tbuckley/cabot-search huggingface dataset:
Abstract 011: Sex Hormone-Binding Globulin (SHBG) and Risk of Clinical Diabetes in American Black, Hispanic, and Asian/Pacific Islander Postmenopausal Women.
Authors: Brian H Chen, Kathleen Brennan, Atsushi Goto, Yiqing Song, Najib Aziz, Nai-chieh Y You, Melissa F Wellons, JoAnn E Manson, Donna L White, Anthony W Butch, Simin Liu
Journal: Circulation (2012)

BACKGROUND: Recent prospective studies have shown a strong inverse association between sex hormone-binding globulin (SHBG) levels and risk of clinical diabetes in Whites. However, it remains unknown whether this relation extends to other racial/ethnic populations. METHODS: We evaluated the association between baseline levels of SHBG and risk of clinical diabetes in the Women’s Health Initiative Observational Study. Over a median follow-up of 5.9 years, 542 postmenopausal women developed clinical diabetes (338 Blacks, 128 Hispanics, 76 Asians) and were matched to 1,110 controls (707 Blacks, 249 Hispanics, 154 Asians). To complement our protein-level findings, we also genotyped 5 SHBG polymorphisms. We performed Mendelian randomization analysis to assess the potential causal relation between SHBG levels and risk of clinical diabetes. RESULTS: Overall, higher levels of SHBG at baseline were associated with a significantly lower risk of clinical diabetes (Relative risk [RR]=0.24, 95% confidence interval [CI]=0.15-0.39 for highest versus lowest quartile of SHBG, adjusted for BMI and other known diabetes risk factors). The associations remained consistent across ethnic groups (p-for-heterogeneity=0.72): RR=0.29 (95%CI=0.16-0.54) for Blacks, RR=0.26 (95%CI=0.09-0.74) for Hispanics, and RR=0.32 (95%CI=0.06-1.73) for Asians, comparing highest to lowest quartiles of SHBG. In addition, SHBG polymorphisms affected diabetes risk proportional to serum SHBG levels. Mendelian randomization analysis confirmed the significant direct effect of SHBG on diabetes development (p=0.03). CONCLUSIONS: In this prospective cohort of postmenopausal women, we observed a robust, inverse relation between serum levels of SHBG and clinical diabetes risk in American Blacks, Hispanics, and Asian/Pacific Islanders. Genetic variants associated with SHBG levels demonstrated a similar relationship, providing support for a causal role of SHBG in the pathogenesis of type 2 diabetes.
Neuroendocrine tumors (NET) of the gastrointestinal tract: A decade of experience at the Princess Margaret Hospital
Authors: J. Rothenstein, S. Cleary, G. R. Pond, D. Dale, S. Gallinger, L. L. Siu
Journal: Journal of Clinical Oncology (2006)

4093 Background: NET are uncommon malignancies with variable natural history and often indolent biological behavior. Over the past decade novel treatment approaches have been developed. There have been few recent descriptions of large institutional experiences with multi-modality therapy for this disease. Methods: The Princess Margaret Hospital cancer registry identified 207 patients (pts) with NET of the gastrointestinal tract or unknown primary who had their initial visits between 1992 and 2002. A retrospective chart review was performed. Results: The median follow-up duration was 25 months for pts who have died and 54 months for those alive at last follow-up. Demographics of the entire cohort of 207 pts were as follows: M:F = 53%:47%; mean age = 55 years; age-adjusted Charlson score 0 = 71%. Anatomical distribution of the primary location revealed that 33% were from the foregut, 37% from midgut, 13% from hindgut and 17% from unknown origin. Pathological distribution demonstrated that 73% were NET/carcinoids, 21% were islet cell tumors and 6% were small cell carcinomas. One-third of the cohort had biochemically and/or clinically functional tumors, 24% were non-functional, and 43% were not biochemically tested and were clinically non-functional. At presentation, 61% of pts had distant metastases and 39% had locoregional disease. Curative surgery was performed in 38% of the cohort, whereas radiotherapy and chemotherapy of any intent were delivered to 15% and 34% respectively. Octreotide LAR was part of the therapeutic regime in 13% of pts. Two-year survival analysis was evaluated among 114 pts, with the remaining cohort being excluded due to either insufficient follow-up or because pts were seen for second-opinion only. Factors that were significantly related to decreased survival in univariate analyses were the presence of distant metastases and small cell histology. All pts who underwent curative surgery in this subgroup were alive at 2 years, and 88% were alive at 5 years. Conclusions: Pts with NET who are offered curative surgery have a good outcome. Distant metastases are commonly found at presentation and portend a worse prognosis. These patients should be evaluated by a multidisciplinary team regarding new approaches to surgery and other therapies. No significant financial relationships to disclose.
Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone
Authors: David A. Stempel, Ibrahim H. Raphiou, Kenneth M. Kral, Anne M. Yeakey, Amanda H. Emmett, Charlene M. Prazma, Kathleen S. Buaron, Steven J. Pascoe
Journal: New England Journal of Medicine (2016)

