tbuckley/cabot-search huggingface dataset:
Allergic diseases and long-term risk of autoimmune disorders: longitudinal cohort study and cluster analysis
Authors: Mamidipudi Thirumala Krishna, Anuradhaa Subramanian, Nicola J. Adderley, Dawit T. Zemedikun, Georgios V. Gkoutos, Krishnarajah Nirantharakumar
Journal: European Respiratory Journal (2019)

Introduction The association between allergic diseases and autoimmune disorders is not well established. Our objective was to determine incidence rates of autoimmune disorders in allergic rhinitis/conjunctivitis (ARC), atopic eczema and asthma, and to investigate for co-occurring patterns. Methods This was a retrospective cohort study (1990–2018) employing data extracted from The Health Improvement Network (UK primary care database). The exposure group comprised ARC, atopic eczema and asthma (all ages). For each exposed patient, up to two randomly selected age- and sex-matched controls with no documented allergic disease were used. Adjusted incidence rate ratios (aIRRs) were calculated using Poisson regression. A cross-sectional study was also conducted employing Association Rule Mining (ARM) to investigate disease clusters. Results 782 320, 1 393 570 and 1 049 868 patients with ARC, atopic eczema and asthma, respectively, were included. aIRRs of systemic lupus erythematosus (SLE), Sjögren's syndrome, vitiligo, rheumatoid arthritis, psoriasis, pernicious anaemia, inflammatory bowel disease, coeliac disease and autoimmune thyroiditis were uniformly higher in the three allergic diseases compared with controls. Specifically, aIRRs of SLE (1.45) and Sjögren's syndrome (1.88) were higher in ARC; aIRRs of SLE (1.44), Sjögren's syndrome (1.61) and myasthenia (1.56) were higher in asthma; and aIRRs of SLE (1.86), Sjögren's syndrome (1.48), vitiligo (1.54) and psoriasis (2.41) were higher in atopic eczema. There was no significant effect of the three allergic diseases on multiple sclerosis or of ARC and atopic eczema on myasthenia. Using ARM, allergic diseases clustered with multiple autoimmune disorders. Three age- and sex-related clusters were identified, with a relatively complex pattern in females ≥55 years old. Conclusions The long-term risks of autoimmune disorders are significantly higher in patients with allergic diseases. Allergic diseases and autoimmune disorders show age- and sex-related clustering patterns.
Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis
Authors: Ji-Yeon Shin, Antonio Hernandez-Ono, Tatyana Fedotova, Cecilia Östlund, Michael J. Lee, Sarah B. Gibeley, Chun-Chi Liang, William T. Dauer, Henry N. Ginsberg, Howard J. Worman
Journal: Journal of Clinical Investigation (2019)

