tbuckley/cabot-search huggingface dataset:
PANORAMA1: A randomized, double-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma.
Authors: J. F. San-Miguel, S. Lonial, V. Hungria, P. Moreau, H. Einsele, J. H. Lee, S. Yoon, P. Corradini, W. W. Jedrzejczak, D. C. Tan, K. Yong, A. Guenther, M. M. Wroclawska-Swacha, H. J. Weber, P. M. Bourquelot, P. G. G. Richardson
Journal: Journal of Clinical Oncology (2011)

TPS227 Background: The development of novel agents, including the proteasome inhibitor bortezomib (BTZ), has resulted in significant improvements in survival for patients (pts) with multiple myeloma (MM). Despite these advancements, MM remains incurable with a significant unmet need as pts relapse and/or become refractory. Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) with synergistic anti-myeloma activity in combination with BTZ which may occur through dual inhibition of DACs and the proteasome. Responses (≥ MR) were preliminarily observed in 36/47 (72%) of pts with relapsed or relapsed and refractory MM in the early phase of a PAN + BTZ phase Ib study, and a less frequent PAN schedule is currently being evaluated. Based on these data, a global, randomized, double-blind, phase III study of PAN + BTZ + dexamethasone (DEX) vs placebo (PBO) + BTZ + DEX has been initiated to determine if PAN can improve outcomes in pts with relapsed MM. Methods: Pts (N=672) with relapsed or relapsed and refractory MM (1-3 prior lines of therapy) will be enrolled. Prior BTZ treatment is permitted; however, pts with BTZ-refractory MM are excluded (evaluated in another study in the US, PANORAMA 2). This study has two treatment phases and a follow-up. In phase I (8x 3-week cycles), PAN/PBO (po 20 mg) is administered thrice weekly and BTZ (IV 1.3 mg/m2) is administered twice weekly for 2 of 3 weeks. DEX (po 20 mg) is administered on the days of and after BTZ dosing. Pts who did not progress or relapse can proceed to treatment phase II (4x 6-week cycles) with a once weekly BTZ schedule. The primary endpoint is progression-free survival (PFS) and the key secondary endpoint is overall survival. Other secondary endpoints include overall response rate, duration of response, and safety. Response endpoints are assessed by the investigator according to modified EMBT criteria. Exploratory analyses include evaluation of the relationship between the IMWG criteria of sCR, CR, and VGPR and PFS and biomarker analyses including FISH and IHC analysis at baseline and minimal residual disease determination by flow cytometry and ASO-PCR. As of Jan 31, 2011, 270 pts were randomized.
Abstract 2568: Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women
Authors: Qing Lan, Zhaoming Wang, Wei Jie Seow, Kouya Shiraishi, Hongbing Shen, Chao A. Hsiung, Keitaro Matsuo, Jie Liu, Kexin Chen, Taiki Yamji, Yang Yang, I-Shou Chang, Chen Wu, Meredith Yeager, Takashi Kohno, Wei Zheng, Xiao-Ou Shu, Pan-Chyr Yang, Tangchun Wu, Dongxin Lin, Baosen Zhou, Jinming Yu, Michiaki Kubo, Stephen J. Chanock, Nathaniel Rothman
Journal: Cancer Research (2016)