The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).
Hypoglycemia as an indicator of good diabetes care:
Authors: Rene Rodriguez-Gutierrez, Kasia J Lipska, Rozalina G McCoy, Naykky Singh Ospina, Henry H Ting, Victor M Montori,
Journal: BMJ (2016)

Rene Rodriguez-Gutierrez and colleagues argue that more attention should be paid to hypoglycemia when assessing management of diabetes
10. Signal transduction and apoptosis
Authors: S Bo, M Schlitzer, B Ahlemeyer, J Sakowski', J Krieglstein, L Liu, H Hosoi, M Dilling, T Shikata, G Germain, R Abraham, P Houghton, T Mainou-Fowler, S Proctor, A Dickinson, S Dillon, P Lamb, S Tian, A King, S Miller, L Kessler, J Luengo, L Averill, R Johnson, J Gleason, L Pelus, J Rosen, Smith- Kline Beecham, Ligand Pharmaceuticals
Journal: Annals of Oncology (1998)
The role of filaggrin mutations during pregnancy and postpartum: atopic dermatitis and genital skin diseases
Authors: P. Bager, J. Wohlfahrt, H. Boyd, J. P. Thyssen, M. Melbye
Journal: Allergy (2016)

Mutations in the epidermal filaggrin gene (FLG) are associated with skin barrier dysfunction (dry skin, less acidic skin, and fissured skin), and atopic dermatitis (AD) with a severe and persistent course. Because pregnancy and delivery further impairs normal skin barrier functions (immune suppression, mechanical stress), we studied the possible role of FLG mutations on the risk of AD flares, genital infections, and postpartum problems related to perineal trauma. FLG-genotyping was performed in a population-based sample of 1837 women interviewed in the 12th and 30th weeks of pregnancy and 6 months postpartum as part of the Danish National Birth Cohort study 1996-2002. We found that FLG mutations also influence pregnancy-related skin disease; thus, women with FLG mutations had an increased risk of AD flares during pregnancy (OR 10.5, 95% CI 3.6-30.5) and of enduring postpartum physical problems linked to perineal trauma during delivery (OR 11.1, 95% CI 1.1-107.7).
Interim analysis of a phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC)
Authors: R. A. Juergens, F. Vendetti, B. Coleman, R. S. Sebree, M. A. Rudek, S. Belinsky, M. Brock, J. Herman, S. Baylin, C. M. Rudin
Journal: Journal of Clinical Oncology (2009)

