tbuckley/cabot-search huggingface dataset:
Predicting gene targets from integrative analyses of summary data from GWAS and eQTL studies for 28 human complex traits
Authors: Jennifer M. Whitehead Pavlides, Zhihong Zhu, Jacob Gratten, Allan F. McRae, Naomi R. Wray, Jian Yang
Journal: Genome Medicine (2016)

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with complex traits and diseases. However, elucidating the causal genes underlying GWAS hits remains challenging. We applied the summary data-based Mendelian randomization (SMR) method to 28 GWAS summary datasets to identify genes whose expression levels were associated with traits and diseases due to pleiotropy or causality (the expression level of a gene and the trait are affected by the same causal variant at a locus). We identified 71 genes, of which 17 are novel associations (no GWAS hit within 1 Mb distance of the genes). We integrated all the results in an online database ( http://www.cnsgenomics/shiny/SMRdb/ ), providing important resources to prioritize genes for further follow-up, for example in functional studies.
Phase Ib/II study of an IL-2/T-cell receptor fusion protein in combination with gemcitabine and cisplatin in advanced or metastatic chemo-refractory urothelial cancer (UC).
Authors: Mayer N. Fishman, Daniel A. Vaena, Parminder Singh, Joel Picus, Ulka N. Vaishampayan, Joel Slaton, John Francis Mahoney, Sanjiv S Agarwala, Charles Joel Rosser, Danny Landau, Julio Hajdenberg, Peter J. Van Veldhuizen, Rahul Atul Parikh, Sarah Alter, Liza Hernandez, Peter Rhode, Hing C. Wong
Journal: Journal of Clinical Oncology (2015)

4515 Background: Although UC is sensitive to platinum-based chemotherapy such as gemcitabine (G) + cisplatin (C), patients who are refractory to GC have limited therapeutic options. ALT-801 is an IL-2/single-chain T-cell receptor fusion protein previously tested in various murine models. ALT-801 demonstrated potent activity against syngeneic and xenograft UC, suggesting sensitivity of this disease to IL-2 based immunotherapy. Methods: We report efficacy and safety results of co-administration of G (1000 mg/m2/dose, d 1 & 8) + C (70 mg/m2/dose, d 1) with ALT-801 (0.06 mg/kg/dose, d3, 5, 8, 12) on a 21 day schedule for 3 cycles in patients with advanced/metastatic chemo-refractory UC. The initial ALT-801 dose escalation and expansion study included chemo-naïve or refractory subjects of group 1. Group 2 are patients in a 2-armed Phase II dose expansion study of only chemo-refractory subjects receiving either 0.06 mg/kg ALT-801 + GC or 0.06 mg/kg ALT-801 + G based on the renal function. Those with at least stable disease (SD) after 3 cycles may receive addition cycles of study treatment. Results: To date, 62 were enrolled of whom 34 were chemo-refractory receiving ALT-801+GC (group 1, n = 17; group 2, n = 17). They were 82% male, had median age 62 y (47-74); 47% were ECOG PS = 1, and 76% had visceral metastases. Favorable responses including complete response (CR) were seen in both groups 1 and 2 with an overall response rate of 35% (95% CI: 20 - 54%) (3 CR, 9 PR, 6 SD, 12 PD, 4 non-evaluable). Median OS was 12.3 months for group 1; the group 2 results are pending follow-up. Grade 3/4 toxicities observed (n = 31) include thrombocytopenia (62%), neutropenia (48%), anemia (39%), lymphopenia (26%), hypophosphatemia (19%) and low WBC (13%). Evaluation of treatment-induced immune responses is ongoing. Conclusions: Based on responses seen in both groups, we conclude that ALT-801+GC has clinical activity in advanced/metastatic chemo-refractory UC patients. Observed toxicities are consistent with GC and with ALT-801 known pharmacological effects. Further evaluation of this regimen in randomized trials is warranted. Clinical trial information: NCT01326871 Clinical trial information: NCT01326871.
Abstract 1477: Targeting immunosuppressive myeloid cells in oral cavity cancer with the PI3Kδ/γ isoform inhibitor duvelisib
Authors: Ruth Davis, Ellen Moore, Paul E. Clavijo, Chris Silvin, Carter Van Waes, Zhong Chen, Clint Allen
Journal: Cancer Research (2016)

