tbuckley/cabot-search huggingface dataset:
Identification of Four Novel Loci in Asthma in European American and African American Populations
Authors: Berta Almoguera, Lyam Vazquez, Frank Mentch, John Connolly, Jennifer A. Pacheco, Agnes S. Sundaresan, Peggy L. Peissig, James G. Linneman, Catherine A. McCarty, David Crosslin, David S. Carrell, Todd Lingren, Bahram Namjou-Khales, John B. Harley, Eric Larson, Gail P. Jarvik, Murray Brilliant, Marc S. Williams, Iftikhar J. Kullo, Erik B. Hysinger, Patrick M. A. Sleiman, Hakon Hakonarson
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered.To identify additional genetic susceptibility factors of asthma in European American and African American populations.A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status.The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E2 synthesis has been associated with airway remodeling.This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.
P0520 : Acceptability, reliability and applicability of liver biopsy and non-invasive methods for assessment of hepatic fibrosis and cirrhosis among hepatologists; a web based survey
Authors: M. Alboraie, M. Khairy, A. Elsharkawy, N. Asem, M. El Kassas, F. Elghamry, F. Hassan, G. Esmat
Journal: Journal of Hepatology (2015)
Oncologists perceptions and behaviors regarding genomic-based targeted therapy: Findings of a pilot study.
Authors: Jennifer Arney, Guoqing J. Chen, Ashley Helm, Ursula Braun, Peter A. Richardson, Ping Chen, Teresa Gray Hayes
Journal: Journal of Clinical Oncology (2015)

e17560 Background: Little is known about oncologists’ knowledge, perception, and utilization of genomic-based targeted therapy (GBTT) in routine practice. The objective of this pilot study was to elicit oncologists’ beliefs and practices surrounding genomic medicine in lung cancer management. Methods: We conducted individual interviews with 10 oncology fellows to elicit perceptions of GBTT in four domains: 1) knowledge; 2) attitudes; 3) intent; and 4) barriers and facilitators for practicing genomic-based targeted therapy in an academically affiliated VA medical center. Results: Analysis of the pilot interviews reflected varying degrees of knowledge regarding genomic testing and therapy. Although the majority of participants reported they referred to the guidelines when making testing and treatment decisions, some gaps in knowledge were reported, such as the use of GBTT in 2nd and 3rd line settings. Participants’ attitudes toward GBTT and support for testing and treatment were consistently positive. The most common advantages that were cited involve tolerability, efficacy, and convenience for the patient. Most participants acknowledged that they test all patients with advanced adenocarcinoma; however, some participants indicated that they focus testing efforts on patients who they perceive as having a higher likelihood of having a mutation. The most commonly mentioned barrier to testing and treatment include insufficient tissue sample to conduct the mutation analysis. Other common barriers to testing include cost and inconvenience of ordering the test. According to the pilot interviews, the ease of ordering the test, the ease of deciphering results, and VA insurance coverage were cited as facilitators to mutation testing. Conclusions: To our knowledge this is the first study to examine decision-making surrounding the use of GBTT in lung cancer management. Pilot data demonstrated that there are variations and gaps in oncologists’ knowledge, attitudes, and use of GBTT. Future research will assess decision-making among a national sample of oncologists, and will provide useful information for system-wide implementation of GBTT to enhance personalized medicine.
Outcome of Hodgkin's Lymphoma Patients After Reduced-Intensity Allogeneic Stem Cell Transplantation: Complete Remission Status Has the Most Relevant Clinical Impact along with Extranodal Disease and C-Reactive Protein Before Transplant
Authors: Lucia Farina, Francesco Spina, Anna Dodero, Simonetta Viviani, Vittorio Montefusco, Raffaella Milani, Serena Dalto, Jacopo Mariotti, Carmelo Carlo-Stella, Paolo Corradini
Journal: Blood (2010)
Lower Transplant-Related Mortality and Improved Survival for Patients with AML in First CR Receiving BuCy Compared to Cy/TBI As Myeloablative Preparation for Allogeneic Transplantation: A Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)
Authors: Edward A. Copelan, Betty K. Hamilton, Kwang W Ahn, Xiaochun Zhu, Belinda Avalos, Brian J. Bolwell, Robert Peter Gale, Jorge E. Cortes, Matt Kalaycio, Richard T. Maziarz, Wael Saber
Journal: Blood (2012)
Augmenting SRIs for Obsessive-Compulsive Disorder: Patient Preference for Risperidone Does Not Limit Effectiveness of Exposure and Ritual Prevention
Authors: Michael G. Wheaton, Joseph K. Carpenter, Eyal Kalanthroff, Edna B. Foa, Helen Blair Simpson
Journal: Psychotherapy and Psychosomatics (2016)

