tbuckley/cabot-search huggingface dataset:
Multibipolar Radiofrequency Ablation for the Treatment of Mass-Forming and Infiltrative Hepatocellular Carcinomas &gt; 5 cm: Long-Term Results
Authors: Gisele N’Kontchou, Jean-Charles Nault, Olivier Sutter, Valerie Bourcier, Emmanuelle Coderc, Veronique Grando, Pierre Nahon, Nathalie Ganne-Carrié, Abou Diallo, Nicolas Sellier, Olivier Seror
Journal: Liver Cancer (2018)

Only few patients with cirrhosis and hepatocellular carcinoma (HCC) larger than 5 cm are amenable to resection or straight liver transplantation, and in such circumstances, multibipolar radiofrequency ablation (mbp-RFA) could be a reliable alternative. This study was aimed to assess the long-term outcome in patients treated with mbp-RFA for unresectable HCC > 5 cm.Eighty-three consecutive patients with cirrhosis (median age 70 years [37-93 years], 67 males, BCLC A/B/C: 54/21/8, 74 naive) with up to three HCCs, the largest > 5 cm in diameter (median: 6.2 cm, 5.1-9 cm, 22 infiltrative forms, 12 with segmental portal invasion of which 10 were infiltrative forms) were treated with mbp-RFA. Overall (OS) and recurrence-free (RFS) survival and their associated predictive factors were assessed.Complete ablation was observed in 78/83 (94%) patients. Thirty-one side effects occurred, including 6 (7%) severe complications. After a median follow-up of 26.1 months (1-112 months), in naive patients the 3- and 5-year OS was 51% (38-62) and 24% (13-36), 63 and 30% for mass-forming and 25 and 6% for infiltrative form, respectively. Infiltrative form (HR: 2.5 [1.33-4.69], p = 0.004) was the only independent OS predictor. In naive patients with mass-forming and infiltrative form, the 3- and 5-year RFS were 47 and 17 and 18 and 18%, respectively. Alpha-fetoprotein (HR: 2.86 [1.32-6.21], p = 0.008), multinodular form (HR: 2.74 [1.4-5.38], p = 0.003) and infiltrative form (HR: 3.43 [1.67-7.01], p = 0.0007) were independent RFS predictors.mbp-RFA offers good OS in inoperable patients with cirrhosis and large HCC, with acceptable safety profile. For infiltrative forms, although mbp-RFA leads to complete responses in more than 80% cases, few only remain tumor progression-free in long-term.
Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant
Authors: Chao Liu, Theresa Guo, Guorong Xu, Akihiro Sakai, Shuling Ren, Takahito Fukusumi, Mizuo Ando, Sayed Sadat, Yuki Saito, Zubair Khan, Kathleen M. Fisch, Joseph Califano
Journal: Clinical Cancer Research (2018)

Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)-negative HNSCC.Experimental Design: RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays.Results: A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival.Conclusions: Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. Clin Cancer Res; 24(20); 5123-32. ©2018 AACR.
Reply to Maurizio Bologna, Amerigo Vitagliano, and Mauro Cervigni's Letter to the Editor re: Jean-Philippe Lucot, Michel Cosson, Georges Bader, et al. Safety of Vaginal Mesh Surgery Versus Laparoscopic Mesh Sacropexy for Cystocele Repair: Results of the Prosthetic Pelvic Floor Repair Randomized Controlled Trial. Eur Urol 2018;74:167–76
Authors: Jean-Philippe Lucot, Arnaud Fauconnier
Journal: European Urology (2018)
Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion
Authors: Alen Faiz, Markus Weckmann, Haitatip Tasena, Corneel J. Vermeulen, Maarten Van den Berge, Nick H.T. ten Hacken, Andrew J. Halayko, Jeremy P.T. Ward, Tak H. Lee, Gavin Tjin, Judith L. Black, Mehra Haghi, Cheng-Jian Xu, Gregory G. King, Claude S. Farah, Brian G. Oliver, Irene H. Heijink, Janette K. Burgess
Journal: European Respiratory Journal (2018)

Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitro . IL-1β-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air–liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed. The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls . IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients. Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.
Wnt antagonists in osteosarcoma patients.
Authors: Dalibel Bravo, Kristen L. Shogren, Scott M. Riester, Eric R. Wagner, James L. Herrick, Scott H. Okuno, Michael J. Yaszemski, Avudaiappan Maran
Journal: Journal of Clinical Oncology (2013)

