tbuckley/cabot-search huggingface dataset:
Abstract 1162: Multiple genes on chromosome 17q25 were involved in sporadic esophageal squamous cell carcinoma development
Authors: Takeshi Iwaya, Suburu Amano, Fumitaka Endo, Yuji Akiyama, Yoshihiro Shioi, Kohei Kume, Satoshi Nishizuka, Chie Ito, Akira Sasaki, Koshi Mimori
Journal: Cancer Research (2016)

Abstract [Background] Tylosis is an autosomal dominant skin disorder that is associated with the early onset of esophageal squamous cell carcinoma (ESCC) in several families. The tylosis esophageal cancer (TOC) gene locus has been mapped to chromosome 17q25.1 using linkage analyses. This region is also frequently lost in sporadic ESCC. [Materials and Methods] Gene expression profiles on 17q25 in tumor samples from 3 ESCC patients were analyzed using RNA-seq. We validated the expression status of candidate genes in samples from 90 ESCC patients using qRT-PCR. Direct sequence, microsatellite LOH analysis, and methylation assay were also performed in the candidate gene, ST6GALNAC1. Mutation profiles of genes on 17q were also evaluated by exome sequence analysis from 144 ESCC patients. [Result] EVPL and ST6GALNAC1 were found to be significantly downregulated in tumor samples using RNA-seq. Significant downregulation of ST6GALNAC1 and EVPL expression in cancer tissues was confirmed by qRT-PCR in 90 ESCC samples. Although direct sequence of ST6GALNAC1 demonstrated missense mutations in 7 out of 46 (15%) cases, these mutations were not tumor specific. ST6GALNAC1 expression was significantly upregulated in 5-aza-dC treatment groups compared with control in the 5 ESCC cell lines. LOH in ST6GALNAC1 gene locus were identified 18 of 27 informative cases (67%). On chromosome 17q, exome sequence revealed that recurrent mutations were observed only in ZNF750 (14.5%) on 7q25.3. Recently, missense mutations in RHBDF2 were identified tylosis familys. However, RHBDF2 mutation was not observed in sporadic ESC samples by exome sequence analysis. [Conclusion] Our results suggest that ST6GALNAC1 is a putative tumor suppressor gene for ESCC. Furthermore, recent studies on tylosis families and our results on sporadic ESC suggest that multiple genes on chromosome 17q25 are involved in ESCC development. Citation Format: Takeshi Iwaya, Suburu Amano, Fumitaka Endo, Yuji Akiyama, Yoshihiro Shioi, Kohei Kume, Satoshi Nishizuka, Chie Ito, Akira Sasaki, Koshi Mimori. Multiple genes on chromosome 17q25 were involved in sporadic esophageal squamous cell carcinoma development. [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 1162.
Immune response in breast cancer brain metastases (BM) and their microenvironment.
Authors: Renata Duchnowska, Rafał Pęksa, Barbara Radecka, Tomasz Mandat, Tomasz Trojanowski, Bozena Jarosz, Bogumila Czartoryska-Arlukowicz, Wojciech Olszewski, Waldemar Och, Ewa Kalinka-Warzocha, Anna Kowalczyk, Wojciech Biernat, Jacek Jassem
Journal: Journal of Clinical Oncology (2015)

