel, Yves Humblet, Antonio Lopez-Pousa, Ricardo Hitt, M. Eugenia Vega Villegas, Lionel Duck, Dominique Rosine, Nadia Amellal, Armin Schueler, Andreas Harstrick
Journal: Journal of Clinical Oncology (2006)

Purpose This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Treatment comprised cetuximab (initial dose 400 mg/m 2 with subsequent weekly doses of 250 mg/m 2 ) in combination with 3-week cycles of either cisplatin (100 mg/m 2 ) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m 2 /d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity. Results Fifty-three patients were enrolled onto the study. The incidence of dose-limiting toxicities in phase A was acceptable. The most common grade 3/4 adverse events in both groups were leucopenia (38%), asthenia (25%), vomiting (14%), and thrombocytopenia (15%), which are consistent with the known safety profiles of cetuximab, cisplatin/carboplatin, and FU. The overall response rate among patients was 36%, with no clear trend toward an increased efficacy at the highest dose of FU, and no impact of the concomitant chemotherapy regimens on cetuximab pharmacokinetics. Conclusion The combination of cetuximab, cisplatin/carboplatin, and FU was reasonably well tolerated and active in recurrent/metastatic SCCHN, and merits additional investigation. An FU dose of 1,000 mg/m 2 /d in combination with cisplatin or carboplatin can be recommended for additional studies.
Circulating biomarker tissue kallikrein-related peptidase KLK5 impacts ovarian cancer patients' survival.
Authors: J. Dorn, T. Schuster, A. Gkazepis, M. Kiechle, E. P. Diamandis, A. Harlozinska, V. Magdolen, M. Schmitt
Journal: Journal of Clinical Oncology (2010)

5088 Background: KLK5 is a secreted serine protease expressed in hormonally regulated tissues, including the ovary. KLK5 is almost undetectable in the serum of normal individuals and in patients with malignancies other than that of the ovary or the breast. Besides that, high levels of KLK5 were detected in the ascitic fluid obtained from advanced ovarian cancer patients. KLK5 expression in ovarian cancer tissues was also demonstrated at the gene and the protein level. Thus, KLK5 appears to be a promising disease forecast marker for predicting the clinical course of ovarian cancer. Methods: 52 patients with histologically confirmed primary ovarian carcinoma FIGO I-IV were enrolled in this study. Patients were treated by primary cytoreductive surgery followed by platinum-containing chemotherapy. Antigen concentration of KLK5 in serum and ascitic fluid was quantified by ELISA. No cross- reactivity of the KLK5-ELISA with the other 14 members of the kallikrein-like peptidase family was observed. For comparison, a collective of sera obtained from 45 patients with benign ovarian neoplasms was studied. Results: We confirm earlier findings acquired on another own set of patients that ovarian cancer patients release significant amounts of KLK5 into the blood stream. With respect to patients with benign ovarian tumor, we now report that KLK5 is also released into the blood of these patients but at a much lower rate. Regarding progression-free survival of the ovarian cancer patients, KLK5 content both in ascitic fluid and serum was of prognostic relevance. Conclusions: These data, taken as a whole, endorse present knowledge that KLK5 is a valid and important biomarker in ovarian cancer patients, both in tumor tissue and serum. Yet, since KLK5 protein is not present in normal female donors and low in patients with benign ovarian tumors but increased in ovarian cancer patients, we propose that KLK5 could serve as a potential serum biomarker to identify patients afflicted with ovarian tumors, either in the benign or malignant state. No significant financial relationships to disclose.
Accuracy of Administrative Coding for Type 2 Diabetes in Children, Adolescents, and Young Adults
Authors: Erinn T. Rhodes, Lori M.B. Laffel, Tessa V. Gonzalez, David S. Ludwig
Journal: Diabetes Care (2006)

Administrative data are used with increasing frequency in research. However, validity of such data, including International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes (1), varies across diseases and settings (2–12). The ICD-9-CM coding for diabetes in youth may be especially susceptible to errors. While most diagnoses of diabetes in American youth are type 1 diabetes (13), incidence of type 2 diabetes is increasing (14). Rising prevalence of pediatric obesity (15) makes distinguishing between type 1 and type 2 diabetes at diagnosis difficult, and type 2 diabetes ICD-9-CM codes (250.X0/X2) include “unspecified” diabetes (1). Our aim was to evaluate the positive predictive value (PPV) of type 2 diabetes ICD-9-CM codes in children, adolescents, and young adults.