10531 Background: Osteosarcoma (OS) is a clinically challenging primary malignant bone tumor that has a high rateof local recurrence and metastasis. Disease free survival has been reported to be as low as 19% despite contemporary chemotherapy regimens and surgery. Wnt signaling is known to play a role in osteogenesis and cancer pathogenesis, therefore is a promising target for therapeutic intervention in OS. Secreted Frizzled Related Proteins (sFRPs), Dickkopf-1 (DKK1), and Sclerostin (SOST) are secreted Wnt inhibitor proteins that regulate Wnt signaling in bone. This study investigates the activity of sFRP3, DKK1, and SOST in serum from OS patients with the goal of developing therapeutic Wnt inhibitors and clinically useful biomarkers. Methods: Enzyme linked immunosorbent assayswere used to quantify sFRP3, DKK1 and SOST levels in human serum (n=40 pairs; 20 OS patients, 20 aged matched non-diseased controls). Patients were stratified into 2 age groups: &gt;35 (n=26 pairs) and &lt;30 (n=14 pairs) years of age. Clinical data from the medical records was correlated with experimental results. Using a Wilcoxon signed rank test, a p–value &lt;0.05 was significant. Results: sFRP3 levels were significantly decreased in 55% (22/40) of diseased samples compared to 20% (8/40) of the non-diseased controls (p= 0.007). DKK1 levels were elevated in 40% (16/40) of OS samples compared to 30% (12/40) of the non-diseased controls (p= 0.08). SOST levels were increased in 42.5% (17/40) of diseased samples compared to 32.5% (13/40) of the non-diseased controls (p= 0.38). When stratified by age, the younger patients showed a statistically significant decrease in sFRP3 expression (p&lt;0.001). Serum levels of sFRP3, DKK1, and SOST were not statistically significant between metastatic and non-metastatic OS. Conclusions: Serum sFRP3 levels were significantly decreased in OS patients, a difference that was even more pronounced in the pediatric strata. Since sFRP3 is differentially expressed in patient serum it has potential as a clinical biomarker for initial tumor diagnosis and early detection of recurrence. Decreased sFRP3 expression may be responsible for the up regulation of Wnt signaling in OS. Wnt inhibitors such as sFRP3 have potential as therapeutic agents in OS warranting further investigation.
Decision Tree Model vs Traditional Measures to Identify Patterns of Sun-Protective Behaviors and Sun Sensitivity Associated With Sunburn
Authors: Kasey L. Morris, Frank M. Perna
Journal: JAMA Dermatology (2018)

<h3>Importance</h3> Understanding patterns of sun-protective behaviors and their association with sunburn can provide important insight into measurement approaches and intervention targets. <h3>Objective</h3> To assess whether decision-based modeling can be used to identify patterns of sun-protective behaviors associated with the likelihood of sunburn and to compare the predictive value of this method with traditional (ie, composite score) measurement approaches. <h3>Design, Setting, and Participants</h3> This cross-sectional study used a nationally representative sample of 31 162 US adults from the 2015 National Health Interview Survey, consisting of household interviews conducted in person and completed by telephone when necessary. Participants included civilian noninstitutionalized US adults. Data were collected from January 1 through December 31, 2015. <h3>Main Outcomes and Measures</h3> The associations among sun sensitivity, multiple sun-protective behaviors (ie, using sunscreen, seeking shade, wearing a hat, and wearing protective clothing), and sunburn were examined using a χ<sup>2</sup>automatic interaction detection method for decision tree analysis. Results were compared with a composite score approach. <h3>Results</h3> In our study population of 28 558 respondents with complete data (54.1% women; mean [SD] age, 49.0 [18.0] years), 20 patterns of sun protection were identified. Among 15 992 sun-sensitive individuals, those who used only sunscreen had the highest likelihood of sunburn (62.4%). The group with the lowest likelihood of sunburn did not report using sunscreen but engaged in the other 3 protective behaviors (24.3% likelihood of sunburn). Among 12 566 non–sun-sensitive individuals, those who engaged in all 4 protective behaviors had the lowest likelihood of sunburn (6.6%). The highest likelihood of sunburn was among those who only reported sunscreen use (26.2%). The decision tree model and the composite score approach correctly classified a similar number of cases; however, the decision tree model was superior in classifying cases with sunburn (44.3% correctly classified in the decision tree vs 25.9% with the composite score). <h3>Conclusions and Relevance</h3> This innovative application of a decision tree analytic approach demonstrates the interactive and sometimes counterintuitive effects of multiple sun-protective behaviors on likelihood of sunburn. These data show where traditional measurement approaches of behavior may fall short and highlight the importance of linking behavior to a clinically relevant outcome. Given the scope of those affected and enormous associated health care costs, improving efforts in skin cancer prevention has the potential for a significant effect on public health.
Author Correction: A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes
Authors: Bénédicte Machiels, Mickael Dourcy, Xue Xiao, Justine Javaux, Claire Mesnil, Catherine Sabatel, Daniel Desmecht, François Lallemand, Philippe Martinive, Hamida Hammad, Martin Guilliams, Benjamin Dewals, Alain Vanderplasschen, Bart N Lambrecht, Fabrice Bureau, Laurent Gillet
Journal: Nature Immunology (2018)
Professional Football Participation and Mortality
Authors: Brendan T. Smith, Arjumand Siddiqi
Journal: JAMA (2018)