Abstract BACKGROUND: IPI-145 (duvelisib) is an oral inhibitor of the p110δ/γ isoforms of phosphinositide 3-kinase (PI3K) that are differentially expressed in leukocytes. IPI-145 is currently under study in phase II/III trials for the treatment of hematologic malignancies, but has not previously been studied in solid tumors. In this study we sought to determine if p110δ/γ inhibition could suppress solid tumor growth through functional inhibition of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment of syngeneic murine oral cavity (MOC) tumor models of head and neck cancer. METHODS: In pilot experiments, highly immunogenic MOC1 and poorly immunogenic MOC2 tumor-bearing mice were treated with daily oral doses of 15 mg/kg IPI-145 for 14 days and monitored for tumor progression. Flow cytometry was used to study cellular immune correlates in both the periphery and tumor microenvironment. MDSCs were sorted using FACS and functionally evaluated in a carboxyfluorescein succinimidyl ester (CFSE)-based T-cell proliferation assay. RESULTS: Selective inhibition of p110δ/γ with low-dose IPI-145 resulted in a trend toward growth suppression of established MOC1 tumors, and had no effect on the growth of poorly immunogenic MOC2. IPI-145 increased infiltration and activation of CD8 T-lymphocytes and NK cells along with increased tumor cell expression of MHC class I and PD-L1 in MOC1 tumor bearing mice. MDSCs sorted from IPI-145 treated MOC1 tissues demonstrated a reduction in their capacity to suppress CD3/28 stimulated T-cell proliferation. MOC2 tumor bearing mice demonstrated no immune correlative changes. CONCLUSION: Daily oral treatment with low-dose IPI-145 resulted in a trend toward inhibition of primary tumor growth and enhanced immune activation in the tumor microenvironment in an immunogenic murine model of head and neck cancer. This data shows promise for future studies of IPI-145 as a monotherapy at higher doses or as a sensitizer for immunotherapies such as checkpoint inhibitors, and these studies are underway. This work was supported by the NIDCD Intramural Program ZIA-DC-000087-01 Citation Format: Ruth Davis, Ellen Moore, Paul E. Clavijo, Chris Silvin, Carter Van Waes, Zhong Chen, Clint Allen. Targeting immunosuppressive myeloid cells in oral cavity cancer with the PI3Kδ/γ isoform inhibitor duvelisib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1477.
Abstract 3996: KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity
Authors: Stephen J. Shuttleworth
Journal: Cancer Research (2016)

Abstract Two de novo-designed classes of orally-active immunotherapeutics - selectively targeting the PI3K-p110β/p110δ and HDAC6 enzymes - for solid and hematological cancer treatment will be described. The former, exemplified by the clinical candidate KA2237, are uniquely-selective inhibitors of the PI3K-p110β/p110δ isoforms, displaying immunotherapeutic activity and inhibiting primary tumor growth and metastasis. The latter, for which KA2507 is the candidate compound, are HDAC6-specific inhibitors, which inhibit tumor growth through regulation of aggresome formation, and inhibition of PD-L1 expression via decrease of STAT3 phosphorylation. In both cases, selectivity has been achieved over other enzyme superfamily members, with the aim being to minimize mechanism-related toxicity, thereby potentially providing opportunities to enable elevated single dose levels - and broad combination modalities not possible with pan-inhibitors of both enzymes - to be investigated. The PI3K-p110β/p110δ and HDAC6 inhibitors display potent oral activity as single agents in in vivo tumor syngeneic models, impacting on growth inhibition, PD and tumor marker responses; the PI3K-p110β/p110δ inhibitors also inhibit metastatic spread and, following surgical removal of primary tumor, confer promising inhibition of tumor regrowth. Crucially, the inhibitors work in combination with one another, making this co-therapy approach unique in oncology, and potentially important clinically in overcoming resistance mechanisms in both solid and hematological cancer. The rationale for this combination is based upon immunotherapeutic and cell signalling mechanisms, which will be described. KA2237 is entering Phase I studies in patients with lymphoma as a single agent in Q1 2016, with KA2507 scheduled to follow in Q3 to treat multiple myeloma. Further clinical investigations into solid tumor immunotherapy - both single agent- and combination-studies - are planned. Citation Format: Stephen J. Shuttleworth. KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3996.
Randomized trial of combined treatment versus usual care plus antidepressant in depressed oncologic patients: One-year follow-up.
Authors: A. Palao Tarrero, C. Bayón Perez, G. Torres Sancho, A. Hospital Moreno, B. Castelo Fernandez, J. Barriuso, B. Rodriguez Vega
Journal: Journal of Clinical Oncology (2010)

