tbuckley/cabot-search huggingface dataset:
Abstract 102: Pan-cancer analysis of sex differences in somatic mutation profiles
Authors: Constance H. Li, Syed Haider, Paul C. Boutros
Journal: Cancer Research (2016)

Abstract Sex influences the clinical and pathological characteristics of a number of cancers including those of the lung, colon and kidney. Men and women differ in incidence rate, response to treatment and survival - even after controlling for confounding factors such as smoking status, age and weight. Some gene-specific sex differences have been identified in these cancers, but there has not been a rigorous, genome-wide analysis of the mutational differences in tumors between men and women. We fill this gap, providing a comprehensive assessment of sex-associated differences in cancer genomics. We leverage resources from the International Cancer Genome Consortium-The Cancer Genome Atlas pan-cancer project, which includes genomic, transcriptomic and epigenomic profiles of 25,000 tumours and whole genome sequences of 5,000 tumours. Using this data, we analyzed mutational differences between the sexes in 15 tumor types. We use both univariate (t-test, proportions test) and multivariate (multinomial logistic regression) statistical techniques, along with bioinformatics and pathway analyses. We found distinct sex-associated genomic differences in the copy number aberration (CNA) profiles of six tumor types and in pan-cancer analysis. We observe higher genome instability in male-derived tumors and sex-biased mutations in specific genes and across genomic intervals. Using multivariate modeling to control for confounding variables reinforces the significance of sex in these genomic regions and also reveals additional sex-biased CNAs. Ongoing work with mRNA abundance data suggests an association between sex-differences in CNAs and mRNA abundance both in cis and in trans. Further investigation into affected genes and pathways may reveal fundamental differences in how tumors develop in men and women and provide explanations for reported clinical and pathological sex differences. Citation Format: Constance H. Li, Syed Haider, Paul C. Boutros. Pan-cancer analysis of sex differences in somatic mutation profiles. [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 102.
Abstract 1716: The role of CD44v9+ colorectal cancer stem cells in the resistance to cetuximab treatment
Authors: Chia-Nung Hung, Ching-Yu Chang, Jou Hsiao, Wan-Chen Wei, Wei-Ting Chao
Journal: Cancer Research (2016)