Patients with obsessive-compulsive disorder (OCD) often only partially respond to serotonin reuptake inhibitors (SRIs), the first-line pharmacotherapy for OCD. The American Psychiatric Association's Practice Guidelines suggest augmenting SRIs with either cognitive behavioral therapy consisting of exposure and ritual prevention (EX/RP) or antipsychotic medication (e.g., risperidone) [1]. EX/RP has been shown to be more effective [2]. However, some patients prefer medications over EX/RP [3]. How should treating clinicians respond in these situations? Conventional wisdom would suggest that patients who prefer one treatment may not benefit if assigned to another. Indeed, meta-analyses of randomized controlled trials (RCTs) show that patients are less likely to improve and more likely to drop out when matched to a therapy condition they did not prefer [4]. However, this issue has never been investigated empirically for OCD treatment specifically. Therefore, we examined the effect of patient preference on outcomes in a RCT of SRI augmentation in adult OCD patients. We specifically compared the effectiveness of EX/RP in OCD patients who stated that they prefer risperidone, and vice versa.
Environmental and mucosal microbiota and their role in childhood asthma
Authors: L. T. Birzele, M. Depner, M. J. Ege, M. Engel, S. Kublik, C. Bernau, G. J. Loss, J. Genuneit, E. Horak, M. Schloter, C. Braun-Fahrländer, H. Danielewicz, D. Heederik, E. von Mutius, A. Legatzki
Journal: Allergy (2016)

Background High microbial diversity in the environment has been associated with lower asthma risk, particularly in children exposed to farming. It remains unclear whether this effect operates through an altered microbiome of the mucosal surfaces of the airways. Methods DNA from mattress dust and nasal samples of 86 school age children was analyzed by 454 pyrosequencing of the 16S rRNA gene fragments. Based on operational taxonomic units (OTUs), bacterial diversity and composition were related to farm exposure and asthma status. Results Farm exposure was positively associated with bacterial diversity in mattress dust samples as determined by richness (P = 8.1 × 10−6) and Shannon index (P = 1.3 × 10−5). Despite considerable agreement of richness between mattress and nasal samples, the association of richness with farming in nasal samples was restricted to a high gradient of farm exposure, that is, exposure to cows and straw vs no exposure at all. In mattress dust, the genera Clostridium, Facklamia, an unclassified genus within the family of Ruminococcaceae, and six OTUs were positively associated with farming. Asthma was inversely associated with richness [aOR = 0.48 (0.22–1.02)] and Shannon index [aOR = 0.41 (0.21–0.83)] in mattress dust and to a lower extent in nasal samples [richness aOR 0.63 = (0.38–1.06), Shannon index aOR = 0.66 (0.39–1.12)]. Conclusion The stronger inverse association of asthma with bacterial diversity in mattress dust as compared to nasal samples suggests microbial involvement beyond mere colonization of the upper airways. Whether inhalation of metabolites of environmental bacteria contributes to this phenomenon should be the focus of future research.
Phase Ib/II study of eribulin mesylate administered in combination with gemcitabine/cisplatin as first-line therapy for locally advanced or metastatic bladder cancer: Phase Ib results.
Authors: Nicholas J. Vogelzang, Paul Conkling, Ignacio Duran, José Pablo Maroto, Manuel Modiano, Piero De Leonardis, Jeff Paul Hodge, Ronald Lieberman
Journal: Journal of Clinical Oncology (2012)