9095 Background: Treating depressive symptoms in cancer patients is important due to the impact on health-related quality of life besides the relief of psychological distress. The goal of our study was to evaluate the effectiveness of combined therapy, escitalopram plus narrative therapy, and escitalopram plus usual care on measures of quality of life and depressive symptoms in depressed patients with oncologic disease at 1-year-follow-up. Methods: After screening 1,026 subjects with non-metastatic colon, breast and lung cancer for depressive symptomatology, 72 subjects (mean age 54.6 years), predominantly female, with depressive disorder (DSM-IV-TR) were randomized to receive combined treatment (n=39) or escitalopram plus usual care (n=33). The main outcome measures were changes in dimensions of quality of life measured by the European Organization for Research and treatment of cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30) and depressive symptomatology measured by the Hospital Anxiety and Depression Scale (HADS) depression subscale at weeks 12, 24 and 48. Results: Comparison of adjusted mean scores between groups over time found that combined treatment group showed significantly greater improvement in all the functioning dimensions (physical, social, emotional, cognitive and role), pain scale (.04), global health (.03), and global quality of life (.05). Depression scores measured by HADS-D were reduced over time in both treatment groups, with no statistically significant differences. However, depression scores in the combined therapy group remained lower than scores in the usual care group. Conclusions: Combined therapy was superior than usual care and antidepressant in improving functioning dimensions of quality of life in depressed cancer patients at 1-year-follow-up. No statistically significant difference was found for depressive symptoms This study is part of the FIS 05/0737 and 05/2062 Investigation Projects. No significant financial relationships to disclose.
Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities
Authors: Kristen J. Nadeau, Barbara J. Anderson, Erika G. Berg, Jane L. Chiang, Hubert Chou, Kenneth C. Copeland, Tamara S. Hannon, Terry T.-K. Huang, Jane L. Lynch, Jeff Powell, Elizabeth Sellers, William V. Tamborlane, Philip Zeitler
Journal: Diabetes Care (2016)

Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments.
Early Antibiotic Exposure and Childhood Weight Gain—Reply
Authors: Jeffrey S. Gerber, Matthew Bryan, Virginia A. Stallings
Journal: JAMA (2016)

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High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation
Authors: Cristina Gasparetto, Wendi A. Bacon, Phuong Doan, David A. Rizzieri, Mitchell E. Horwitz, John P. Chute, Keith M. Sullivan, Amanda Yopp, Zhiguo Li, Nelson J. Chao, Gwynn D. Long
Journal: Blood (2011)
Laparoscopy-assisted endoscopic full-thickness resection of gastric subepithelial tumors using a nonexposure technique
Authors: Osamu Goto, Hiroya Takeuchi, Motoki Sasaki, Hirofumi Kawakubo, Teppei Akimoto, Ai Fujimoto, Yasutoshi Ochiai, Tadateru Maehata, Toshihiro Nishizawa, Yuko Kitagawa, Naohisa Yahagi
Journal: Endoscopy (2016)