e22112 Background: Better understanding of immune reactions in BM may prompt new preventive and therapeutic strategies. Methods: Material included 84 excised BM, derived from breast cancers representing 4 primary phenotypes: 23 hormone receptor (HR) positive/HER2-negative (HR+/HER2-), 21 HR+/HER2+, 21 HR-/HER2- and 19 HR-/HER2+. Immunohistochemical expression of infiltrating stromal lymphocytes (sTIL: CD4, CD8, CTLA4) and macrophage/microglial cells (CD68), PD1, PD-L1, PD-L2 and glial fibrillary acid protein (GFAP) was assessed in BM and in adjacent brain microenvironment. PD1-L1 and PD1-L2 expression was counted using H-score, considering staining intensity and percentage of positive cells. We determined correlations between particular parameters (rang Spearman correlation for continuous variable) and their impact on overall survival (OS) after BM excision. Results: Median time to BM occurrence from diagnosis of breast cancer was 41.6 months (range 0.9-152.7), and median OS after BM excision was 18.3 months (range 0-99 months). Median sTIL CD4, CD8 and CD68 infiltration was 49, 69 and 76, respectively. PD1-L1 (present in 63 BM) correlated positively with sTIL CD4 (P = 0.04), whereas PD1-L2 (present in 50 BM) - with sTIL CD4 (P = 0.01), in both cases irrespective of primary tumor and BM phenotypes. PD1 expression on sTIL (n = 17) correlated positively with sTIL CD4 (P = 0.03) and CD8 (P = 0.01). CD68 correlated positively with sTIL CD4 and CD8, and PD-L2 with CD4 and CD68. In multivariate analysis OS after BM excision was negatively impacted by HR-/HER2+ phenotype of primary tumor (HR = 3.0; P = 0.03) and HER2 expression in BM (HR = 6.5; P = 0.01), and positively by PD1 expression on sTIL (HR = 0.3; P = 0.004), CD68 expression (HR = 0.1; P < 0.001), brain radiotherapy (HR = 0.1; P < 0.001) and endocrine therapy after BM (HR = 0.1; P < 0.001). Conclusions: PD-L1 and PD-L2 expression is a common occurrence in BM, irrespective of primary tumor and BM phenotypes. Positive prognostic impact of PD1 expression on sTIL suggests beneficial effect of efficient immune response in the brain and potential preventive role of anti-PD1 therapies in breast cancer patients with high risk of BM.
Use of Thrombin Generation Assay As Tool for the Evaluation of the Antithrombotic Samenesse of Enoxaparine Copies
Authors: Grigorios T. Gerotziafas, Patrick Van Dreden, Aurélie Rousseau, Amir Khaterchi, Jeanine M. Walenga, Jawed Fareed, Ismail Elalamy
Journal: Blood (2014)
Response to lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC): Updated results from SELECT.
Authors: Andrew G. Gianoukakis, Elton George Mathias, Corina Dutcus, Parmida Kalantari, Steve Yoon
Journal: Journal of Clinical Oncology (2016)

6089 Background: Lenvatinib (LEN) significantly prolonged median progression-free survival (PFS) vs placebo (PBO) in the primary analysis of the phase 3 SELECT study of RR-DTC (18.3 vs 3.6 mos; HR 0.21; 99% CI 0.14–0.31; P< 0.001). Median duration of overall response (DOR; per RECIST 1.1) to LEN was not reached at the time of the primary analysis. Here we present new efficacy data with a focus on DOR. Methods: The data cutoff was 31 Aug 2015 (LEN: n = 261, PBO: n = 131); primary endpoint was PFS. DOR was examined for patients (pts) who had partial (PR) or complete responses (CR) and by subgroup (age, sex, tumor subtype, baseline disease burden, baseline Eastern Cooperative Oncology Group score, metastasis site, prior vascular endothelial growth factor [VEGF] therapy). For this analysis, tumor assessments were per investigator. We also report clinical features of 2 pts with RR-DTC with prolonged responses to LEN. Results: At cutoff, median PFS was 19.4 mos (95% CI 14.8–29.3) for LEN and 3.7 mos (95% CI 3.5–5.4) for PBO (HR 0.24; 99% CI 0.17–0.35; P< 0.0001). 157 Pts (60.2%) responded to LEN and median DOR was 30 mos (95% CI 18.4–35.2). 3 Pts (2.3%) responded to PBO and the median DOR was 14.7 mos (95% CI 7.5–not evaluable [NE; median not yet reached]). Median DOR to LEN was similar among subgroups except in pts with greater disease burden (tumor size ≤ 35mm: NE; 35–60mm: 27.5 mos; 60–92mm: 18.0 mos; > 92mm: 15.7 mos), and pts with liver metastasis (yes: 15.7 mos; no: 31.3 mos). 2 Pts with prolonged DOR are still receiving LEN: 1 woman (Hürthle cell follicular thyroid cancer; no prior VEGF therapy) received LEN since Nov 2011 and achieved CR with a DOR of 46 mos (ongoing) and a PFS of 48 mos; 1 man (Hürthle cell variant of papillary thyroid carcinoma; no prior VEGF therapy) received LEN since Jul 2012 and achieved PR with a DOR of 35 mos (ongoing) and a PFS of 41 mos (of note, this pt has multiple metastases in the lung, abdomen, and bone). Conclusions: In this analysis, LEN PFS benefit was maintained along with a notable DOR. The case studies profiled demonstrate that an extended DOR to LEN can occur in pts with RR-DTC who show significant variation in the severity of disease. Clinical trial information: NCT01321554.
Food insecurity as a driver of obesity in humans: The insurance hypothesis
Authors: Daniel Nettle, Clare Andrews, Melissa Bateson
Journal: Behavioral and Brain Sciences (2016)