Abstract Recent studies found that conventional therapy combined with cetuximab treatment (EGFR inhibitor) to treat metastatic colorectal cancer, had no improvement of patient survival rate in some population. One of possibilities might be cancer stem cells (CSCs) population resist to cetuximab treatment and modulate metastasis, however, the detail mechanism has not been addressed in colorectal cancer. Thus, our study is to decipher the mechanism of resistance to cetuximab in CD44v9+ specific colorectal cancer stem cells. First, to reveal clinical significance of CD44v9, the tumor samples of colorectal cancer patients were analyzed by immunohistochemistry to evaluate CD44v9 expression status in patients. To further investigate the biological mechanism, single cell analysis in CD44v9+ population of HT29 cells was performed with Fluidigm Biomark™ HD system. The results showed that 67% patients had highly expressed CD44v9 with lower survival rate. In vitro studies showed that when HT29 cells were in 5uM cetuximab treatment for 48 hours, CD44v9, Oct4, CD133, CD24, Lgr5, CSCs markers, were up-regulated in RNA level. Furthermore, CD44v9+/Oct4+ cancer cell population was increased but CD44v9+/pEGFR+ cancer cells were eliminated according to immunofluorescence results. The results of single cell analysis demonstrated that CD44v9+/Oct4+ cancer cells highly expressed proliferation markers consistently with cetuximab treatment. Trans-well migration results showed that CD44v9+/Oct4+ cancer cells migrated collectively via mediating E-cadherin dynamics. Furthermore, in clinical outcome, CD44v9 and E-cadherin co-expression were associated with recurrence and metastasis and decreased survival rate significantly. In conclusion, cetuximab failed to target CD44v9+/Oct4+ cancer cells, which characterized as cancer stem cells and might modulate collective cell migration. This finding suggested that new therapeutic strategy to against CSCs would be the potential clinical treatment in colon cancer. Citation Format: Chia-Nung Hung, Ching-Yu Chang, Jou Hsiao, Wan-Chen Wei, Wei-Ting Chao. The role of CD44v9+ colorectal cancer stem cells in the resistance to cetuximab treatment. [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 1716.
Subsequent Hematopoietic Stem Cell Transplantation in Belinostat-Treated Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL)
Authors: Andrei R. Shustov, Haifa Kathrin Al-Ali, Gerald Wulf, Pamela Hsu, Mi Rim Choi, Lee F Allen, Otto J Visser, Pierre Zachee, Steven M. Horwitz
Journal: Blood (2014)
Sustained Mutant KIT Activation in the Golgi Complex Is Mediated by PKC-θ in Gastrointestinal Stromal Tumors
Authors: Won Kyu Kim, SeongJu Yun, Cheol Keun Park, Sebastian Bauer, Jiyoon Kim, Min Goo Lee, Hoguen Kim
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Tumorigenesis of gastrointestinal stromal tumors (GIST) is driven by gain-of-function mutations in the KIT gene, which result in overexpression of activated mutant KIT proteins (MT-KIT). However, the mechanism of MT-KIT overexpression is poorly understood. Experimental Design: By protein expression analysis and immunofluorescent microscopic analysis, we determine the stability and localization of MT-KIT in four GIST cell lines with different mutations and HeLa cells transfected with mutant KIT model vectors. We also used 154 human GIST tissues to analyze the relationship between the expression of PKC-θ and MT-KITs, and correlations between PKC-θ overexpression and clinicopathological parameters. Results: We report that four different MT-KIT proteins are intrinsically less stable than wild-type KIT due to proteasome-mediated degradation and abnormally localized to the endoplasmic reticulum (ER) or the Golgi complex. By screening a MT-KIT-stabilizing factor, we find that PKC-θ is strongly and exclusively expressed in GISTs and interacts with intracellular MT-KIT to promote its stabilization by increased retention in the Golgi complex. In addition, Western blotting analysis using 50 GIST samples shows strong correlation between PKC-θ and MT-KIT expression (correlation coefficient = 0.682, P &amp;lt; 0.000001). Immunohistochemical analysis using 154 GISTs further demonstrates that PKC-θ overexpression significantly correlates with several clinicopathological parameters such as high tumor grade, frequent recurrence/metastasis, and poor patient survival. Conclusions: Our findings suggest that sustained MT-KIT overexpression through PKC-θ-mediated stabilization in the Golgi contributes to GIST progression and provides a rationale for anti-PKC-θ therapy in GISTs. Clin Cancer Res; 23(3); 845–56. ©2016 AACR.
MAIT cells: not just another brick in the wall
Authors: Karlijn Debusschere, Rik J Lories, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2016)

The link between gut and joint inflammation in spondyloarthritis (SpA) is well established, in particular in ankylosing spondylitis (AS) and peripheral SpA. In 1995, Mielants et al 1 discovered that almost 50% of patients with SpA have subclinical gut inflammation, of which a fraction develops Crohn's disease over time. Recent studies clearly showed that the onset of disease and disease severity are linked to the presence of subclinical gut inflammation.2 However, the mechanism behind this phenomenon is hitherto not fully elucidated. Over the past decade, the interleukin (IL)-23/IL-17-axis has been put forward as a key player in the pathogenesis of SpA. Polymorphisms in the IL23R gene were found both in SpA and in inflammatory bowel disease (IBD),3 linking pathology in these physically distant sites. Cells that are typically responsive to IL-23 are IL-23R+RORγt+ IL-17A-producing cells, such as TH17 cells. In multiple inflammatory diseases, such as multiple sclerosis (MS), IBD and SpA, it is assumed that there is an overall distortion of the cytokine profile towards IL-17A, contributing to disease.4 However, it should be noted that in IBD IL-17A might also exert tissue-protective functions and that mechanisms driving gut inflammation in SpA do not necessarily represent those contributing to the development of full-blown IBD.3 Intriguingly, Sherlock et al 5 showed that systemic IL-23 overexpression is able to drive the development of enthesitis via enthesis-resident CD3+CD4−CD8−RORγt+IL23R+ T cells, independently of TH17 cells. The concept that not TH17 cells but innate-like T cells such as γδ T cells, invariant natural killer T cells (iNKT) and mucosal-associated invariant T (MAIT) cells are the main source of IL-17A recently gained support.6