In a retrospective chart review, we evaluated 432 patients aged <26 years as of 31 January 2005 with at least one visit to the Endocrine/Diabetes or Obesity Programs at Children’s Hospital Boston in Boston, Massachusetts, from 1 July 2003 to 31 January 2005 and at least one type 2 diabetes ICD-9-CM code (250.X0/X2, X = 0–9) from inpatient/outpatient sites before 5 April 2005. We identified 455 patients utilizing scheduling and billing information, and excluded 23 patients without completed visits.

To contrast the accuracy of type 2 diabetes ICD-9-CM codes with type 1 diabetes ICD-9-CM codes, we reviewed charts of patients <26 years as of 31 January 2005 with at least one visit to the Endocrine/Diabetes Program from 1 July 2003 to 31 January …
Confirmation of Family Cancer History Reported in a Population-Based Survey
Authors: Phuong L. Mai, Anne O. Garceau, Barry I. Graubard, Marsha Dunn, Timothy S. McNeel, Lou Gonsalves, Mitchell H. Gail, Mark H. Greene, Gordon B. Willis, Louise Wideroff
Journal: JNCI Journal of the National Cancer Institute (2011)

Knowledge of family cancer history is essential for estimating an individual's cancer risk and making clinical recommendations regarding screening and referral to a specialty cancer genetics clinic. However, it is not clear if reported family cancer history is sufficiently accurate for this purpose. In the population-based 2001 Connecticut Family Health Study, 1019 participants reported on 20 578 first-degree relatives (FDR) and second-degree relatives (SDR). Of those, 2605 relatives were sampled for confirmation of cancer reports on breast, colorectal, prostate, and lung cancer. Confirmation sources included state cancer registries, Medicare databases, the National Death Index, death certificates, and health-care facility records. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for reports on lung, colorectal, breast, and prostate cancer and after stratification by sex, age, education, and degree of relatedness and used to estimate report accuracy. Pairwise t tests were used to evaluate differences between the two strata in each stratified analysis. All statistical tests were two-sided. Overall, sensitivity and positive predictive value were low to moderate and varied by cancer type: 60.2% and 40.0%, respectively, for lung cancer reports, 27.3% and 53.5% for colorectal cancer reports, 61.1% and 61.3% for breast cancer reports, and 32.0% and 53.4% for prostate cancer reports. Specificity and negative predictive value were more than 95% for all four cancer types. Cancer history reports on FDR were more accurate than reports on SDR, with reports on FDR having statistically significantly higher sensitivity for prostate cancer than reports on SDR (58.9% vs 21.5%, P = .002) and higher positive predictive value for lung (78.1% vs 31.7%, P < .001), colorectal (85.8% vs 43.5%, P = .004), and breast cancer (79.9% vs 53.6%, P = .02). General population reports on family history for the four major adult cancers were not highly accurate. Efforts to improve accuracy are needed in primary care and other health-care settings in which family history is collected to ensure appropriate risk assessment and clinical care recommendations.
Netrin-1 acts as a survival factor for aggressive neuroblastoma
Authors: Céline Delloye-Bourgeois, Julien Fitamant, Andrea Paradisi, David Cappellen, Setha Douc-Rasy, Marie-Anne Raquin, Dwayne Stupack, Akira Nakagawara, Raphaël Rousseau, Valérie Combaret, Alain Puisieux, Dominique Valteau-Couanet, Jean Bénard, Agnès Bernet, Patrick Mehlen
Journal: The Journal of Experimental Medicine (2009)

Neuroblastoma (NB), the most frequent solid tumor of early childhood, is diagnosed as a disseminated disease in &amp;gt;60% of cases, and several lines of evidence support the resistance to apoptosis as a prerequisite for NB progression. We show that autocrine production of netrin-1, a multifunctional laminin-related molecule, conveys a selective advantage in tumor growth and dissemination in aggressive NB, as it blocks the proapoptotic activity of the UNC5H netrin-1 dependence receptors. We show that such netrin-1 up-regulation is a potential marker for poor prognosis in stage 4S and, more generally, in NB stage 4 diagnosed infants. Moreover, we propose that interference with the netrin-1 autocrine loop in malignant neuroblasts could represent an alternative therapeutic strategy, as disruption of this loop triggers in vitro NB cell death and inhibits NB metastasis in avian and mouse models.
New rules drive off NIH researchers
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

Tough new rules on ethics and on competing interests have caused four top researchers at the US National Institutes of Health (NIH) to quit and a prospective new head of one of the institutes to reconsider taking up the position. Meanwhile, the director of the NIH, Elias Zerhouni, told a Senate committee on 6 April that the rules had had a “deleterious impact” on the institutes and that he would consider changes.