273 Background: Eribulin mesylate (E) is a synthetic analog of the natural, marine-sponge product halichondrin B. A phase (Ph) II study of E monotherapy in urothelial carcinoma with no prior cytotoxic therapy for advanced disease reported an overall response rate of 38% (95% CI: 23%, 54%; Quinn et al ASCO 2010, abstract 4539). Therefore, we combined E with gemcitabine (G) and cisplatin (C) to assess the feasibility, safety, and preliminary activity of the combination, in patients (pts) with advanced bladder cancer. This is an open-label, multicenter study consisting of a Ph Ib and Ph II portion. Methods: In the Ph Ib portion, three ascending doses of E were to be administered IV on days 1 and 8 q21d to determine the MTD with standard doses of G (1000 mg/m 2 , days 1 and 8 q21d) and C (70 mg/m 2 , day 1). In Ph II, pts are randomized 1:1 to E plus G/C, or G/C alone. Results: Nine pts (median age: 59 years; 7 male/2 female) entered Ph Ib. Pts received E 0.7 mg/m 2 (n=3) or 1.0 mg/m 2 (n=6), with standard dose G/C. Thirty-four cycles were given (2 pts are ongoing). One dose-limiting toxicity (DLT) was observed at 1.0 mg/m 2 (Gr 4 thrombocytopenia). The 1.4 mg/m 2 dose of E was not explored due to an investigator consensus that, with that dose, the probability of DLTs (severe hematologic toxicity) developing was high. Thus, the MTD was not achieved or defined. The recommended Ph II dose (RP2D) of E in combination with G/C was established as 1.0 mg/m 2 . Most common adverse events at the RP2D were nausea (83%), neutropenia (83%), fatigue (83%), thrombocytopenia (83%), anemia (83%), and anorexia (50%). Best responses at 1.0 mg/m 2 were 1 complete response (CR) (unconfirmed) and 4 partial responses (PR) (all confirmed). Overall response for both cohorts was 89% – 2 CRs (1 confirmed, 1 unconfirmed) and 6 PRs (4 confirmed, 2 unconfirmed). Six pts have been randomized into the Ph II portion of the study to date. Conclusions: E combined with standard G/C chemotherapy is feasible and has encouraging clinical activity. Hematologic toxicity is the main limiting factor.
Increased levels of ERFE-encoding FAM132B in patients with congenital dyserythropoietic anemia type II
Authors: Roberta Russo, Immacolata Andolfo, Francesco Manna, Gianluca De Rosa, Luigia De Falco, Antonella Gambale, Mariasole Bruno, Alessandro Mattè, Paolo Ricchi, Domenico Girelli, Lucia De Franceschi, Achille Iolascon
Journal: Blood (2016)
Chemoprevention of basal cell carcinoma: reply from authors
Authors: I. Hoorens, L. Brochez
Journal: British Journal of Dermatology (2016)

The review started from the question whether early detection of BCC in the general (asymptomatic) population could lead to any benefit in terms of outcome and cost. In other words, should early detection efforts for skin cancer (secondary prevention) also include BCC? Review of available literature suggests that early detection and adequate treatment of BCC of the face could increase cost-effectiveness. Although these results could also pertain to patients who have had already a history of BCC, their setting is different since they may already be in a follow-up programme (tertiary prevention). This article is protected by copyright. All rights reserved.
Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy
Authors: Rahul D. Tendulkar, Shree Agrawal, Tianming Gao, Jason A. Efstathiou, Thomas M. Pisansky, Jeff M. Michalski, Bridget F. Koontz, Daniel A. Hamstra, Felix Y. Feng, Stanley L. Liauw, Matthew C. Abramowitz, Alan Pollack, Mitchell S. Anscher, Drew Moghanaki, Robert B. Den, Kevin L. Stephans, Anthony L. Zietman, W. Robert Lee, Michael W. Kattan, Andrew J. Stephenson
Journal: Journal of Clinical Oncology (2016)

We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era.Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated.Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM).Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.
Aquaporin gene therapy for cholestasis
Authors: Raúl A. Marinelli, Julieta Marrone
Journal: Hepatology (2016)