Abstract Integrative explanations of why obesity is more prevalent in some sectors of the human population than others are lacking. Here, we outline and evaluate one candidate explanation, the insurance hypothesis (IH). The IH is rooted in adaptive evolutionary thinking: The function of storing fat is to provide a buffer against shortfall in the food supply. Thus, individuals should store more fat when they receive cues that access to food is uncertain. Applied to humans, this implies that an important proximate driver of obesity should be food insecurity rather than food abundance per se. We integrate several distinct lines of theory and evidence that bear on this hypothesis. We present a theoretical model that shows it is optimal to store more fat when food access is uncertain, and we review the experimental literature from non-human animals showing that fat reserves increase when access to food is restricted. We provide a meta-analysis of 125 epidemiological studies of the association between perceived food insecurity and high body weight in humans. There is a robust positive association, but it is restricted to adult women in high-income countries. We explore why this could be in light of the IH and our theoretical model. We conclude that although the IH alone cannot explain the distribution of obesity in the human population, it may represent a very important component of a pluralistic explanation. We also discuss insights it may offer into the developmental origins of obesity, dieting-induced weight gain, and anorexia nervosa.
Federal privacy rules offer scant protection for users of health apps and wearable devices
Authors: Michael McCarthy
Journal: BMJ (2016)

Federal privacy laws designed to protect people’s health information often do not apply to information provided by consumers to mobile health devices, over social media, and on websites, US health officials warned in a report released last week.1 As a result many consumers may have unknowingly allowed their personal health information to be used for advertising, marketing, and behavior tracking, and to be shared and sold to a wide variety of businesses, such as drug companies, …
Abstract 3168: Your targeted population might not be what you predict: Changes in tumor genetic landscapes post standard of care
Authors: Danielle Greenawalt, Austin Dulak, Manasa Ramakrishna, Zhongwu Lai, Justin Johnson, Hongyue Dai, Melissa Mitchell, Carl Barrett, Stephen Fawell, Jonathan Dry
Journal: Cancer Research (2016)

Abstract Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Public sequencing efforts have focused by design, on primary tumors, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard protocol. We have performed whole exome sequencing on post standard of care biopsies from 3 patient cohorts, 47 DLBCL patients post-relapse following R-CHOP, 49 triple negative breast (TNBC) following taxol alone or in combination and 41 lung adenocarcinoma (LUAD) following platinum alone or in combination. Comparative analysis of the mutation spectrum of these cohorts was performed against available clinically matched primary tumor cohorts. Comparison of the mutational signatures, somatic variant frequencies and copy number variation between matched pre- and post-treatment samples, and treated-primary tumor cohorts were performed. Significant differences were identified in the frequency of oncogenic drivers including PIK3CA in TNBC and KRAS in LUAD. We also observed mutational signature differences between cohorts that could impact treatment regimens post standard of care. Collectively these data further highlight the value of re-assessing the tumor genetic landscape at the time of treatment rather than relying on primary tumor samples, which may not be representative of the cohort to be treated. Citation Format: Danielle Greenawalt, Austin Dulak, Manasa Ramakrishna, Zhongwu Lai, Justin Johnson, Hongyue Dai, Melissa Mitchell, Carl Barrett, Stephen Fawell, Jonathan Dry. Your targeted population might not be what you predict: Changes in tumor genetic landscapes post standard of care. [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 3168.
ATNT-07FAVORABLE RESPONSE OF PATIENTS WITH GLIOBLASTOMA AT SECOND OR THIRD RECURRENCE TO REPEATED INJECTION OF ONCOLYTIC PARVOVIRUS H-1 IN COMBINATION WITH BEVACICUMAB
Authors: Karsten Geletneky, Assia Angelova, Barbara Leuchs, Andreas Bartsch, David Capper, Jacek Hajda, Jean Rommelaere
Journal: Neuro-Oncology (2015)

