tbuckley/cabot-search huggingface dataset:
Abstract 1755: Weight change, prostate cancer-specific mortality, and biochemical recurrence in a prospective cohort study of U.S. men
Authors: Barbra Dickerman, Thomas Ahearn, Edward Giovannucci, Lorelei Mucci, Kathryn Wilson
Journal: Cancer Research (2016)

Abstract Obesity is associated with an increased risk of fatal prostate cancer. However, the relevant timing of obesity for risk has not been established, and the impact of weight change on prognosis has been understudied. We prospectively investigated the association between weight change and obesity with prostate cancer outcomes among 5,173 men diagnosed with prostate cancer (clinical TNM-stage &amp;lt;T3b) from 1986 to 2012 in the Health Professionals Follow-up Study. Men were followed for biochemical recurrence, development of distant metastasis, and mortality until 2014. Cox proportional hazards models were used to estimate hazard ratios for change in weight from age 21 to diagnosis and in the 4 years prior to diagnosis, adjusting for potential confounding by lifestyle and clinical factors. Because weight, weight change, and mortality are strongly associated with smoking, we conducted the analysis among all prostate cancer patients and among never smokers only (N = 2,554). Among all patients, weight gain from age 21 to the time of diagnosis was associated with risk of lethal prostate cancer (distant metastases or prostate cancer death). Compared to those with stable weight (±10 lbs) from age 21 to diagnosis, those who gained &amp;gt;30 lbs had a 1.44-fold higher risk of lethal cancer (95% CI 1.03-2.01, p-trend = 0.06, adjusting for lifestyle factors, stage, grade, PSA at diagnosis, and weight at age 21). Among never smokers, this association was stronger (HR 2.19, 95% CI 1.31-3.68, p-trend = 0.005). Weight gain in the 4 years preceding diagnosis was suggestively, but not significantly, associated with lethal cancer among never smokers (HR for &amp;gt;5 lbs gain vs stable weight [±5 lbs] 1.48, 95% CI, 0.96, 2.28). No significant associations were found between weight change and biochemical recurrence. Our findings suggest a positive association between adult weight gain and risk of lethal prostate cancer. Metabolic changes associated with weight gain may promote prostate cancer progression. Citation Format: Barbra Dickerman, Thomas Ahearn, Edward Giovannucci, Lorelei Mucci, Kathryn Wilson. Weight change, prostate cancer-specific mortality, and biochemical recurrence in a prospective cohort study of U.S. men. [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 1755.
Exome sequencing of geographically diverse barley landraces and wild relatives gives insights into environmental adaptation
Authors: Joanne Russell, Martin Mascher, Ian K Dawson, Stylianos Kyriakidis, Cristiane Calixto, Fabian Freund, Micha Bayer, Iain Milne, Tony Marshall-Griffiths, Shane Heinen, Anna Hofstad, Rajiv Sharma, Axel Himmelbach, Manuela Knauft, Maarten van Zonneveld, John W S Brown, Karl Schmid, Benjamin Kilian, Gary J Muehlbauer, Nils Stein, Robbie Waugh
Journal: Nature Genetics (2016)
Abstract 2822: TPX2 overexpression is essential for the survival of MYC-driven triple negative breast cancer
Authors: Julia Rohrberg, Alexandra Corella, Sanjeev Balakrishnan, Andrei Goga
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancer (TNBC) presents the most challenging subtype with the poorest clinical outcome and no targeted therapy. Our lab previously showed that oncogenic MYC pathways are deregulated in human TNBC tumors and predict patients’ poor prognosis. However, clinical development of small molecule inhibitors for MYC has not been successful yet. We identified a synthetic-lethal interaction in which inhibition of cyclin-dependent kinase 1 (CDK1) resulted in the selective killing of MYC overexpressing cancer cells. CDK1 is a mitotic kinase that regulates a large number of substrates and its inhibition causes proliferation arrest in all cells, which may be associated with toxicity. We hypothesize that the MYC-CDK1 synthetic lethality can be attributed to the loss of function of only one or a handful of CDK1 substrates. To identify those substrates, we combined bioinformatics analysis of gene expression data from patient samples and cell based screening approaches. We identified TPX2 depletion to efficiently kill MYC overexpressing cells, while sparing normal cells. Using analog-sensitive CDK1 we confirmed that TPX2 is a direct substrate of CDK1. TPX2 is highly overexpressed in TNBC and predicts patients’ poor prognosis. Its loss of function efficiently kills TNBC cells in a MYC dependent manner. We hypothesize that TPX2 is a novel synthetic lethal interaction partner of MYC. Our studies will help elucidate the biology of MYC-driven cancer such as TNBC, which will eventually lead to the development of less toxic and more efficacious targeted therapies. Citation Format: Julia Rohrberg, Alexandra Corella, Sanjeev Balakrishnan, Andrei Goga. TPX2 overexpression is essential for the survival of MYC-driven triple negative breast 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 2822.
Abstract 1149: Interaction with NHERF1 enhances protein stability of G protein-coupled estrogen receptor
Authors: Ran Meng, Ying Xiong, Yuan Zhao, Yan Wang, Tao Tao, Qiqi Wang, Hua Liu, Songlin Wang, Qiong Qin, Junfang Zheng, Junqi He
Journal: Cancer Research (2016)