Interestingly, innate-like T cells such as MAIT cells act at the …
Methylsulfonylmethane (MSM), an organosulfur compound, is effective against obesity-induced metabolic disorders in mice
Authors: Inês Sousa-Lima, Shin-Young Park, Michelle Chung, Hyun Ju Jung, Min-Cheol Kang, Joana M. Gaspar, Ji A. Seo, M. Paula Macedo, Kyong Soo Park, Christos Mantzoros, Seung-Hoon Lee, Young-Bum Kim
Journal: Metabolism (2016)
Abstract 3349: Differential expression of CD44 and CD24 markers discriminates the epithelioid from fibroblastoid subset in a sarcomatoid renal cell carcinoma cell line: evidence of the existence of cancer stem cells in both subsets
Authors: Chin-Hsuan Hsieh, Cheng-Keng Chuang, See-Tung Pang, Samuel Chien, Paul Lin, Shuen-Kuei Liao
Journal: Cancer Research (2016)

Abstract The co-existence of epithelioid and fibroblastoid subsets in the human sarcomatoid renal carcinoma cell line, RCC52, has been demonstrated previously based on clonal studies, in which only the epithelioid subset was found to be tumorigenic in NOD/SCID mice. Since only few clonal isolates were used to analyze in that study, we argued that the tumorigenicity results might not be truly reflective of this tumor line. We therefore in this study determined to use cytofluorometrically sorted cells to re-evaluate certain biological parameters including xenotransplantation. Using two monoclonal antibodies to CD44 and CD24 markers, we succeeded in identification and isolation of the two populations, and showed the CD44bright/CD24dim and CD44bright/CD24bright phenotypes corresponding to the epithelioid and fibroblastoid subsets, respectively. At variance with the results of clonal studies, both cytofluorometrically sorted subsets displayed different but significant degrees of tumorigenicities, indicating that each subset harbored its own cancer stem cells (CSCs). In consistence with the tumorigenicity findings, both sorted subsets showed in vitro migratory/invasive potential with greater ability exhibited by the CD44bright/CD24bright subset which was associated with higher expression of MMP-7, -8 and TIMP-1 transcripts. On the other hand, the CD44bright/CD24dim subset was found to be associated with higher expression of MMP-2, -9 and TIMP-2 transcripts. Furthermore, both sorted subsets expressed the RCC stem cell marker CD105 in a small proportion of cells (4-5%), and were able to covert to PAX2+ clear cells in areas in the xenografts to a greater extent by the CD44bright/CD24dim subset, highlighting high plasticity of each subset in different ways. Collectively, our findings confirm the co-existence of two morphologically and phenotypically distinct subsets, and document the presence of CSCs in both subsets for the first time in sarcomatoid RCC. The CSCs/mCSCs in the two subsets should therefore be considered as emerging therapeutic targets in the design of future treatment strategies for this subtype of renal cancer. Citation Format: Chin-Hsuan Hsieh, Cheng-Keng Chuang, See-Tung Pang, Samuel Chien, Paul Lin, Shuen-Kuei Liao. Differential expression of CD44 and CD24 markers discriminates the epithelioid from fibroblastoid subset in a sarcomatoid renal cell carcinoma cell line: evidence of the existence of cancer stem cells in both subsets. [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 3349.
Results of a Phase II Trial of Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
Authors: Robert W Chen, Joycelynne Palmer, Peter Martin, Nicole Tsai, Young Kim, Michelle Mott, Firoozeh Sahebi, Tanya Siddiqi, Leslie L. Popplewell, John P. Leonard, Tsiporah B. Shore, Stephen J. Forman
Journal: Blood (2014)
Follow-up study of the arrhythmic graduates from the schools under the heart disease program for students in Osaka.
Authors: Mitsuo Kitada, Kinichi Uheda, Tadashi Nakagawa, Yukimasa Yamaguchi
Journal: Circulation (1984)