Deciphering novel pathways that regulate liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent evidence suggests that the nuclear envelope is a site of regulation of lipid metabolism, but there is limited appreciation of the responsible mechanisms and molecular components within this organelle. We showed that conditional hepatocyte deletion of the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) causes defective VLDL secretion and steatosis, including intranuclear lipid accumulation. LAP1 binds to and activates torsinA, an AAA+ ATPase that resides in the perinuclear space and continuous main ER. Deletion of torsinA from mouse hepatocytes caused even greater reductions in VLDL secretion and profound steatosis. Mice from both of the mutant lines studied developed hepatic steatosis and subsequent steatohepatitis on a regular chow diet in the absence of whole-body insulin resistance or obesity. Our results establish an essential role for the nuclear envelope–localized torsinA-LAP1 complex in hepatic VLDL secretion and suggest that the torsinA pathway participates in the pathophysiology of NAFLD.
Effect of Bismuth Subsalicylate vs Placebo on Use of Antibiotics Among Adult Outpatients With Diarrhea in Pakistan
Authors: Anna Bowen, Mubina Agboatwalla, Adam Pitz, Sadaf Salahuddin, Jose Brum, Brian Plikaytis
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Many of the 4.5 billion annual episodes of diarrhea are treated unnecessarily with antibiotics; prevalence of antibiotic resistance among diarrheal pathogens is increasing. Knowledge-based antibiotic stewardship interventions typically yield little change in antibiotic use. <h3>Objective</h3> To compare antibiotic use among adult outpatients with diarrhea given bismuth subsalicylate (BSS) or placebo. <h3>Design, Setting, and Participants</h3> This randomized clinical trial took place from April to October 2014. Participants were patients aged 15 to 65 years with acute, nonbloody diarrhea from 22 outpatient clinics in Karachi, Pakistan. Participants were interviewed about symptoms and health care utilization during the 5 days after enrollment. Group assignment was concealed from participants, field staff, and the statistician. Primary analysis occurred from August to September 2015. <h3>Interventions</h3> Participants were randomly assigned (1:1) to receive BSS or placebo for 48 hours or less. <h3>Main Outcomes and Measures</h3> Use of systemic antibiotics within 5 days of enrollment. Secondary outcomes included measures of duration and severity of illness. <h3>Results</h3> Among eligible patients, 39 declined to participate, 440 enrolled, and 1 enrolled participant was lost to follow-up, for a total of 439 patients included in the analysis. Median (interquartile range) participant age was 32 (23-45) years and 187 (43%) were male. Two hundred twenty patients were randomized to BSS and 220 were randomized to placebo. Overall, 54 participants (12%) used systemic antibiotics (16% in the placebo group and 9% in the BSS group); all antibiotic use followed consultation with a physician. Use of any antibiotic was significantly lower in the BSS group (20 of 220 vs 34 of 219 patients; odds ratio [OR], 0.54; 95% CI, 0.30-0.98), as was use of fluoroquinolones (8 of 220 vs 20 of 219 patients; OR, 0.38; 95% CI, 0.16-0.88). Rates of care seeking and hospitalization were similar between groups and no difference was detected in timing of diarrhea resolution. However, those in the BSS group less commonly received intravenous rehydration (14 of 220 vs 27 of 219 patients; OR, 0.48; 95% CI, 0.25-0.95) and missed less work (median [interquartile range], 0 [0-1] vs 1 [0-1] day;<i>P</i> = .04) during follow-up. <h3>Conclusions and Relevance</h3> This study found less antibiotic use among participants given BSS for acute diarrhea in a setting where antibiotics are commonly used to treat diarrhea. Encouraging health care professionals in such settings to recommend BSS as frontline treatment for adults with diarrhea, and promoting BSS for diarrhea self-management, may reduce antibiotic use and rates of antibiotic resistance globally. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT02047162
GSK-3 modulates autophagy after growth factor depletion
Authors: Jun Yang, Jianxi Tang, Benyi Li
Journal: Cancer Research (2008)

LB-44  Autophagy usually occurs in response to nutrient depletion or growth factor withdrawal. Glycogen synthase kinase 3 (GSK-3) is a protein serine/threonine kinase involved in multiple cellular functions, and its activity in cells increases dramatically under the condition of serum starvation. Because serum starvation leads to autophagic response in cells, we sought to understand if GSK-3 controls autophagic activities after serum depletion. Consistent with previous reports, serum starvation led to autophagic responses including LC-3 processing and MDA-positive staining in rostate cancer PC-3 and LNCaP cells. Treatment of serum-starved cells with GSK-3 inhibitors, peptide inhibitor L803mts but not PI3K inhibitor LY294002, caused a profound necrostic cell death. L803mts-induced cell death could not be suppressed by a broad caspase inhibitor and no caspase activation and PARP cleavage (apoptotic features) were detected indicating an non-apopotic cell death. However, autophagy suppressor 3-methyladenine (3-MA) did not block L803mts-induced cell death but shift the necrotic cell death response to a dramatic apoptotic response, as evidenced by caspase activation and PARP cleavage. No significant cell death was observed under full culture media (10% serum) with the GSK-3 inhibitor L803 or 3-MA. Taken together, our data suggest that GSk-3 activity is critical for autophagy-dependent survival under the condition of serum starvation, and suppression of autophagy converts GSK-3 inhibition-induced necrotic cell death to apoptotic cell death. This study opened a novel field regarding GSK-3’s control of cell survival.
Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors
Authors: Y. Zafar, J. Bendell, J. Lager, D. Yu, D. George, A. Nixon, W. Petros, R. Beci, C. Arrowood, H. Hurwitz
Journal: Journal of Clinical Oncology (2006)