Abstract G Protein-Coupled Estrogen Receptor (GPER), also called GPR30, has been demonstrated to play important roles in a variety of physiological and pathological responses, especially in cancer cells proliferation, migration and invasion. Despite increasing evidences have showed clinical correlations between GPER expression level and poor prognosis in human cancer specimens, little is known regarding the regulation of GPER expression level, especially in protein level. Our previous studies have shown that PDZ protein NHERF1 can interact with ACTN4 (FASEB J. 2015) or PTEN (Endocrinology. 2011) and prevent their degradation. In this study, NHERF1 was demonstrated to interact with GPER in HEK293 cells and breast cancer cells MCF7 and T47D. GST Pull-down, Co-IP and immunocytochemistry analysis revealed that this interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal of GPER. Mutation of the last c-terminal amino acid of GPER V375A could abolish the interaction of NHERF1 with GPER. Change of NHERF1 expression level by overexpression or knockdown affects the overall protein level of GPER. NHERF1 overexpression improved the GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in an interaction dependent manner. Further analysis of public TCGA data revealed that NHERF1 expression level positively associated with activation of GPER downstream genes in invasive breast cancer, in which GPER mRNA level was similar with that of normal breast tissue. Our findings identify NHERF1 as a novel binding partner for GPER and uncover a novel role of NHERF1 in promoting GPER protein stability by inhibiting ubiquitin-proteasome degradation of the receptor. Considering the importance of GPER in breast cancer progression, these findings may help elucidate mechanisms associated with breast cancer invasion and metastasis. Citation Format: Ran Meng, Ying Xiong, Yuan Zhao, Yan Wang, Tao Tao, Qiqi Wang, Hua Liu, Songlin Wang, Qiong Qin, Junfang Zheng, Junqi He. Interaction with NHERF1 enhances protein stability of G protein-coupled estrogen receptor. [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 1149.
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Authors: Alejandro Sifrim, Marc-Phillip Hitz, Anna Wilsdon, Jeroen Breckpot, Saeed H Al Turki, Bernard Thienpont, Jeremy McRae, Tomas W Fitzgerald, Tarjinder Singh, Ganesh Jawahar Swaminathan, Elena Prigmore, Diana Rajan, Hashim Abdul-Khaliq, Siddharth Banka, Ulrike M M Bauer, Jamie Bentham, Felix Berger, Shoumo Bhattacharya, Frances Bu'Lock, Natalie Canham, Irina-Gabriela Colgiu, Catherine Cosgrove, Helen Cox, Ingo Daehnert, Allan Daly, John Danesh, Alan Fryer, Marc Gewillig, Emma Hobson, Kirstin Hoff, Tessa Homfray, Anne-Karin Kahlert, Ami Ketley, Hans-Heiner Kramer, Katherine Lachlan, Anne Katrin Lampe, Jacoba J Louw, Ashok Kumar Manickara, Dorin Manase, Karen P McCarthy, Kay Metcalfe, Carmel Moore, Ruth Newbury-Ecob, Seham Osman Omer, Willem H Ouwehand, Soo-Mi Park, Michael J Parker, Thomas Pickardt, Martin O Pollard, Leema Robert, David J Roberts, Jennifer Sambrook, Kerry Setchfield, Brigitte Stiller, Chris Thornborough, Okan Toka, Hugh Watkins, Denise Williams, Michael Wright, Seema Mital, Piers E F Daubeney, Bernard Keavney, Judith Goodship, Riyadh Mahdi Abu-Sulaiman, Sabine Klaassen, Caroline F Wright, Helen V Firth, Jeffrey C Barrett, Koenraad Devriendt, David R FitzPatrick, J David Brook, Matthew E Hurles
Journal: Nature Genetics (2016)
Abstract 1627: Kinase-independent function of focal adhesion kinase in lung metastasis of breast cancer
Authors: Ming Luo, Max S. Wicha, Jun-Lin Guan
Journal: Cancer Research (2016)