A long term follow-up study of arrhythmic graduates from junior or senior high schools under the Heart Disease Program in Osaka was performed by mailing questionaires. The age of the total 515 subjects ranged from 20 to 38 years, 26.9 years on an average. From 397 graduates (77%), answers to questionaires were obtained. We could confirm 92 graduates were alive (18% of total subjects) among the 118 graduates who did not return their answers to the questionaires. The following is what we could confirm through the present study: 1) The prognoses of simple premature beats, Wenckebach type heart block and complete right bundle branch block are good in young adults. 2) The prognosis of sick sinus syndrome does not warrant an optimistic prognosis even in young adults. 3) The prognosis of WPW syndrome in young adults is not always fair if they have a history of paroxysmal tachycardia. 4) From 95 to 97% of the graduates with arrhythmia as a whole answered that their daily lives are quite similar to those of healthy people. 5) Attitudes toward daily life and medical checks were also studied.
Iris Crypts Influence Dynamic Changes of Iris Volume
Authors: Jacqueline Chua, Sri Gowtham Thakku, Tin A. Tun, Monisha E. Nongpiur, Marcus Chiang Lee Tan, Michael J.A. Girard, Tien Yin Wong, Joanne Hui Min Quah, Tin Aung, Ching-Yu Cheng
Journal: Ophthalmology (2016)
Low incidence of pneumocystis pneumonia utilizing PCR-based diagnosis in patients with B-cell lymphoma receiving rituximab-containing combination chemotherapy
Authors: Jason N. Barreto, Lauren L. Ice, Carrie A. Thompson, Pritish K. Tosh, Douglas R. Osmon, Ross A. Dierkhising, Matthew F. Plevak, Andrew H. Limper
Journal: American Journal of Hematology (2016)

Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R-CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R-CHOP administration in patients with B-cell lymphoma. Consecutive patients diagnosed with B-cell lymphoma receiving R-CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy-three percent of patients completed at least 6 cycles of R-CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57-2.43, at maximum follow-up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R-CHOP treatment of B-cell lymphoma and argue against universal anti-Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti-Pneumocystis prophylaxis for patients presenting with high-risk baseline characteristics or when receiving rituximab-inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113-1117, 2016. © 2016 Wiley Periodicals, Inc.
LBA-02 A multicenter randomized phase III trial of neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy in resectable gastric cancer: first results from the CRITICS study
Authors: M. Verheij, A. Cats, P.M. Jansen Edwin, C.T. van Grieken Nicole, K. Aaronson Neil, H. Boot, A. Lind Pehr, E. Meershoek – Klein Kranenbarg, M. Nordsmark, H. Putter, H. van Tinteren, J.H. Van De Velde Cornelis
Journal: Annals of Oncology (2016)
Hospitals and birth centers remain safest setting for giving birth, US obstetricians say
Authors: Michael McCarthy
Journal: BMJ (2016)

Women considering a planned home birth should be fully informed of the benefits and risks when making their choice, such as a reduced risk of medical interventions but increased risk of perinatal death and neonatal seizures or neurologic dysfunction, the American College of Obstetricians and Gynecologists’ committee on obstetric practice has advised in a new opinion document.1

After reviewing the latest evidence the committee said that women should be informed that, although a planned home birth is associated with fewer maternal interventions than planned hospital birth, it is also associated with more than twice the risk of perinatal death (3.9 per 1000 births v 1.8 per 1000 hospital births; odds ratio 2.43) and a threefold increased risk of …
Kidney Transplantation Outcomes across GN Subtypes in the United States
Authors: Michelle M. O’Shaughnessy, Sai Liu, Maria E. Montez-Rath, Colin R. Lenihan, Richard A. Lafayette, Wolfgang C. Winkelmayer
Journal: Journal of the American Society of Nephrology (2016)