3097 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD. [Table: see text]
Mechanisms of Azacitidine Chemotherapy Resistance in AML and MDS and New Therapy Options
Authors: Lubomir Minarik, Leylah M. Drusbosky, Taher Abbasi, Karina Vargova, Vojtech Kulvait, Anna Jonasova, Neeraj Kumar Singh, Chandan Kumar, Rakhi Purushothaman Suseela, Mamatha Patil, Patil Nilesh Dattatraya, Krishna Kumar Tiwari, Shireen Vali, Christopher R. Cogle, Tomas Stopka
Journal: Blood (2018)
Therapeutic Effects of Hyaluronic Acid in Bacterial Pneumonia in<i>Ex Vivo</i>Perfused Human Lungs
Authors: Airan Liu, Jeong-Hyun Park, Xiwen Zhang, Shinji Sugita, Yoshifumi Naito, Jae-Hoon Lee, Hideya Kato, Qi Hao, Michael A. Matthay, Jae-Woo Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Recent studies have demonstrated that extracellular vesicles (EVs) released during acute lung injury (ALI) were inflammatory.Objectives: The current study was undertaken to test the role of EVs induced and released from severe Escherichia coli pneumonia (E. coli EVs) in the pathogenesis of ALI and to determine whether high-molecular-weight (HMW) hyaluronic acid (HA) administration would suppress lung injury from E. coli EVs or bacterial pneumonia.Methods: E. coli EVs were collected from the perfusate of an ex vivo perfused human lung injured with intrabronchial E. coli bacteria for 6 hours by ultracentrifugation and then given intrabronchially or intravenously to naive human lungs. One hour later, HMW HA was instilled into the perfusate (n = 5–6). In separate experiments, HMW HA was given after E. coli bacterial pneumonia (n = 6–10). In vitro experiments were conducted to evaluate binding of EVs to HMW HA and uptake of EVs by human monocytes.Measurements and Main Results: Administration of HMW HA ameliorated the impairment of alveolar fluid clearance, protein permeability, and acute inflammation from E. coli EVs or pneumonia and reduced total bacteria counts after E. coli pneumonia. HMW HA bound to E. coli EVs, inhibiting the uptake of EVs by human monocytes, an effect associated with reduced TNFα (tumor necrosis factor α) secretion. Surprisingly, HMW HA increased E. coli bacteria phagocytosis by monocytes.Conclusions: EVs induced and released during severe bacterial pneumonia were inflammatory and induced ALI, and HMW HA administration was effective in inhibiting the uptake of EVs by target cells and decreasing lung injury from E. coli EVs or bacterial pneumonia.
Inhaled corticosteroids in asthma and the need for universal health coverage
Authors: Mina Gaga, Nikolai Khaltaev, Cherian Varghese
Journal: European Respiratory Journal (2019)

We read with great interest the article on inhaled corticosteroids (ICS) and their effect on asthma progression and mortality recently published in the European Respiratory Journal [1]. The article presents an excellent review on asthma natural history, lung function evolution and the role of exacerbations in the course of the disease, and on mortality as well as the effect of ICS on the disease. We absolutely agree with the writers that the introduction of ICS has indeed made a huge impact on asthma morbidity and mortality. Before their introduction, severe asthma exacerbations and deaths were frequently seen in Europe, North America, Australia and New Zealand [2–4]. These were reduced drastically after the introduction of ICS and health programmes to ensure access to medications and training of healthcare personnel working in the community to diagnose and manage asthma: In Finland, the 10 year asthma plan showed that with the initiation of the programme in 1993, asthma morbidity fell and hospital days were reduced by 54% from 1993 to 2003 [5]. At the same time, more asthma patients were diagnosed and treated but the overall cost and per patient cost was also reduced. Evidence and ICS-based asthma care reduces morbidity and mortality, and improves quality of life. It should be instituted worldwide. <http://bit.ly/2J4sW7E>
Epigenetic alteration of the MDR1 gene in human breast cancer
Authors: Hiroshi Yoshida, Kiyomi Taniyama, Kazuaki Miyamoto
Journal: Cancer Research (2008)