To the Editor The retrospective cohort study by Dr Venkataramani and colleagues1 found a hazard ratio (HR) for mortality in career National Football League (NFL) players compared with NFL replacement players following NFL retirement of 1.38 (95% CI, 0.95-1.99); P = .09.
Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation
Authors: Eric R. Gamazon, Ayellet V. Segrè, Martijn van de Bunt, Xiaoquan Wen, Hualin S. Xi, Farhad Hormozdiari, Halit Ongen, Anuar Konkashbaev, Eske M. Derks, François Aguet, Jie Quan, Dan L. Nicolae, Eleazar Eskin, Manolis Kellis, Gad Getz, Mark I. McCarthy, Emmanouil T. Dermitzakis, Nancy J. Cox, Kristin G. Ardlie
Journal: Nature Genetics (2018)
<i>PDSS2</i>Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism
Authors: Yan Li, Shuhai Lin, Lei Li, Zhi Tang, Yumin Hu, Xiaojiao Ban, Tingting Zeng, Ying Zhou, Yinghui Zhu, Song Gao, Wen Deng, Xiaoshi Zhang, Dan Xie, Yunfei Yuan, Peng Huang, Jinjun Li, Zongwei Cai, Xin-Yuan Guan
Journal: Cancer Research (2018)

Abstract Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and for antioxidant defense. Here, we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 (PDSS2), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis (P = 0.027). PDSS2 downregulation was a prognostic factor independent of T status and stage (P = 0.028). Downregulation of CoQ10 was significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R = 0.414; P &amp;lt; 0.001). Of the six different splicing isoforms of PDSS2, the five variants other than full-length PDSS2 showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the MIHA immortalized human liver cell line. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development. Significance: Downregulation of PDSS2 is a driving factor in hepatocellular carcinoma tumorigenesis. Cancer Res; 78(16); 4471–81. ©2018 AACR.
End of life decisions—the patient comes first
Authors: Simon Kenwright
Journal: BMJ (2018)

Black was faced with a dilemma, but a relative’s priority should be to help doctors make the appropriate decision in line with the wishes of an elderly parent.1 Fraught relatives may not be in the best position to do this. The trend is to give them greater influence, but the decision must be a medical—or surgical—one. 

A …
No Benefit of Diaphragm Pacing in Upper Motor Neuron–Dominant Forms of Amyotrophic Lateral Sclerosis
Authors: Capucine Morélot-Panzini, Marie-Cécile Nierat, Marie-Laure Tanguy, Gaëlle Bruneteau, Pierre-François Pradat, François Salachas, Jésus Gonzalez-Bermejo, Thomas Similowski
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Abstract 4454: Ecdysoneless, a novel regulator of cell cycle progression and oncogenesis
Authors: Irfana Saleem, Sameer Mirza, Aniruddha Sarkar, Hamid Band, Vimla Band
Journal: Cancer Research (2018)

Abstract Precisely regulated cell proliferation is essential for embryonic development and for homeostasis in adult organs and tissues, whereas uncontrolled cell proliferation is a hallmark of cancer. We have identified the human orthologue of Drosophila Ecdysoneless (ECD) as a critical regulator of cell cycle progression and oncogenesis. ECD is overexpressed in cancers of several organs, and its overexpression correlates with shorter survival in breast cancer patients. Overexpression of ECD leads to an oncogenic phenotype in immortal mammary epithelial cells. ECD deletion in breast cancer cells on the other hand decreased the in vitro oncogenic phenotype and the in vivo tumorigenesis. Mechanistically, we showed that ECD associates with a protein complex called R2TP, composed of RUVBL1, RUVBL2, RPAP3, PIHID1 proteins, which is involved in several biological functions, including the dynamic assembly of protein-protein and protein-RNA complexes. In addition, affinity purification followed by Mass Spec analyses showed that ECD binds to several proteins, including PRPF8, that are components of critical protein complexes required for RNA splicing. Based on these findings, we hypothesize that ECD interacts with the R2TP complex and protein complexes that control key steps in the cellular mRNA processing. We hypothesize that these complexes are required for the overexpressed ECD to regulate mRNA processing to promote cell proliferation and cell survival in cancer cells. We will present data to document the ECD complexes required for cell cycle regulation and cell survival. Our studies reveal novel roles of ECD in cancer cells, and support the rationale for use of overexpression of ECD and its interacting proteins as molecular biomarkers of tumor progression as well as explore the targeting of these complexes to develop novel cancer therapy agents. Citation Format: Irfana Saleem, Sameer Mirza, Aniruddha Sarkar, Hamid Band, Vimla Band. Ecdysoneless, a novel regulator of cell cycle progression and oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4454.
The scope of possible combination therapy with immunotherapy and targeted therapy.
Authors: Leandro Machado Colli, Mitchell J Machiela, Han Zhang, Timothy A Myers, Lea Jessop, Olivier Delattre, Kai Yu, Stephen J. Chanock
Journal: Journal of Clinical Oncology (2017)