Abstract Background: The incidence rates of lung cancer among never-smoking females in some parts of East Asia are among the highest in the world. Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk including 3q28, 5p15.33, 6p21.32, 6q22.2, 10q25.2 and 17q24.3. This study aims to discover additional lung cancer susceptibility loci among never-smoking Asian females. Methods: We imputed data from four GWAS of Asian non-smoking female lung cancer (6,877 cases and 6,277 controls) using the 1,000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5,878 cases and 7,046 controls) for potential replication. Results: In our meta-analysis, three new loci achieved genome-wide significance, marked by the single nucleotide polymorphisms rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10-13), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 ×10-10), and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 ×10-9). Conclusions: We identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia. These findings merit follow-up to understand their biological underpinnings and potential interactions with environmental exposures. Citation Format: Qing Lan, Zhaoming Wang, Wei Jie Seow, Kouya Shiraishi, Hongbing Shen, Chao A. Hsiung, Keitaro Matsuo, Jie Liu, Kexin Chen, Taiki Yamji, Yang Yang, I-Shou Chang, Chen Wu, Meredith Yeager, Takashi Kohno, Wei Zheng, Xiao-Ou Shu, Pan-Chyr Yang, Tangchun Wu, Dongxin Lin, Baosen Zhou, Jinming Yu, Michiaki Kubo, Stephen J. Chanock, Nathaniel Rothman. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. [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 2568.
Exercise and Prognosis on the Basis of Clinicopathologic and Molecular Features in Early-Stage Breast Cancer: The LACE and Pathways Studies
Authors: Lee W. Jones, Marilyn L. Kwan, Erin Weltzien, Sarat Chandarlapaty, Barbara Sternfeld, Carol Sweeney, Philip S. Bernard, Adrienne Castillo, Laurel A. Habel, Candyce H. Kroenke, Bryan M. Langholz, Charles P. Queensberry, Chau Dang, Britta Weigelt, Lawrence H. Kushi, Bette J. Caan
Journal: Cancer Research (2016)

To investigate whether the impact of postdiagnosis exercise on breast cancer outcomes in women diagnosed with early-stage breast cancer differs on the basis of tumor clinicopathologic and molecular features. Using a prospective design, 6,211 patients with early-stage breast cancer from two large population-based cohort studies were studied. Age-adjusted and multivariable Cox regression models were performed to determine the relationship between exercise exposure (total MET-hours/week) and recurrence and breast cancer-related death for: (i) all patients ("unselected" cohort), and on the basis of (ii) classic clinicopathologic features, (iii) clinical subtypes, (iv) PAM50-based molecular intrinsic subtypes, and (v) individual PAM50 target genes. After a median follow-up of 7.2 years, in the unselected cohort (n = 6,211) increasing exercise exposure was not associated with a reduction in the risk of recurrence (adjusted Ptrend = 0.60) or breast cancer-related death (adjusted Ptrend = 0.39). On the basis of clinicopathologic features, an exercise-associated reduction in breast cancer-related death was apparent for tumors <2 cm [HR, 0.50; 95% confidence interval (CI), 0.34-0.72], well/moderately differentiated tumors (HR, 0.63; 95% CI, 0.43-0.91), and ER-positive tumors (HR, 0.72; 95% CI, 0.53-0.97). Stratification by clinical subtype indicated that the ER(+)/PR(+)/HER2(-)/low-grade clinical subtype was preferentially responsive to exercise (recurrence: adjusted HR, 0.63; 95% CI, 0.45-0.88; breast cancer-related death: adjusted HR, 0.57; 95% CI, 0.37-0.86). The impact of exercise on cancer outcomes appears to differ as a function of pathologic and molecular features in early-stage breast cancer. Cancer Res; 76(18); 5415-22. ©2016 AACR.
Abstract 29: MEK and PI3K signaling cooperate through mTORC1/2 to promote PIK3CA mutant melanoma cell proliferation
Authors: Jillian M. Silva, Marian M. Deuker, Bruce C. Baguley, Martin McMahon
Journal: Cancer Research (2016)