Abstract Focal adhesion kinase (FAK) has been shown to promote mammary tumorigenesis, lung metastasis and the maintenance of cancer stem cells in the MMTV-PyMT breast cancer model. Using mammary epithelial cell (MaEC)-specific FAK knockout and kinase-defective (KD) knockin mouse models, we recently demonstrated that loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas FAK kinase-independent function was sufficient to support ductal invasion and basal mammary stem cell activity. To further elucidate this kinase-independent role of FAK in mammary tumorigenesis and lung metastasis, we established and analyzed three cohorts of PyMT mice expressing wild type FAK (Ctl-MT), KD-FAK (cKD-MT) and FAK-null (cKO-MT) in MaECs. This study revealed that both FAK deletion and KD knockin mutation in MaECs significantly suppressed mammary tumorigenesis and the content of stem-like tumor cells (CD24+CD29+CD61+). However, in contrast to cKO-MT mice that displayed diminished metastatic nodule formation in the lungs, loss of FAK kinase activity by KD knockin mutation did not affect lung metastatic nodule formation. Using a Boyden chamber assay, we further demonstrated that, unlike cKO-MT tumor cells that displayed diminished cell migration induced by fibronectin or TGFβ1 (as compared to Ctl-MT tumor cells), cKD-MT tumor cells exhibited strong fibronectin-, but not TGFβ1-induced migratory activity. Immunofluorescence of primary tumor sections also revealed that both Ctl-MT and cKD-MT tumors displayed strong ERK activation at tumor periphery, whereas cKO-MT tumors had weak ERK activation in this region. Lastly, when treated with or without paclitaxel in culture, we found that paclitaxel was able to induce strong expression of cleaved caspase 3 and p21 in cKO-MT but not Ctl-MT and cKD-MT tumor cells, suggesting a role for FAK kinase-independent function in the suppression of p21 expression and protection of apoptosis. Together, this study strongly implicates a role for FAK kinase-independent function in promoting lung metastasis. Citation Format: Ming Luo, Max S. Wicha, Jun-Lin Guan. Kinase-independent function of focal adhesion kinase in lung metastasis of breast 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 1627.
Abstract 757: p16INK4A negatively regulates Leptin through miR-141 and miR-146b-5p in breast stromal adipocytes
Authors: Huda H. Alkhalaf, Abdelilah Aboussekhra
Journal: Cancer Research (2016)

Abstract Obesity, a disease linked to increased number of adipocytes in various tissues, is increasingly recognized as a risk factor for the development of breast cancer. Obesity has been reported to be associated with the occurrence of larger, more advanced tumors and aggressive cancer pathological features, including lymph node metastasis, advanced tumor stage, and high grade. Accumulating recent evidence highlights the tumor-surrounding adipose tissue as a key component of breast cancer progression. However, the molecular basis of adipocyte-related breast carcinogenesis remains elusive. To shed light on this important phenomenon, we investigated the autocrine and paracrine roles of the tumor suppressor p16 INK4A protein in adipocytes. We have found that down-regulation of p16INK4A by specific shRNA in breast adipocytes enhanced their migration/invasion abilities and increased the expression/secretion levels of various adipokines including leptin. In addition, we have shown that p16INK4A protein inhibits the pro-carcinogenic effects of breast stromal adipocytes in vitro and in tumor xenografts through repressing the expression/secretion of Leptin. Indeed, p16INK4A suppresses Leptin at the mRNA level. This effect is mediated trough miR-141 and miR-146b-5p, which inhibits Leptin expression through a specific sequence at the Leptin 3’UTR. In addition, we present clear evidence that down-regulation of p16INK4A is sufficient to trans-activate breast stromal adipocytes, which promote epithelial-to-mesenchymal-transition in normal breast luminal cells in a leptin-dependent manner. These results provide the first indication that p16INK4A and miR-141 and miR-146b-5p represses Leptin and its procarcinogenic effects in breast stromal adipocytes. This indicates that p16 pathway has non-cell-autonomous tumor suppressor function. Citation Format: Huda H. Alkhalaf, Abdelilah Aboussekhra. p16INK4A negatively regulates Leptin through miR-141 and miR-146b-5p in breast stromal adipocytes. [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 757.
Safety and Pharmacokinetics Of Clofarabine In Combination With High-Dose Cytarabine and Liposomal Daunorubicin In Pediatric AML: Results Of a Phase 1 Combination Study By The ITCC Consortium
Authors: Christian M. Zwaan, Michael Dworzak, Thomas Klingebiel, Claudia Rossig, Guy Leverger, Jan Stary, Evelina S. De Bont, Satianand Ramnarain, Yves Bertrand, Essam A Ghazaly, Dirk Reinhardt
Journal: Blood (2013)
Final clinical results of a randomized phase II international trial of everolimus vs. sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN).
Authors: Andrew J. Armstrong, Samuel Broderick, Tim Eisen, Walter Michael Stadler, Robert J. Jones, Jorge A. Garcia, Ulka N. Vaishampayan, Joel Picus, Robert E. Hawkins, John D. Hainsworth, Christian K. Kollmannsberger, Theodore F. Logan, Igor Puzanov, Lisa M. Pickering, Christopher W. Ryan, Andrew Protheroe, Christine M. Lusk, Sadie Oberg, Susan Halabi, Daniel J. George
Journal: Journal of Clinical Oncology (2015)