3056 Background: Combination treatment of two recent trends in cancer therapy, namely immunotherapy with checkpoint inhibitors and drugs that target specific gene mutations, could improve cancer survivorship overall. Targeted drugs usually induce rapid tumor death leading to the release of neoantigens, and can affect immune development pathways, which could increase the efficacy of checkpoint inhibitor treatment. Assessment of somatic mutation profiles from large public databases provides an estimate of the prevalence of targetable somatic mutations and the burden of somatic nonsynonymous mutations (NsM), used as a surrogate for overall neoantigen load, which, in turn, correlates with clinical utility of checkpoint inhibitors for melanoma and lung adenocarcinoma. The rational design of these combinations based on somatic genomic profiles offers a prioritization scheme for new clinical trials. Methods: We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents and/or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a recently suggested threshold for response to checkpoint inhibitors. Results: Overall, 8.9% of cases have profiles that could benefit from combination therapy, which corresponds to approximately 11.2% of US annual incident cancer cases; the most commonly targetable mutations were observed in PIK3CA, BRAF, NF1, NRAS, and PTEN genes . Interestingly, cases with mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and/or MET appear to be enriched in those with high burdens of NsM, who have a higher likelihood of responding to immunotherapy. Of the 13,349 cases that could benefit from combination therapy, 50.9% had BRAF, NF1, GNAQ and/or GNA11 mutations which can be targeted by Trametinib ; 26.1% by Taselisib (targets PIK3CA mutations); and 19.8% by Afatinib ( EGFR and ERBB2 mutations). Conclusions: Our results indicate a significant proportion of solid tumor patients are eligible for combination therapy and suggest prioritizing specific cancers for combination trials using target drugs and checkpoint inhibitor therapy.
Abstract 1004: Tuft cell chemosensory signaling during pancreatic ductal adenocarcinoma
Authors: Megan T. Hoffman, Howard Crawford
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the second most common cause of cancer death in the US with a 10% 5-year survival rate and, as such, is one of the most common deadly cancers. PDA is characterized by a robust stromal reaction, a large portion of which is composed of infiltrating immune cells. This inflammatory response has been previously shown to promote both the initiation and progression of PDA. Current research has been to understand the interaction between tumor cells and infiltrating immune cells and the contribution to cancer progression. In this work we focus on a specific cell population present in the epithelium during pancreatic tumorigenesis called a tuft cell. Tuft cells have been found in luminal surfaces throughout the body, most notably characterized in the intestine where these cells have been shown to directly regulate the immune response to parasitic infection, but have also been found in the nasal, respiratory and bladder epithelium. These solitary chemosensory cells, as they are also known, use a common chemosensory pathway, previously characterized in type-II taste cells, in order to interact with the luminal environment. Interestingly, tuft cells in the metaplastic pancreas uniquely express TRPM5 and alpha-gustducin, both components of the chemosensory cascade, suggesting these cells have the potential to mediate a response to extracellular signals. Pancreatic tuft cells also make an array of cytokines and immunomodulatory factors that can directly alter the immune response in the tumor microenvironment. These data leads us to hypothesize that tuft cells utilize the chemosensory response pathway to remodel the tumor microenvironment in PDA. In order to answer this question, we ablated a key protein in the chemosensory cascade, alpha-gustducin, and found that this loss increases aggressiveness in a model of pancreatitis-associated tumorigenesis. We are currently exploring differences in the tumor microenvironment that may explain these results. Citation Format: Megan T. Hoffman, Howard Crawford. Tuft cell chemosensory signaling during pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1004.