Differences in kidney transplantation outcomes across GN subtypes have rarely been studied. From the US Renal Data System, we identified all adult (≥18 years) first kidney transplant recipients (1996–2011) with ESRD attributed to one of six GN subtypes or two comparator kidney diseases. We computed hazard ratios (HRs) for death, all-cause allograft failure, and allograft failure excluding death as a cause (competing risks framework) using Cox proportional hazards regression. Among the 32,131 patients with GN studied, patients with IgA nephropathy (IgAN) had the lowest mortality rates and patients with IgAN or vasculitis had the lowest allograft failure rates. After adjusting for patient- and transplant-related factors, compared with IgAN (referent), FSGS, membranous nephropathy, membranoproliferative GN, lupus nephritis, and vasculitis associated with HRs (95% confidence intervals) for death of 1.57 (1.43 to 1.72), 1.52 (1.34 to 1.72), 1.76 (1.55 to 2.01), 1.82 (1.63 to 2.02), and 1.56 (1.34 to 1.81), respectively, and with HRs for allograft failure excluding death as a cause of 1.20 (1.12 to 1.28), 1.27 (1.14 to 1.41), 1.50 (1.36 to 1.66), 1.11 (1.02 to 1.20), and 0.94 (0.81 to 1.09), respectively. Considering external comparator groups, and comparing with IgAN, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy associated with higher HRs for mortality [1.22 (1.12 to 1.34) and 2.57 (2.35 to 2.82), respectively], but ADPKD associated with a lower HR for allograft failure excluding death as a cause [0.85 (0.79 to 0.91)]. Reasons for differential outcomes by GN subtype and cause of ESRD should be examined in future research.
Abstract 606: Similar 3D pharmacodynamic (3D-PD) responses of human tumor spheroids and xenografts to topoisomerase 1 inhibitor-induced DNA damage
Authors: David M. Evans, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Silvers Thomas, Robert Kinders, Tony Navas, Scott Lawrence, Anne Monks, Annamaria Rapisarda, Ralph E. Parchment, James H. Doroshow, Beverly Teicher
Journal: Cancer Research (2016)

Abstract Three-dimensional (3D) cultures have been proposed as higher fidelity models of in vivo tumors than 2D cultures. To determine whether this idea extends to drug pharmacodynamics, we examined whether 3D cultures of the human melanoma line A375 (grown as tumor spheroids) could replicate the timing and magnitude of the nuclear γH2AX response to the topoisomerase 1 inhibitor, topotecan observed in A375 tumor xenografts (Kinders et al, Clin Can Res 2010). The appearance of γH2AX-positive nuclear foci has been used as a biomarker for drug- and radiation-induced double-strand breaks in DNA; we reported previously that treatment of nu/nu mice harboring A375 xenografts with a single-dose of topotecan induced nuclear γH2AX foci in a dose- and time-dependent manner, which peaked 4 hours after drug administration. A375 spheroids were generated by seeding cells into ULA U-bottom plates; 4 hours of exposure to 0.1 μM topotecan elicited a γH2AX signal in these 3D cultures while cell viability and intracellular ATP levels remained unchanged, indicating a DNA damage repair response at the maximally tolerated topotecan concentration for human hematopoietic cells (Erickson-Miller et al, Can Chemo Pharmacol 2009). Extending drug exposure to 24 hours caused substantial loss of viable cells (calcein AM+) and 50% decline in ATP levels but no further increase in γH2AX. In contrast, the HT29 tumor line was refractory to topotecan in vivo, and exposing 3D cultures of HT-29 spheroids to 0.1 μM topotecan for 24 hours elicited a strong nuclear γH2AX biomarker response in only a small fraction of cells at the surface of the spheroids. Longer exposure durations or supra-pharmacological concentrations (1 μM) of topotecan were required to achieve a strong nuclear γH2AX response in HT-29 spheroids. These results support the hypothesis that the 3D pharmacodynamics (PD) of drug response is similar to PD drug response in vivo for the camptothecin class of topoisomerase 1 inhibitors. Funded by NCI Contract No. HHSN261200800001E. Citation Format: David M. Evans, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Silvers Thomas, Robert Kinders, Tony Navas, Scott Lawrence, Anne Monks, Annamaria Rapisarda, Ralph E. Parchment, James H. Doroshow, Beverly Teicher. Similar 3D pharmacodynamic (3D-PD) responses of human tumor spheroids and xenografts to topoisomerase 1 inhibitor-induced DNA damage. [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 606.