3221  Background: P-glycoprotein (P-gp) encoded by the MDR1 gene is a membrane protein that can export many kinds of antineoplastic agents from cells. Over-expression of P-gp may contribute to poor outcome in breast cancer treatment. DNA methylation, a major epigenetic process, can affect every step in carcinogenesis, as well as genetic alterations. However, the contribution of such epigenetic alteration to the expression of MDR1 remains largely unexplored. Materials and Methods: In this study, we evaluated DNA methylation status of the MDR1 gene promoter by means of methylation-specific PCR in 8 breast cancer cell lines and 31 cases, and the expression of MDR1 in 31 primary human breast cancer specimens by immunohistochemistry using the monoclonal antibody. Results: MDR1 was hypermethylated in 8 of 8 (100%) breast cancer cell lines and 8 of 22 (36%) primary breast cancers. We detected MDR1 expression by immunohistochemistry in 16/31 cases (52%), and the clinicopathological features were not significantly associated with MDR1expression. MDR1expression was associated with the DNA methylation status of the MDR1 gene. Conclusion: Our results suggest that epigenetic regulation might play a role in the expression of MDR1 in human breast cancer.
A modeling framework to simulate motesanib efficacy in thyroid cancer
Authors: L. Claret, J. Lu, Y. Sun, D. Stepan, R. Bruno
Journal: Journal of Clinical Oncology (2009)

e14553 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR, and Kit with antiangiogenic and direct antitumor activity. A modeling framework that simulates clinical endpoints, including objective response rate (ORR; per RECIST) and progression-free survival (PFS), was developed to support clinical development of motesanib. This study evaluated the framework using results from a trial of motesanib in thyroid cancer (TC). Methods: Models for tumor growth inhibition (J Clin Oncol 24[18S]:abstract 6025, 2006) with drug effect driven by area under the curve (AUC) (as predicted by a population pharmacokinetic model), overall survival, and probability and duration of dose reductions were developed based on data from 93 differentiated TC (DTC) and 91 medullary TC patients who received motesanib monotherapy (125 mg once daily [QD]) in a phase 2 study (Horm Res 68[suppl 3]:28–9, 2007; NEJM 359:31–42, 2008). The full simulation framework was assessed in predicting dose intensity (starting dose of 125 mg QD), tumor size over time, ORR, and PFS. Dose-response simulations were performed in DTC patients. Results: Survival times followed a Weibull distribution with ECOG performance status, baseline tumor size, and change in tumor size from baseline at week 7 as predictors. The probability of dose reductions was dependent on time and AUC. Time to event Weibull models predicted the duration of dose reductions and dose interruptions. The models correctly predicted median daily exposure intensities up to week 24. The predicted ORR in DTC patients was 15.0% (95% prediction interval [PI], 7.5%-23.7%) compared with the observed ORR of 14.0%. Predicted median PFS was 40 weeks (95% PI, 32–49 wk) compared with the observed median PFS of 40 weeks. Dose- response simulations confirmed the appropriateness of 125-mg QD dosing in DTC: the modeling framework predicted no clinically relevant improvement in PFS would be obtained by dose intensification. Conclusions: This modeling framework (dose reduction/tumor growth inhibition/survival) will be an important tool to simulate clinical response and support clinical development decisions. Further evaluation of the model using additional datasets will be required. [Table: see text]
Low expression of the CDK inhibitor p27Kip1 confers tamoxifen resistance in premenopausal breast cancer patients.
Authors: Caroline Holm, Maria Stendahl, Goran Landberg
Journal: Cancer Research (2007)