8055 Background: Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Pre-clinical studies suggest that combining inhibitors of DNA methyltransferase (DNMT) with inhibitors of histone deacetylase (HDAC) synergistically induce re-expression of epigenetically-silenced tumor suppressor genes. Clinical studies at our institution combining the DNMT inhibitor, 5AC, with the HDAC inhibitor, entinostat, in hematologic malignancies have shown remarkable clinical activity. We hypothesized a similar effect would be seen in lung cancer. This study aims to assess the response rate and time to progression of 5AC and entinostat in NSCLC. Methods: Patients (pts) include adults with histologically confirmed recurrent NSCLC and progressive disease after ≥1 prior chemotherapy regimen. 40 mg/m 2 of 5AC is administered SQ days 1–6 and 8–10 with 7 mg of entinostat PO days 3 and 10 of a 28 day cycle. A standard Simon two stage design is being used. The sample size is calculated with a power of 90% and a two-sided type 1 error allowance of 5%. Stage 1 included 18 pts, with subsequent expansion to a total of 32. Results: 25 pts have enrolled to date. Demographic characteristics include: mean age (range) - 63 (46- 80); M:F - 1:2; 80% former smokers; 80% adenocarcinomas; mean # of previous therapies - 3. One pt. has had a complete response. She remained on therapy for 14 m and came off therapy due to a new nodule which was resected. Molecular analysis suggests a second primary stage I NSCLC. She remains disease free at 20 m. Another man has stabilization of disease (SD) for ≥16 m with marked symptomatic improvement. Another pt had SD for 4 months. The remaining pts have progressed after 2 cycles of therapy. Main toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and hematologic toxicities. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. 2 pts have had durable benefit from treatment, including a complete response. Pharmacodynamic and pharmacokinetic analyses are being conducted to identify characteristics of the subset of pts responding to this novel therapy. [Table: see text]
Discontinuation of Antihypertensive Treatment in Elderly Patients and Cognitive Function
Authors: Konstantinos Imprialos, Chrysoula Boutari, Michael Doumas
Journal: JAMA Internal Medicine (2016)

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Intramitochondrial Fibers With Deoxyribo-nucleic Acid Characteristics: Observations of Ehrlich Ascites Tumor Cells2
Authors: Sylvan Nass, Margit M. K. Nass
Journal: JNCI Journal of the National Cancer Institute (1964)

Ehrlich ascites tumor cells were examined in the electron microscope for mitochondrial fibers with deoxyribonucleic acid (DNA) properties similar to those demonstrated in chick embryo mitochondria. Fibers with fixation and electron-staining properties characteristic of bacterial nucleoplasm and purified DNA were repeatedly observed. The rod-shaped structures of clumped fibrils typically observed in mitochondria of most tissues after fixation with osmium tetroxide were also seen in numerous mitochondria of ascites cells after sections were stained with uranyl acetate and lead hydroxide. In many other mitochondria of these tumor cells, however, the fibers were fixed as curved, circular, or figure-eight-shaped profiles. These curved fibers were often intimately associated with a globular body observed frequently in structurally damaged mitochondria. Usually the globules appeared homogeneous, but occasionally a substructure was recognizable. A deeply staining rim partly or completely surrounded the globules. Micrographs are presented which are interpreted as indicative of a stepwise destruction of mitochondria leading to the formation of vesicular structures in the cytoplasm. The vesicular structures contain the globular products characteristic of degenerating mitochondria. In some sections, the vesicles are filled with virus-like particles. The observations are discussed in relation to a possible role of the mitochondrial fibers with DNA characteristics in neoplasia.
Development and validation of the mastocytosis quality of life questionnaire: MC-QoL
Authors: F. Siebenhaar, E. von Tschirnhaus, K. Hartmann, A. Rabenhorst, P. Staubach, A. Peveling-Oberhag, N. Wagner, P. Martus, M. C. Carter, D. D. Metcalfe, M. K. Church, M. Maurer, K. Weller
Journal: Allergy (2016)

Background Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients affected suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific instrument to measure health-related quality of life (HRQoL) impairment in patients with mastocytosis. Objective The aim of this study was to develop and validate a disease-specific tool to assess HRQoL impairment in patients with cutaneous and indolent systemic mastocytosis, the Mastocytosis Quality of Life Questionnaire (MC-QoL). Methods Sixty-two potential MC-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients and a final review for face validity. The resulting MC-QoL was tested for validity, reliability and influence factors. In parallel, an US American-English version of the MC-QoL was developed. Results A total of 158 patients (41 CM, 41 MIS and 76 ISM) took part in the MC-QoL validation study. The final 27-item questionnaire was found to have a four-domain structure (‘symptoms’, ‘emotions’, ‘social life/functioning’ and ‘skin’), a valid total score and an excellent test–retest reliability. Multiple regression analysis revealed disease duration, but not age, gender or skin involvement to be a significant determinant of HRQoL impairment in mastocytosis. Conclusions The MC-QoL is the first disease-specific HRQoL questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This short, validated and reliable instrument will serve as a valuable tool in future clinical studies and in routine patient care.
Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer
Authors: Andrew J. Gunderson, Megan M. Kaneda, Takahiro Tsujikawa, Abraham V. Nguyen, Nesrine I. Affara, Brian Ruffell, Sara Gorjestani, Shannon M. Liudahl, Morgan Truitt, Peter Olson, Grace Kim, Douglas Hanahan, Margaret A. Tempero, Brett Sheppard, Bryan Irving, Betty Y. Chang, Judith A. Varner, Lisa M. Coussens
Journal: Cancer Discovery (2015)

Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell-dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ(+) tumor-associated macrophages, resulting in T(H)2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a T(H)1 phenotype that fostered CD8(+) T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.
Progress on Covalent Inhibition of KRASG12C
Authors: Kenneth D. Westover, Pasi A. Jänne, Nathanael S. Gray
Journal: Cancer Discovery (2016)

Abstract Summary: Recent reports of small-molecule approaches to directly inhibit oncogenic KRASG12C have invigorated the RAS research community by raising the possibility of drugging a protein that was long considered “undruggable.” A new iteration of covalent compounds targeting the allosteric switch II pocket of KRASG12C showed improved potency and selectivity and enabled studies demonstrating that KRASG12C rapidly cycles its nucleotide substrate. This report illustrates the value of chemical probes in dissecting RAS biology and raises additional hope for development of viable pharmacologic strategies for directly targeting KRASG12C. Cancer Discov; 6(3); 233–4. ©2016 AACR. See related article by Patricelli et al., p. 316.
Abstract 114: Diurnal Variability in Inpatient Cardiopulmonary Arrest Incidence Based on Arrest Etiology
Authors: Edward Mims, Rebecca E Sell, Ruth W Chappell, Anushirvan Minokadeh, Daniel P Davis
Journal: Circulation (2013)

Introduction: Little information exists regarding inpatient cardiopulmonary arrest (CPA). We hypothesized that variability would exist in the incidence of CPA “after hours” due to the presence of f...
A controlled clinical trial of the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen.
Authors: B R Meyer, V O'Mara, M M Reidenberg
Journal: Journal of Clinical Oncology (1987)

A randomized prospective clinical trial was conducted to evaluate the potential utility of adding transdermal scopolamine to a standard regimen of metoclopramide and dexamethasone for the prevention of cisplatin-induced emesis. Thirty-one patients who were about to receive their first cycle of chemotherapy, using a combination regimen including cisplatin at a dose greater than or equal to 60 mg/m2 were randomized to receive an antiemetic regimen of either metoclopramide and dexamethasone alone, or these two drugs plus transdermal scopolamine patches. The mean number of episodes of emesis was .63 +/- 1.31 in the 16 scopolamine-treated patients, and 2.27 +/- 2.66 in the 15 patients who did not receive scopolamine (P less than .01). The scopolamine appeared to inhibit extrapyramidal reactions to the metoclopramide, but the number of cases was too small for statistical significance. We conclude that the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen provides additive benefit in the control of cisplatin-induced emesis.
Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?
Authors: Alan T. Nurden, Paquita Nurden
Journal: American Journal of Hematology (2016)

There is much current interest in the role of the platelet storage pool of α-granule proteins both in hemostasis and non-hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α-granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant α-granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet α-granule biogenesis and to urge caution in grouping all genetic defects of α-granules as GPS. Am. J. Hematol. 91:714-718, 2016. © 2016 Wiley Periodicals, Inc.
Spotlight on measles 2010: Update on the ongoing measles outbreak in France, 2008-2010
Authors: I Parent du Châtelet, D Antona, F Freymuth, M Muscat, F Halftermeyer-Zhou, C Maine, D Floret, D Lévy-Bruhl
Journal: Eurosurveillance (2010)

Since early 2008, France has been experiencing a measles outbreak with almost 5,000 notified cases as of 30 June 2010, including three measles-related deaths. The proportion of cases 20 years or older reached 38% during the first half of 2010. This situation is the consequence of insufficient vaccine coverage (90% at age 24 months in 2007) that led to the accumulation of susceptibles over the last years. It underlines the need for additional measures targeting susceptible children and young adults.