The most senior of the top researchers to leave is James Battey, chairman of the NIH's stem cell task force and head of its National Institute on Deafness and Other Communication Disorders, who will retire in September. He has applied to be president of the new California Institute for …
The Apolipoprotein L1 (APOL1) Gene and Nondiabetic Nephropathy in African Americans
Authors: Barry I Freedman, Jeffrey B Kopp, Carl D Langefeld, Giulio Genovese, David J Friedman, George W Nelson, Cheryl A Winkler, Donald W Bowden, Martin R Pollak
Journal: Journal of the American Society of Nephrology (2010)

Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.
Recent Trends in Cardiovascular Complications Among Men and Women With and Without Diabetes
Authors: Gillian L. Booth, Moira K. Kapral, Kinwah Fung, Jack V. Tu
Journal: Diabetes Care (2006)

OBJECTIVE—To compare recent trends in cardiovascular disease (CVD) outcomes among men and women with diabetes with those in the nondiabetic population. RESEARCH DESIGN AND METHODS—We conducted a retrospective cohort study using provincial health claims data to identify adults with (n = 670,602) and without (n = 9,190,721) diabetes living in Ontario, Canada, between 1 April 1992 and 31 March 2000. We compared changes in the annual age-/sex-adjusted rates and numbers of subjects admitted for acute myocardial infarction (AMI) and stroke and of deaths from AMI, stroke, and all causes between those with and without diabetes. RESULTS—Over the 8-year period, the rate of patients admitted for AMI and stroke fell to a greater extent in the diabetic than the nondiabetic population (AMI: −15.1 vs. −9.1%, P &amp;lt; 0.0001; stroke: −24.2 vs. 19.4%, P &amp;lt; 0.0001). Diabetic patients experienced similar reductions in case-fatality rates related to AMI and stroke than those without diabetes (−44.1 vs. −33.2%, P = 0.1; −17.1 vs. −16.6%, P = 0.9, respectively). Declines in all-cause mortality were also comparable in the two populations. Over the same period, the number of diabetes cases increased from 405,471 to 670,602. Thus, while CVD rates fell, the number of events occurring in this population rose substantially (AMI: +44.6%, stroke: +26.1%, AMI deaths: +17.2%, and stroke deaths: +13.2%). CONCLUSIONS—Our findings demonstrate a significant reduction in the rate of people affected by CVD within the diabetic population. However, as the number of people with diabetes rises, so may the absolute burden of CVD in our society.
Practicing Internal Medicine Onboard the USNS COMFORT in the Aftermath of the Haitian Earthquake
Authors: Dennis Amundson
Journal: Annals of Internal Medicine (2010)

On 12 January 2010, a 7.0-magnitude earthquake devastated the island nation of Haiti, leading to the world's largest humanitarian effort in over 6 decades. The catastrophe caused massive destruction of homes and buildings and overwhelmed the Haitian health care system. The United States responded immediately with a massive relief effort, sending U.S. military forces and civilian volunteers to Haiti's aid and providing a tertiary care medical center aboard the USNS COMFORT hospital ship. The COMFORT offered sophisticated medical care to a geographically isolated population and helped to transfer resource-intensive patients from other treatment facilities. Working collaboratively with the surgical staff, ancillary services, and nursing staff, internists aboard the COMFORT were integral to supporting the mission of the hospital ship and provided high-level care to the casualties. This article provides the perspective of the U.S. Navy internists who participated in the initial response to the Haitian earthquake disaster onboard the COMFORT.
Time‐course studies of immediate and delayed immune reactivity in patients with atopic dermatitis treated with herbal drugs
Authors: U. Søderberg, B. Windelborg Nielsen, C. Schade Larsen, P. O. Schiøtz, K. Testrup‐Pedersen
Journal: Allergy (1990)

We followed a number of in vitro parameters in nine adult patients with atopic dermatitis for a period of 3 weeks during which the patients took herbal drugs that are claimed to improve chronic eczema. The following investigations were performed weekly: blood leucocytes, circulating eosinophils, serum IgE, mitogen responsiveness of lymphocytes, interleukin 1 release, soluble interleukin 2 receptor levels in serum, and in vitro histamine release from basophils in blood. The study demonstrated increased levels of IgE in six patients, increased levels of soluble interleukin 2 receptor in six patients, and a significant correlation between the amount of IgE in serum and the maximal release of histamine from basophils in blood. In this open study five patients experienced a clinical worsening of their disease during the intake of herbal medicine. All other parameters were within normal levels. There was no significant change in the in vitro parameters during the observation period.