5218  The majority of breast cancers express the estrogen receptor (ER) α and ligand activation results in proliferation and survival of the cell. Estrogen stimulates proliferation by upregulating cyclin D1, which forms complex with CDK4/6, leading to Rb-phosphorylation. Cyclin D1/CDK4/6 also binds and sequesters the inhibitory proteins p21WAF1/CIP1 and p27Kip1 from cyclin E/CDK2 complexes which further promotes Rb-phosphorylation and progression through the cell cycle. Given that estrogen promotes tumor growth, different therapeutic strategies that inhibit the estrogenic effects are used to treat breast cancer. The most common among them is the selective estrogen receptor modulator tamoxifen which is a very efficient therapy for many breast cancer patients. There is nevertheless a substantial fraction of hormone receptor positive breast cancer patients that do not respond to tamoxifen. The reason for tamoxifen resistance is partly unknown but alterations in ER-associated proteins as well as ER-phosphorylation have been implicated in altered tamoxifen response. Cell cycle aberrations as loss of p27 Kip1 has also been suggested to influence the effect of tamoxifen due to the inability for tamoxifen to exert its function when the cdk-inhibitor p27Kip1 is missing. In order to test this hypothesis, the expression of p27Kip1 was analyzed in 321 primary breast cancer samples arranged in a tissue microarray from premenopausal patients that had been included in a randomized trial with long clinical follow-up. Half of the patients had received two years of tamoxifen treatment after surgery whereas the other half did not get any adjuvant therapy. Low expression of p27Kip1, defined as less than 75% positive nuclei, was observed in 40% of the cancer samples and was associated with ER-negativity, low age, no lymph-node metastases, high proliferation, high grade and larger tumor size. In the untreated sub population of patients there was no link between p27 Kip1 and disease recurrence suggesting that low p27 Kip1 is not a prognostic marker. In contrast, there was a strong link between low p27 Kip1 and lack of response to tamoxifen. When comparing tamoxifen treated patients and control patients there was a significant difference in recurrence-free survival for patients having ER- and PR-positive tumors with high p27 Kip1 (p=0.0003), whereas there was no difference for patients with receptor positive but low p27Kip1 tumors (p=0.8204). This difference was further significant in a multivariate interaction analysis (p=0.024). These data strongly indicate that p27Kip1 has a key role in mediating the effects of tamoxifen and that loss of p27 Kip1 is a predictive marker for poor tamoxifen response in premenopausal breast cancer but interestingly not a prognostic marker. Different experimental models will be used to further validate the importance of p27Kip1 in tamoxifen response.
Abstract #5394: MicroRNA-based assay for differential diagnosis of squamous from non-squamous non small cell lung carcinoma
Authors: Danit Lebanony, Hila Benjamin, Hila Cholakh, Naama Barabash, Hadas Gibori, Daisuke Nonaka, Meora Feinmesser, Yael Spector, Nitzan Rosenfeld, Ayelet Chajut, Dalia Cohen, Ranit Aharonov
Journal: Cancer Research (2009)

Background: Lung cancer is the leading cause of cancer mortality in the USA. Recent advances in biologically directed therapies for non-small cell lung carcinoma (NSCLC) emphasize the need for more accurate sub-classification of NSCLC, as treatment may be dictated by histologic subtype. In particular, squamous histology can be a counter-indication for treatment by VEGF inhibitors. MicroRNAs are involved in a variety of biological and pathological processes, and have been demonstrated to be highly tissue-specific biomarkers with potential clinical applicability for defining cancer type and origin. MicroRNAs are well preserved in formalin fixed tissue, making them ideal candidates for molecular markers for use in routinely processed material. Here we report on the development and performance of a microRNA-based assay for the differential diagnosis of squamous from non-squamous NSCLC. Methods: The first phase compared microRNA expression profiles for hundreds of microRNAs in more than a hundred samples of squamous and adenocarcinomas of the lung. This screen identified a strong squamous-specific biomarker, that was verified by qRT-PCR in additional samples. A diagnostic assay was developed that utilized microRNA qRT-PCR to measure the normalized level of this marker in FFPE samples. The performance of this assay was assessed in an independent, blinded test set. Results: The microRNA-based assay that was developed reached sensitivity and specificity exceeding 90% in the identification of squamous cell lung carcinomas in an independent blinded validation set. Conclusions: MicroRNAs are becoming an important tool for classification of cancers. A diagnostic assay based on the specificity of a single microRNA accurately identifies squamous from non-squamous NSCLC.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5394.