BACKGROUND: Among various experimental therapies for glioblastoma is the use of oncolytic viruses that specifically target and destroy cancer cells. Parvovirus H-1 (H-1PV), an apathogenic oncolytic rodent DNA virus, is tested in a phase 1/2a trial in patients with recurrent glioblastoma (ParvOryx01 trial, clinical trial identifier NCT01301430). Here we report on a series of 6 patients previously treated in the ParvOryx01 trial who received at another recurrence an additional local dose of H-1PV based on a compassionate use (CU) agreement. METHODS: 6 patients (all male, age 51 to 71 years) developed another tumor recurrence between 4 and 12,6 months (mean: 7,8 months) after treatment with H1PV in the ParvOryx01 trial. All 6 patients underwent tumor resection and injection of 5x108 plaque forming units (pfu) of H-1PV, followed by chemotherapy (n = 1), bevacicumab (n = 5) or no treatment (n = 1). The CU-virus dose was provided by the sponsor (Oryx GmbH&Co KG, Baldham, Germany) on a humanitarian basis. RESULTS: The censored mean survival of all 6 patients at second or third recurrence of GBM after compassionate use of H-1PV was 14,7 months (9 to 26 months). 3 of 6 patients are still alive 9,11 and 26 months after CU. Of 5 patients treated with bevacicumab after CU, 3 showed striking remissions of another tumor recurrence and the censored mean survival for this subgroup is 15,4 months. CU of H-1PV was tolerated without side effects. CONCLUSIONS: Repeated injection of H-1PV as compassionate use treatment in combination with bevacicumab led to longer survival times in patients at second or third recurrence of GBM compared to previous study treatment. This clinical data points to a synergistic effect of bevacicumab and H-1PV in the treatment of malignant gliomas.
Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins
Authors: David J Marshall, Scott S Harried, John L Murphy, Chad A Hall, Mohammed S Shekhani, Christophe Pain, Conner A Lyons, Antonella Chillemi, Fabio Malavasi, Homer L Pearce, Jon S Thorson, James R Prudent
Journal: Molecular Therapy (2016)

The human Na+/K+-ATPase (NKA) is a plasma membrane ion pump that uses ATP to help maintain the resting potential of all human cells. Inhibition of the NKA leads to cell swelling and death. The results of this investigation show that on cancer cells, the NKA either comes in close proximity to, associate with or complexes to important cancer-related proteins, and thus can be targeted with a new type of precision therapy called the extracellular drug conjugate or EDC. The EDCs reported here exhibit EC50 values in the low to mid-picomolar range, and signal to noise ratios > 1,000:1, both of which are dependent on the cell surface expression of the NKA and corresponding cancer-related target. We demonstrate that a potent small molecule inhibitor of the NKA can be covalently attached to antibodies targeting CD20, CD38, CD56, CD147, or dysadherin, to create a series of selective and powerful EDCs that kill cancer cells extracellularly by a mechanism resembling necrosis. This is therefore a framework for the development of a new type of precision therapy wherein exquisite selectivity is achieved for targeting extracellular disease-related proteins.
Abstract 4378: Discovery and characterization of two novel drivers of hepatocellular carcinoma
Authors: Charlotte R. Feddersen, Adam J. Dupuy
Journal: Cancer Research (2016)