4507 Background: Limited evidence exists to guide therapeutic decisions in patients (pts) with metastatic non-clear cell RCC (NC-RCC). Methods: ASPEN was an international, randomized trial of pts with metastatic papillary, chromophobe, or unclassified histology; any MSKCC risk group, and no prior systemic therapy. Pts were randomized 1:1 to either everolimus (E) or sunitinib (S) until progression, stratified by histology and risk group. The primary endpoint was radiographic PFS by RECIST 1.1. With an expected 90 PFS events, there was 83% power to detect a 38% decrease in the hazard rate of progression/death assuming a two-sided type I error of 0.20 using a stratified log-rank statistic. Results: Between September 2010 and October 2013,we enrolled108 subjects across 17 sites and 3 countries. Median age was 63, 75/25% male/female, 66% papillary, 15% chromophobe, 19% unclassified; 27/59/14% good/intermediate/poor risk; 57 vs. 51 were randomized to E vs S. Treatment arms were well balanced at baseline. With 87 PFS events, 53 deaths, and 2 pts remaining on study treatment, S improved overall PFS, meeting the primary endpoint. S improved PFS in good/intermediate risk and papillary/unclassified pts, but E improved PFS in poor risk and chromophobe pts (Table). No unexpected safety signals emerged. Conclusions: Sunitinib prolonged rPFS as compared with everolimus in patients with NC-RCC, but resulted in higher rates of severe toxicity. This is the largest trial to date in NC-RCC and the first to demonstrate an mTOR-sensitive subgroup of NC-RCC pts as compared with VEGF inhibition in the front-line setting, including chromophobe and poor risk RCC pts. Clinical trial information: NCT01108445. Endpoint E (n=57) S (N=51) HR (80% CI) S as Reference p-value Median PFS (mo) (80% CI) Papillary Chromophobe Unclassified Risk: Good Intermediate Poor 5.6 5.5-6.0 5.5 11.4 5.6 5.7 4.9 6.1 8.3 5.8-11.1 8.1 5.5 11.5 14.0 6.5 4.0 1.41 (1.03-1.92) 1.52 (1.05-2.20) 0.71 (0.31-1.65) 2.55 (1.01-6.45) 3.07 (1.51-6.28) 1.38 (0.96-2.00) 0.21 (0.06-0.69) 0.16 Median OS (mo, 95% CI) 13.2 31.5 1.17 (0.65-2.14) 0.60 Objective Response Rate (%) CR+ PR % SD % PD % Missing % 5 12 67 16 4 31 61 4 - - >Grade 3 Treatment-Related AEs (%) 47% 65% - -
VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites
Authors: Mohamed Khass, Tessa Blackburn, Peter D. Burrows, Mark R. Walter, Emidio Capriotti, Harry W. Schroeder
Journal: Science Immunology (2016)

The VpreB component of the surrogate light chain serves as an invariant antigen that may affect the repertoire of antibody responses.
Second-look operation with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma (RMS): A report from the Children's Oncology Group (COG).
Authors: D. A. Rodeberg, M. D. Wharam, E. Lyden, J. A. Stoner, K. L. Brown, S. L. Wolden, C. N. Paidas, S. S. Donaldson, D. S. Hawkins, C. A. Arndt
Journal: Journal of Clinical Oncology (2010)