<b>Background and study aims:</b> To avoid bacterial contamination and tumor seeding during gastrectomy surgery, we developed a nonexposure technique for endoscopic full-thickness resection with laparoscopic assistance. The feasibility and safety of nonexposed endoscopic wall-inversion surgery (NEWS) for gastric subepithelial tumors (SETs) were investigated. <b>Patients and methods:</b> For protruding gastric SETs ≤ 3 cm in diameter, NEWS was performed in the following sequence: laparoscopic seromuscular incision after endoscopic submucosal injection, laparoscopic seromuscular suturing with the lesion inverted, endoscopic mucosal and submucosal incision, and transoral retrieval. Technical outcomes and postoperative courses were investigated. <b>Results:</b> In all 20 consecutive cases, including six SETs with ulceration, NEWS was completed (mean procedural time, 213.5 minutes) without severe intraoperative or postoperative adverse events. R0 resection and perforation rates were 100 % and 5.0 %, respectively. During the mean observational period of 10.1 months, all patients survived without recurrence or apparent discomfort during food intake. <b>Conclusion:</b> NEWS for gastric SETs was feasible and safe and represents a useful option for minimally invasive local resection even in cases of SETs with ulceration or cancers.
Abstract 4482: Expression profiling of SETD family genes in breast cancer patients
Authors: Joao N. Matos Neto, Doralina do Amaral Rabello, Fabio Pittella-Silva
Journal: Cancer Research (2016)

Abstract Epigenetic alterations have recently been recognized to play an important role in the progression of many tumor types. Protein methyltrasferases are among the most relevant epigenetic effectors. Dysregulation in the expression or activity of these enzymes is among the major epigenetic alterations involved in carcinogenesis. Methyltransferases of the SETD family share a SET domain which is involved in the methylation of lysine residues on histones and non-histone proteins. So far, little is known about the relation of SETD family genes with mammary carcinogenesis. In the present study we evaluated the relative expression of 10 SETD family genes in 18 breast tumor samples and non-tumor breast tissues from patients with breast cancer by real time qPCR. The comparative expression profile of each gene was correlated with the most relevant clinicopathologic prognostic information available from patients. We found a significant increase in the expression of SETMAR in tumor samples compared with the normal breast tissues. In addition, triple negative tumor subtype (n = 7), when compared with a pool of normal tissue samples (n = 13) presented an increased relative expression of SETMAR. Interestingly, SETD8 was 10 times overexpressed when the angiolymphatic invasion (n = 8) was present compared to the absence of this feature (n = 10). Patients with strong axillary tumor burden defined as the presence of at least 10 axillary lymph nodes with cancer (n = 6), showed an increased relative expression of SETD5 and SETD8 genes when compared to the absence of this feature (n = 12). Evaluating the expression on paired samples (normal tissue and tumor tissue from the same patient (n = 7), we observed an increased relative expression of SETD1B. Also in the paired samples, we found a strong correlation among the expression of the genes SETD1B, SETD5, SETD8 and SETMAR in tumor samples with no correlation in normal tissues. Furthermore, immunohistochemical analysis revealed a stronger expression of SETD5 and SETMAR in carcinomas in situ when compared to normal tissues and invasive tumors. Taken together, these data points to a likely role of SETMAR and SETD1B genes in mammary carcinogenesis, with relevant clinical implications and with the possible involvement of SETD5 and SETD8 genes in more advanced stages of the disease. The correlation on the expression of these genes with relevant clinical prognostic factors in breast cancer opens the way to exploit them not only as therapeutic targets, but also as new prognostic markers. Keywords: SETD gene family, expression profile, breast cancer Citation Format: Joao N. Matos Neto, Doralina do Amaral Rabello, Fabio Pittella-Silva. Expression profiling of SETD family genes in breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4482.
Post Autologous Transplant Vorinostat (SAHA) in High Risk Lymphoma: Phase 1 Study of Vorinostat Maintenance
Authors: Craig C. Hofmeister, Mindy A Bowers, Robert A. Baiocchi, Gerard Lozanski, Kristina Humphries, Kristie A. Blum, Pierluigi Porcu, Sam Penza, Carli N Greenfield, Megan Sell, Christian Tyler Earl, Joseph Zitesman, Carl Quinion, Mark E Lustberg, Leslie A Andritsos, Steven M. Devine
Journal: Blood (2012)
Vaccine effectiveness of 2011/12 trivalent seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: evidence of waning intra-seasonal protection
Authors: R  G Pebody, N Andrews, J McMenamin, H Durnall, J Ellis, C I Thompson, C Robertson, S Cottrell, B Smyth, M Zambon, C Moore, D M Fleming, J  M Watson
Journal: Eurosurveillance (2013)