This is regarding the editorial "Aquaporin gene therapy for disorders of cholestasis?" by Tradtrantip and Verkman.1 We thank the authors for their comments in our recent studies.2, 3 Nevertheless, we believe that an analysis of the role of aquaporins (AQPs) in hepatocyte canalicular water transport and bile secretion should take into account several published contributions that were not cited in the editorial. Two independent studies using the polarized rat hepatocyte couplet as in vitro model for bile secretion indicate that the osmotically driven transepithelial transport of water is largely transcellular by AQPs with a minor paracellular contribution.4, 5 In line with this is the assessment of the osmotic water permeability of hepatocyte basolateral and canalicular plasma membranes.6 Studies in bile-canaliculi-forming, human-hepatocyte-derived HepG2 cells provide key additional support by demonstrating that the gene silencing of canalicular AQP8 markedly reduced osmotically driven and bile-agonist-induced canalicular water secretion.7 Altogether, these experimental evidences support the notion that canalicular AQP8 is implicated in bile formation and that a defective expression of this AQP contributes to bile secretory dysfunction. In line with this is the fact that different animal models of cholestasis show defective canalicular AQP protein expression.9-12 In this context, it is conceivable that AQP gene transfer may help to improve certain cholestatic disorders. According to the editorial, studies in AQP8 knockout mice provide evidence against a role of canalicular AQP8 in bile secretion.8 In that study, bile was not collected, and the conclusion was based on the fact that AQP8 knockout mice show only mild dietary fat misprocessing.8 Although this finding may suggest a preserved excretion of bile salts for lipid digestion, direct studies on bile secretion must be done in order to conclude whether AQP8 knockout mice have any alteration in the flow of bile. In the editorial, it is questioned that only a subset of AQP1-expressing hepatocytes was able to increase bile flow. The transduction efficiency of 20% was estimated considering the total number of hepatocytes within the lobule (i.e., periportal, central, and perivenous). Nevertheless, the retrograde biliary vector administration allowed that most of the periportal hepatocytes were transduced with AQP1.2, 3 This is relevant because periportal hepatocytes are exposed to the highest blood concentrations of bile salts and thus are the primary cells involved in bile-salt-dependent bile secretion. We think it may be premature to judge whether the hepatic gene transfer of AQPs is a credible approach for treatment of cholestasis. We anticipate that further studies will clarify its impact as a novel therapeutic strategy. Raúl A. Marinelli, Ph.D. Julieta Marrone, Ph.D. Institute of Experimental Physiology National Council of Scientific and Technological Research School of Biochemical Sciences National University of Rosario Rosario, Argentina
Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma
Authors: Tomoyo Okada, Ann Y. Lee, Li-Xuan Qin, Narasimhan Agaram, Takahiro Mimae, Yawei Shen, Rachael O'Connor, Miguel A. López-Lago, Amanda Craig, Martin L. Miller, Phaedra Agius, Evan Molinelli, Nicholas D. Socci, Aimee M. Crago, Fumi Shima, Chris Sander, Samuel Singer
Journal: Cancer Discovery (2016)

Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.
Multicentric, observational, transversal study to describe the clinical profile of patients with metastatic breast cancer (MBC) treated with first-line bevacizumab (TRANSBREAST): Preliminary results.
Authors: M. Guirado-Risueño, G. Perez Manga, J. Rifa, R. M. Perez Carrion, M. J. García López, A. Velasco, A. Oltra Ferrando, E. Barrajon, G. Lopez-Vivanco, M. Munoz-Mateu
Journal: Journal of Clinical Oncology (2010)

1143 Background: Following the approval of bevacizumab for the treatment of MBC, this study was devised to identify the profile of patients (pt) treated under real conditions of use, their relationship with the regime used and the MBC subtypes by their genetic signature and tolerability of treatment. Methods: Multicentric observational transversal study in 40 centers. We present the results from the first 108 pts who received at least one dose of bevacizumab. Results: Of the women treated, 98.1% were Caucasian, with a mean age of 50.7 years (30-82) and ECOG 0-1 in 88%. In terms of prior history, 3.7% suffered from cardiopathies, 11.1% vascular disorders and 4.8% had kidney pathology. Neoadjuvant or adjuvant chemotherapy (CT) was given to 88% of them. The predominant histology was infiltrating ductal (82%) and histological grade 3 (49%). Positive results for hormone receptors were found in 68.5%, of which 65% were luminal A and 3.5% luminal B; 3.5% were HER2 positive, while 28% were triple negative. The disease-free interval for patients who received adjuvant or neoadjuvant CT was greater than 12 months in 86.3%. The most frequent metastatic locations were liver (38%), bone (59%), and lung (29%). The drugs most commonly used with bevacizumab were taxanes (87%). Of the 71 pt evaluated so far, 59.2% have shown a response (95% CI: 47-71%), 8.5% complete, and 22% stable disease, with 81.7% (95% CI: 73-91) obtaining a benefit from the treatment, without differences being found between subtypes. The main grade 1-2 toxicities were arterial hypertension (17%) and bleeding (18.5%). One case of grade 3-4 toxicity (proteinuria) was detected although only 30% of patients had a urine analysis. Conclusions: Bevacizumab combined with chemotherapy is well-tolerated, safe, and effective as first-line treatment of MBC, with a clinical benefit being obtained in 81.7% of patients. The results are consistent with the data from the three phase III studies in 1L and MO19391 from the clinical practice. No significant financial relationships to disclose.
Depression Severity and Effect of Antidepressant Medications—Reply
Authors: Robert J. DeRubeis
Journal: JAMA (2010)

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