9504 Background: The majority of intermediate risk RMS patients have gross residual disease (Group III) after their first operative procedure. In these patients local control is usually obtained with radiotherapy (RT), which can be combined with second look operation (SLO), after induction chemotherapy. SLO prior to RT could allow subsequent RT dose reduction. COG study D9803 encouraged SLO prior to RT as a strategy to improve local control and allow for RT dose reduction for selected primary tumor sites. Methods: Intermediate risk RMS patients enrolled on COG D9803 (1999-2005) were treated with vincristine, dactinomycin, and cyclophosphamide with or without topotecan during induction. Group III tumors of the bladder, extremity, or trunk (thorax, abdomen, pelvis) were evaluated. After induction chemotherapy SLO was encouraged at week 12 if the primary tumor appeared resectable. Subsequent RT dosing was adjusted by the completeness of SLO: gross residual disease (GRD) received 50.4 Gy, microscopic residual (MR) received 41.4 Gy, and complete resection (CR) received 36 Gy. Results: 161 Group III patients had tumor at one of the three selected primary sites (24 bladder, 63 extremity and 74 trunk). Seventy-three patients (45%) underwent SLO. SLO was feasible and achieved removal of all gross disease in 84% (61/73) of patients who were then eligible for reduced dose RT [42/73 (58%) patients with CR eligible to be treated at 36 Gy, 19/73 (26%) with MR eligible to be treated at 41.4 Gy]. Thus, 12/73 (16%) were left with GRD after SLO and therefore required full dose RT. Conclusions: SLO was performed in approximately half of RMS patients with tumors at select sites. A majority of subjects undergoing induction chemotherapy followed by SLO are then eligible for RT dose reduction. Primary site Total SLO (%) SLO outcome GRD (%) MR (%) CR (%) Bladder 11/24 (46%) 4/11 (36%) 2/11 (18%) 5/11 (45%) Extremity 31/63 (49%) 3/31 (10%) 5/31 (16%) 23/31 (74%) Trunk 31/74 (42%) 5/31 (16%) 12/31 (39%) 14/31 (45%) No significant financial relationships to disclose.
Case 16-1965
Authors: Perry J. Culver, Wallace A. Jones
Journal: New England Journal of Medicine (1965)

Presentation of Case First admission. A sixty-eight-year-old man was admitted to the hospital because of diarrhea.For many years he had consumed large quantities of beer. Three years before admission abdominal swelling and peripheral edema developed, and a diagnosis of cirrhosis of the liver was made. He was subsequently well until one month before admission, when he became anorectic, and three weeks later he began to have pain in the lower portion of the abdomen and diarrhea. On the day of admission black stools were passed.The patient stated that he had consumed no alcohol for the past three months. . . .
Molecular and Pharmacologic Properties of the Anticancer Quinolone Derivative Vosaroxin: A New Therapeutic Agent for Acute Myeloid Leukemia
Authors: Gene C. Jamieson, Judith A. Fox, Ming Poi, Stephen A. Strickland
Journal: Drugs (2016)

Vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Vosaroxin has chemical and pharmacologic characteristics distinct from other topoisomerase II inhibitors due to its quinolone scaffold. The efficacy and safety of vosaroxin in combination with cytarabine were evaluated in patients with relapsed/refractory acute myeloid leukemia (AML) in a phase III, randomized, multicenter, double-blind, placebo-controlled study (VALOR). In this study, the addition of vosaroxin produced a 1.4-month improvement in median overall survival (OS; 7.5 months with vosaroxin/cytarabine vs. 6.1 months with placebo/cytarabine; hazard ratio [HR] 0.87, 95 % confidence interval [CI] 0.73-1.02; unstratified log-rank p [Formula: see text] 0.061; stratified log-rank p [Formula: see text]0.024), with the greatest OS benefit observed in patients ≥60 years of age (7.1 vs. 5.0 months; HR 0.75, 95 % CI 0.62-0.92; p [Formula: see text]0.003) and patients with early relapse (6.7 vs. 5.2 months; HR 0.77, 95 % CI 0.59-1.00; p [Formula: see text] 0.039), two AML patient groups that typically have poor prognosis. Here we review the chemical and pharmacologic properties of vosaroxin, how these properties are distinct from those of currently available topoisomerase II inhibitors, how they may contribute to the efficacy and safety profile observed in the VALOR trial, and the status of clinical development of vosaroxin for treatment of AML.
Profiling Of Polycyclic Aromatic Hydrocarbons-Induced Genotoxicity In Peripheral Blood Stem Cells and Bone Marrow Mesenchymal Stem Cells
Authors: Hwan-Young Kim, Hye-Ran Kim, Trang Nguyen Thi Dai, Hee-Jo Baek, Jae-Dong Moon, Jong-Hee Shin, Soon-Pal Suh, Hoon Kook, Dong-Wook Ryang, Myung-Geun Shin
Journal: Blood (2013)