Abstract Liver cancer is globally the sixth most commonly diagnosed and the third most deadly cancer. Hepatocellular carcinoma (HCC) is the most common form of the disease and a difficult cancer to treat due to inadequately understood pathways involved in tumorigenesis and progression. To obtain a better understanding of key HCC driver mutations, we performed a forward genetic screen using Sleeping Beauty transposon mutagenesis in a damaged liver microenvironment. Briefly, T2Onc3; Rosa26-SB11lsl/lsl;Alb-Cre mice were treated with carbon tetrachloride (CCl4) during ongoing transposition. We then sequenced the resulting liver tumors using linker mediated PCR (LM-PCR) and Illumina sequencing. We analyzed the sequenced data using gene-centric common insertion site (gCIS) analysis that allowed us to determine common insertion sites across tumors. These common insertion sites are referred to as candidate driver mutations. This screen demonstrated the role of Glioma associated protein-2 (Gli2) and Fidgetin (Fign) as candidate driver mutations in a significant subset of HCC tumors (20% and 10% respectively). Gli2 is a key member of the Hedgehog signaling pathway, acting as a transcription factor for genes promoting cell proliferation. Fign is a relatively uncharacterized protein in the AAA-ATPase family with the ability to sever microtubules in vitro. We validated Gli2 as a driver of HCC by generating a hepatocyte specific Gli2-overexpression mouse model using hydrodynamic tail vein injection of Gli2 cDNA into FAH-/- mice. Mice underwent rapid tumorigenesis, regardless of CCl4 treatment, demonstrating that Gli2 is a strong oncogene. Additionally we have demonstrated that overexpression of Fign drives cell proliferation and promotes stabilization of the primary cilium in hepatocytes, a novel finding that provides insight into the mechanism of Fign-driven HCC. The discovery of two novel HCC candidate driver mutations, validation of Gli2 as a bona fide HCC oncogene, and mechanistic insight into these commonly mutated genes in HCC will allow for future research into understanding HCC tumorigenesis and potential therapeutic options. Citation Format: Charlotte R. Feddersen, Adam J. Dupuy. Discovery and characterization of two novel drivers of hepatocellular carcinoma. [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 4378.
Functional Characterization of the BCL11B Breakpoint Region Reveals Multiple Enhancers at Dnase-I Hypersensitive Sites Some of Which Control NK-Family Homeobox Genes in T-ALL Cells with t(5;14)(q35;q32).
Authors: Stefan Nagel, Michaela Scherr, Klaus Hornischer, Alexander Kel, Maren Kaufmann, Hans G. Drexler, Roderick A.F. MacLeod
Journal: Blood (2005)
Safety and activity of TH-302, a hypoxia-activated cytotoxic prodrug (HAP), in patients with metastatic melanoma and lung cancer.
Authors: R. W. Weber, G. J. Weiss, E. G. Chiorean, N. N. Senzer, M. J. Borad, S. Markovic, J. R. Molina, V. K. Langmuir, H. Lee, J. R. Infante
Journal: Journal of Clinical Oncology (2010)

e19009 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. Following the phase I establishment of monotherapy weekly maximum tolerated dose (MTD) of 575 mg/m2 and based on preliminary activity in patients (pts) with metastatic melanoma, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); a dose expansion cohort was opened in these indications at the MTD. Methods: Pts had ECOG ≤ 1, advanced or metastatic melanoma, SCLC or NSCLC, evaluable by RECIST, and acceptable hematologic, liver and renal function. TH-302 was administered IV over 30-60 minutes on Day 1, 8 and 15 of a 28-day cycle. Patients dosed at 480 to 670 mg/m2 are included in analyses. Tumor assessments were performed every 2 cycles. The primary objectives were to determine the activity in each of the three indications and the recommended dose for future weekly monotherapy studies. Results: Thirty-five pts enrolled at 6 sites. Median age: 65y (range 23-79y). 23 male/12 female. ECOG 0/1: 22/13. Primary tumor: metastatic melanoma (19), SCLC (7), and NSCLC (9). Metastatic sites included lymph nodes (77%), liver (51%), lung (49%), bone (31%) and other site(s) (46%). 9 pts are ongoing; 26 pts discontinued (16 PD, 5 Pt/Physician decision, 3 clinical deterioration, 2 AE). Reversible skin and mucosal adverse events (AE) were dose limiting. Skin toxicities occurred in 31 (89%) pts including Gr 3 events in 4 pts: intertriginous perineal/genital rash (3) and cheilitis. Mucosal toxicities occurred in 16 (46%) pts including Gr 3 events in 2 pts: oral and vaginal mucositis. The other most common TH-302-related AEs were nausea, vomiting and fatigue. Hematologic toxicity was limited with no Gr 3/4 neutropenia or thrombocytopenia and 1 pt with Gr 3 anemia. Best PR and SD rates were 16% and 47% in 19 pts with melanoma, 29% and 29% in 7 pts with SCLC and 0% and 33% in 6 pts with NSCLC. 4 pts with melanoma continue on study 4 to 10 months after starting treatment. Conclusions: Antitumor activity observed as part of the dose escalation was confirmed. To improve tolerability and thus dose intensity, a dose of 480 mg/m2 was selected for further investigation of weekly TH-302 monotherapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals
Evidence on value of skin cancer screening is insufficient, US panel finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Evidence on the benefits and harms of routine skin cancer screening of adults is insufficient for assessment, the US Preventive Services Task Force has concluded in a report and evidence review published on 26 July in JAMA .1 2

Full body visual skin cancer screening has been a common practice among US physicians, with 56% of internists, 60% of primary care physicians, and 81% of dermatologists having reported performing the exam on their patients, a 2005 survey showed.3

In its review, the task force panel considered evidence related to screening for basal cell and squamous cell carcinomas (also known as non-melanoma skin cancer), as well as melanoma. Basal and squamous cell carcinomas accounted for …