The 2011/12 season was characterised by unusually late influenza A (H3N2) activity in the United Kingdom (UK). We measured vaccine effectiveness (VE) of the 2011/12 trivalent seasonal influenza vaccine (TIV) in a test-negative case–control study in primary care. Overall VE against confirmed influenza A (H3N2) infection, adjusted for age, surveillance scheme and month, was 23% (95% confidence interval (CI): -10 to 47). Stratified analysis by time period gave an adjusted VE of 43% (95% CI: -34 to 75) for October 2011 to January 2012 and 17% (95% CI: -24 to 45) for February 2012 to April 2012. Stratified analysis by time since vaccination gave an adjusted VE of 53% (95% CI: 0 to 78) for those vaccinated less than three months, and 12% (95% CI: -31 to 41) for those vaccinated three months or more before onset of symptoms (test for trend: p=0.02). For confirmed influenza B infection, adjusted VE was 92% (95% CI: 38 to 99). A proportion (20.6%) of UK influenza A(H3N2) viruses circulating in 2011/12 showed reduced reactivity (fourfold difference in haemagglutination inhibition assays) to the A/Perth/16/2009 2011/12 vaccine component, with no significant change in proportion over the season. Overall TIV protection against influenza A(H3N2) infection was low, with significant intraseasonal waning.
Recovery from ICU-acquired weakness; do not forget the respiratory muscles!
Authors: Rik Gosselink, Daniel Langer
Journal: Thorax (2016)

Skeletal muscle dysfunction acquired during critical illness (intensive care unit (ICU)-acquired weakness, ICUAW) plays a pivotal role in clinical outcomes such as liberation from mechanical ventilation, ICU length of stay, hospital length of stay, physical function and mortality.1 ,2 ICUAW is a common complication of critical illness with a complex aetiology,3 affecting both limb muscles as well as respiratory muscles. The decline in muscle mass is approximately 2%–4% per day in the first week of ICU stay.4 ,5 Loss of limb muscle mass is more pronounced in patients with multiple organ failure,4 while a rapid decline in diaphragm muscle strength and thickness is associated with sepsis6 and low diaphragm contractile activity.5 Strategies to prevent or treat ICUAW are scarce and mostly focused on the treatment or reduction of risk factors associated with ICUAW (sepsis, hyperglycaemia, catabolism, neuromuscular blockers and corticosteroids).3 In addition, immobility and inactivity contribute considerably to muscle atrophy: ‘mechanical silencing’ has been identified as an important contributor to the loss of contractile properties.7 Therefore, reversing inactivity of the muscle should have the potential to prevent, reverse or ameliorate muscle wasting.

The focus of rehabilitation in patients who are critically ill is on the prevention and treatment of ICUAW, oftentimes specifically targeting lower limb muscle function. Early mobilisation, transferring patients from the bed to the chair, weight-bearing, walking, bed cycling and neuromuscular electrical stimulation are the most common modalities successfully applied to ameliorate limb muscle weakness and functional status.8 It is unclear as to …