Abstract Oncogenic transformation of mutationally activated BRAF or NRAS melanocytes often requires the cooperation of genetic aberrations in the phosphoinositide 3-kinase (PI3K) pathway to promote melanomagenesis. Activating point mutations in the p110α catalytic subunit of PI3K are detected at a low frequency in both BRAF and NRAS mutant melanomas, yet the principle mechanism of this cooperation remains elusive. Thus, using BRAFV600E/PIK3CAH1047R, NRASQ61H/PIK3CAH1047R, and PIK3CAE545K mutant melanoma cells derived from metastatic melanoma patients treated with pathway-targeted inhibitors, we examined the contribution of mutational activation of PIK3CA to melanoma maintenance and signaling and the consequential response of these PIK3CA mutant cells to α-specific PI3K inhibition. Combined MEK and isoform-selective PI3K inhibition elicited more potent anti-proliferative effects and greater suppression of S-phase progression of the cell cycle compared to single-agent inhibition of either pathway. Analysis of signaling downstream of MEK or PI3K revealed that these pathways cooperated to regulate PIK3CA cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Despite the profound anti-proliferative and biochemical effects of α-specific or PI3Kβ-sparing class I PI3K inhibition in vitro, these agents elicited largely cytostatic effects on PIK3CA xenograft tumors. However, combined inhibition of PI3Kβ-sparing class I PI3K and MEK did significantly cooperate to reduce tumor growth compared to the corresponding monotherapies. Furthermore, this study provides a biochemical mechanism to explain how mTORC1/2 moderates the cooperation of MEK and PI3K signaling for the maintenance of PIK3CA mutant melanoma cell proliferation. Citation Format: Jillian M. Silva, Marian M. Deuker, Bruce C. Baguley, Martin McMahon. MEK and PI3K signaling cooperate through mTORC1/2 to promote PIK3CA mutant melanoma cell proliferation. [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 29.
The difficult diagnosis of pulmonary vascular disease in heart failure
Authors: Nazzareno Galiè, Alessandra Manes, Massimiliano Palazzini
Journal: European Respiratory Journal (2016)

Pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure (PAP) ≥25 mmHg, is a well-recognised complication of left heart disease (LHD). PH prevalence is variable ranging from 25% to 80% of LHD patients according to the methods of assessment, cut-off values and characteristics of the patient population [1–3]. All aetiological types of LHD are affected, including heart failure with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction, and valvular LHD. The presence of PH-LHD is associated with advanced symptoms, reduced exercise capacity and impaired outcome after medical, interventional or surgical therapy [1, 3, 4]. Definition and diagnosis of pulmonary vascular disease in heart failure: still an unclear rebus <http://ow.ly/qp1L300x6yY>
Abstract LB-213: NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer
Authors: Gabriele Picco, Francesco Sassi, Claudio Isella, Federica Di Nicolantonio, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
Journal: Cancer Research (2016)

Abstract The NEDD8 conjugation pathway modulates the ubiquitination, stability and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of molecular predictors of response are still missing. We investigated the in vitro sensitivity to pevonedistat in a large panel of molecularly and functionally annotated colorectal cancer (CRC) cell lines, and exploited global gene expression profiles to define a transcriptional predictor. Out of 122 tested cell lines, 16 (13%) displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block and apoptosis. Pevonedistat sensitivity did not significantly correlate with microsatellite instability or mutations in KRAS or BRAF, but was functionally associated with resistance to EGFR pathway blockade. A 184-gene transcriptional predictor generated in cell lines was applied to 87 metastatic CRC clinical samples for which patient-derived xenografts (PDX) were available. For in vivo tests, pevonedistat was provided by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Ltd. In vivo administration of pevonedistat did not affect the growth of any predicted resistant PDX; whereas, it significantly impaired growth of five out of six predicted sensitive models. In human CRC gene expression datasets, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery and early progression under cetuximab treatment. Histological and immunohistochemical analyses revealed that pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma. These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective strategy to treat poorly differentiated, clinically aggressive CRC and identify transcriptional and histological response predictors with possible clinical applicability. Citation Format: Gabriele Picco, Francesco Sassi, Claudio Isella, Federica Di Nicolantonio, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico. NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer. [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 LB-213.
A phase I/Ib, open-label, dose-finding study to evaluate safety, pharmacodynamics, and efficacy of pembrolizumab (MK-3475) in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma.
Authors: Roberto Pili, David Quinn, Noah M. Hahn, Costantine Albany, Theodore F. Logan, Charles G. Drake
Journal: Journal of Clinical Oncology (2016)

TPS4581 Background: Novel strategies to enhance the activity of immune-checkpoint inhibitors are under development. Our group has reported that the HDAC inhibitor entinostat suppresses regulatory T (Treg) cell function, enhances the anti-tumor effects of immunotherapies. A Phase I/II clinical study with entinostat and high dose interleukin 2 in renal cell carcinoma patients is showing some promising results. Preliminary data from our group also suggest that entinostat enhances the anti-tumor activity of PD-1 blockade in a renal cell carcinoma model. The current study will test the following hypotheses: 1) HDAC inhibition by vorinostat will decrease Tregs and enhance the anti-tumor activity of immune-check point inhibition; 2) Vorinostat will re-sensitize refractory patients previously treated with immune-check point inhibitors. Methods: This is a Phase I study to assess the immunomodulatory activity of the HDAC inhibitor vorinostat in patients with urothelial or renal cell carcinoma receiving the PD-1 inhibitor pembrolizumab. Key eligibility criteria include previously treated urothelial or renal cell carcinoma. Treatment cycles consist of daily oral dosing of vorinostat (Days 1 through 14) and intravenous dosing of pembrolizumab (Day 1, Cycle 1). The two-drug regimen will be given every 3 weeks. The starting dose of vorinostat will be 100 mg orally once per day for Days 1 through 14. The dose of pembrolizumab will be 200 mg IV on Day 1, every 21 days. Patients will be enrolled according to a standard 3 + 3 design and two dose levels of vorinostat will be tested (100 and 200 mg). The primary endpoint is to determine the recommended Phase 2 dose (RP2D) based on the safety and tolerability of this combination. Once the RP2D is identified, two cohorts of patients with anti-PD-1/PD-L1 sensitive disease or anti-PD-1/PD-L1 resistant disease will be treated. Secondary endpoints include assessing the objective response rate and progression-free survival. Correlative studies include assessment of PD-L1 (2) expression, immune cell subsets, and microRNAs in tumor and blood samples. Clinical trial information: NCT02619253.
Abstract 2292: Reconstitution of myeloid derived suppressor cells after the induction of lymphopenia and TIL therapy
Authors: Krithika N. Kodumudi, Doris Wiener, Amy Weber, Erica Royster, Linda Kelley, Amod Sarnaik, Shari Pilon-Thomas
Journal: Cancer Research (2016)

Abstract Factors such as T regulatory (Treg) cells and myeloid derived suppressor cells (MDSC) limit the effectiveness of current immunotherapy protocols. Several reports have shown that administration of chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells reduces or eliminates the immunosuppressive populations such as Tregs and MDSC. A previous study in our lab has shown that MDSC that reconstitute after lymphodepletion are highly suppressive compared to the endogenous MDSC in a B16 melanoma model. Blockade of MDSC expansion in combination with adoptive T cell transfer delayed tumor growth and improved survival rate. However, there is very little known about the MDSC reconstitution after the adoptive transfer of tumor infiltrating lymphocytes (TIL) in melanoma patients. Melanoma patients were treated with non- myeloablative therapy that included cyclophosphamide and fludarabine. At the time of TIL transfer, no circulating lymphoid or myeloid cells were detected in the PBMC. One day after completion of chemotherapy, up to 100 billion TIL were transferred followed by high dose bolus IL-2. At weeks 1-4 after TIL transfer, PBMC were collected and we investigated the reconstitution and the suppressive function of MDSC. MDSC were phenotyped by flow cytometry as HLA-DR− Lin− CD14+CD33+ or CD11b+CD14−CD33+. While 3-15% of MDSC was observed in the PBMC of melanoma patients as their baseline, after lymphodepletion and one week post TIL infusion, the percent of MDSC increased to 10-30% and gradually dropped to baseline by week 4. To examine suppressive function, MDSC were isolated from peripheral blood at 1-2 weeks after TIL infusion and co-cultured with healthy donor T cells or patient TIL. MDSC were highly suppressive and abrogated T cell proliferation and IFN-gamma secretion. Furthermore, in patients that responded to TIL therapy, the ratio of peripheral MDSC to total CD8+ T cells was lower. These studies demonstrate that MDSC that reconstitute post- lymphodepletion are suppressive and may potentially interfere with robust T cell function. Further studies are warranted to clarify the role of MDSC in the efficacy of TIL therapy. Blocking MDSC in combination with TIL therapies represent an improved strategy for the treatment of melanoma patients. Citation Format: Krithika N. Kodumudi, Doris Wiener, Amy Weber, Erica Royster, Linda Kelley, Amod Sarnaik, Shari Pilon-Thomas. Reconstitution of myeloid derived suppressor cells after the induction of lymphopenia and TIL therapy. [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 2292.
HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia
Authors: M Kontro, A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, Y Fløisand, M Höglund, K Remes, B T Gjertsen, O Kallioniemi, K Wennerberg, C A Heckman, K Porkka
Journal: Leukemia (2016)
Robust Induction Of Th1-Like γδ T Cells With Anti-Myeloma Activity By Lenalidomide In Combination With HMB-PP As Well As Zoledronic Acid
Authors: Takeshi Harada, Qu Cui, Shingen Nakamura, Hirokazu Miki, Asuka Oda, Ryota Amachi, Masami Iwasa, Kengo Udaka, Shiro Fujii, Kumiko Kagawa, Shuji Ozaki, Yoshimasa Tanaka, Toshio Matsumoto, Masahiro Abe
Journal: Blood (2013)
Injury risk and a tackle ban in youth Rugby Union: reviewing the evidence and searching for targeted, effective interventions. A critical review
Authors: Ross Tucker, Martin Raftery, Evert Verhagen
Journal: British Journal of Sports Medicine (2016)

It has recently been proposed that the tackle, an integral part of Rugby Union, be banned in school rugby, as a means to reduce the risk of injury. This proposal held that harmful contact should be removed in response to what was termed an unacceptably high-injury risk. Such a ban would represent a significant intervention that could change the nature of Rugby Union. As such, the basis and rationale for such a ban is worthy of critical evaluation. This review aims to describe the research on which such a ban is proposed. It does so through an assessment (identification), estimation (understanding of the magnitude and occurrence) and evaluation (determining acceptability) of the risk before decisions can be made about implementing any risk mitigation strategies. The body of literature describing injury risk, particularly among youths, is indeed thin and fraught with methodological differences that makes definitive conclusions impossible. We describe these, and their implications, arguing that the complete ban on the tackle may be unnecessary in young children, in whom injury risk may not be as high as is often argued, but also that it may have detrimental consequences. Finally, we propose alternative strategies and research questions which must be pursued to effectively reduce risk without creating unintended consequences or changing the nature of the sport.
Rapid Mobilization Of CD34+ Progenitor Cells With TG0054-03, a novel CXC Chemokine Receptor 4 (CXCR4) Antagonoist
Authors: Michael W. Schuster, Nabil Hagog, Bita Jalilizeinali, Sharon Funkhauser, Mary Sophy Yohannan, Jennifer Sadler, Sylvia Wood, Stacy Carey, Karen Kelleher, Chen-En Tsai, Ming-Chu Hsu, Li-Weng Chang, Zora Hsu
Journal: Blood (2013)
Abstract 713: Determining the role of tumor-infiltrating B cells in NSCLC
Authors: Sara M. Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Brandon Larsen, Jesse D. Martinez
Journal: Cancer Research (2016)

Abstract Recent studies in human non-small cell lung cancer (NSCLC) have shown that upregulation of B cell-associated genes strongly correlate with early stage patient survival. After analyzing a gene expression database of lung tumors we showed that CD79A, a pan-B cell marker, had the strongest predictive value, suggesting that B cells are playing a crucial role in NSCLC immunity. In order to evaluate this we first examined where this genetic signature was originating from. We observed that patients with high levels of B cell-related genes also showed high numbers of CD79A+ B cells intimately associated with the tumor, but not being expressed by tumor cells themselves. A closer look at tumor-infiltrating B cells (TIL-B cells) by IHC and flow cytometry of fresh patient tumor samples has confirmed their presence and allowed us to begin elucidating their phenotype. Interestingly, we have found that not all early stage patients have detectable levels of TIL-B cells, but in those that do, TIL-B cells represent a marked proportion of the lymphocytic infiltration. Further evaluation of T cell populations in the same samples indicate that T cell numbers remain relatively consistent but that the numbers of B-cells, especially CD79A+ B-cells, does vary from patient to patient. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in some but not all patients, and are greatly influencing disease survivability. This information may allow us to stratify patients into low and high risk groups based on the presence or absence of TIL-B cells, respectively. Citation Format: Sara M. Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Brandon Larsen, Jesse D. Martinez. Determining the role of tumor-infiltrating B cells in NSCLC. [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 713.