tbuckley/cabot-search huggingface dataset:
DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics
Authors: Nicole de Rosa, Miguel A. Rodriguez-Bigas, George J. Chang, Jula Veerapong, Ester Borras, Sunil Krishnan, Brian Bednarski, Craig A. Messick, John M. Skibber, Barry W. Feig, Patrick M. Lynch, Eduardo Vilar, Y. Nancy You
Journal: Journal of Clinical Oncology (2016)

Purpose DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer. Methods Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer–specific survival were calculated by the Kaplan-Meier method. Results The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer–specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies. Conclusion dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions.
Emerging role of miR-21 in non-alcoholic fatty liver disease
Authors: Samira Benhamouche-Trouillet, Catherine Postic
Journal: Gut (2016)

Non-alcoholic fatty liver disease (NAFLD) has recently been linked to hepatocellular carcinoma (HCC) development, with or without the presence of cirrhosis, both in human disease and animal models. NAFLD is the hepatic manifestation of the metabolic syndrome associated with obesity, hyperinsulinaemia, type 2 diabetes, insulin resistance, hypertriglyceridaemia and hypertension, affecting up to one-third of the population worldwide.1 The diagnosis is related to the presence of excess liver droplets accumulation that can progress from hepatic steatosis to inflammation-associated steatohepatitis (non-alcoholic steatohepatitis, NASH). The pathogenesis of NAFLD is a highly integrated process, and a so-called ‘two-hit’ model is prevailing: the first hit is insulin resistance leading to fat accumulation through unabated lipolysis from the adipose tissue and increased de novo lipogenesis from glucose in the hepatocytes; hepatocyte fat accumulation will lead to the second hit associated with oxidative stress, cellular injury, inflammation and fibrosis. Many factors such as release of free fatty acids from adipose tissue, reactive oxidative stress species, interleukin-6, tumour necrosis factor-α and alteration in key signalling pathways (inflammation, insulin) are proposed to be involved in the pathological processes of NAFLD.

Interestingly, recent evidence indicates that changes in microRNAs (miRNAs) expression may be associated with NAFLD, NASH and related cardiovascular diseases.2 miRNAs are highly conserved 18–25 nucleotide non-coding RNA that regulate gene expression at the post-transcriptional level by destabilising mRNA and/or inhibiting translation. By regulating various target genes, miRNAs play pivotal roles in fine-tuning of metabolic processes in hepatocytes. Their stability in blood circulation makes them attractive biomarkers and potential therapeutic targets for liver …
No Survival Advantage After Double Umbilical Cord Blood (UCB) Compared to Single UCB Transplant in Children with Hematological Malignancy: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) Randomized Trial
Authors: John E. Wagner, Mary Eapen, Shelly L Carter, Paul R. Haut, Edward Peres, Kirk R. Schultz, Jason Thompson, Donna A. Wall, Joanne Kurtzberg
Journal: Blood (2012)
Abstract 1966: Automated miRNA purification without the use of organic solvents
Authors: Jami D. English, Doug Horejsh, Chris Moreland, Marjeta Urh
Journal: Cancer Research (2016)

Abstract MicroRNAs (miRNAs) are endogenous small non-coding RNAs 18-24 nucleotides in size that play important roles involving gene regulation associated with cancer, disease control and gene silencing. Because of the impact on disease progression, miRNA research is rapidly shifting towards biomarker discovery. Many of the commercially available miRNA purification methods involve organic extraction during pre-processing. Here, we describe a novel chemistry that enables total RNA purification including smaller RNA such as miRNA. This chemistry offers significant advantages with a simple automated workflow, no organic extraction and minimal pre-processing. In this study, we successfully show purification of miRNAs from a range of solid and liquid sample types including frozen tissue, whole blood, plasma, exosomes, mammalian cell lines, saliva, bone and FFPE samples. Absorbance yield, absorbance ratios, RINs, and amplification of miRNA show equivalence with organic solvent-based purification methods. The miRNA studied included miR-21, let-7a, miR-141, and miR-125b, depending on starting sample type. Next generation sequencing (NGS) analysis shows equivalent sequence diversity when compared pairwise with a manual, organic pre-processing method. This novel chemistry and method enables purification of small and large RNA from a range of sample types. The purified RNA has little or no detectable DNA contamination and does not require phenol extraction, thus improving safety. Also, the automation of this workflow decreases manual hands on time, saving scientist time and reducing the risk of RNase contamination. Citation Format: Jami D. English, Doug Horejsh, Chris Moreland, Marjeta Urh. Automated miRNA purification without the use of organic solvents. [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 1966.
Telomeres and Telomerase in Pediatric Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL).
Authors: Johann Greil, Elke Kleideiter, Matthias Schwab, Petra Boukamp, Ewa Koscielniak, Ute Bangerter, Ulrich Klotz, Dietrich Niethammer
Journal: Blood (2004)
Salvage Chemotherapy with Inotuzumab Ozogamicin (INO) Combined with Mini-Hyper-CVD for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)
Authors: Koji Sasaki, Hagop M. Kantarjian, Susan O'Brien, Deborah A Thomas, Farhad Ravandi, Guillermo Garcia-Manero, Tapan Kadia, Nitin Jain, Marina Konopleva, Zeev Estrov, Koichi Takahashi, Maria R. Khouri, Jovitta Jacob, Rebecca Garris, Jorge E. Cortes, Elias Jabbour
Journal: Blood (2015)
Use of online communication and social media by newly diagnosed breast cancer patients: Results from the iCanCare Study.
Authors: Sarah T. Hawley, Nancy K. Janz, Lauren P. Wallner, Steven J. Katz
Journal: Journal of Clinical Oncology (2015)

6518 Background: Online communication (OC) and social media (SM) could be used to enhance cancer treatment decision-making and care support. Yet, virtually nothing is known about whether and how newly diagnosed cancer patients use different forms of OC and SM during the treatment decision process. Methods: A weighted random sample of breast cancer patients newly diagnosed in 2013-14 were identified from Los Angeles and Georgia SEER registries and surveyed approximately 6 months after diagnosis (current response rate 68%). Respondents were asked whether they used different forms of OC (email or texting) or SM (facebook, twitter or blogs), how often, and for what purpose. We evaluated patient factors (age, education, race, stage, family history) associated with some/frequent use using logistic regression. We assessed purpose of OC and SM by patient factors using chi-square tests. Results: In a preliminary sample (n=2,021), 37% reported some or frequent use of either OC or SM to discuss the diagnosis, treatment decisions, or care support. There was a strong inverse relationship between increasing age and use (Table). Patients most likely to use any form (vs. never) were younger (age < 45 and 45-54) (OR: 4.0; 95% CI 2.8-5.7 and OR: 2.5; 95% CI 1.8-3.4), more highly educated (OR: 2.5, 95% CI: 1.9-3.5), and white (OR: 2.4; 95% CI 1.8-2.9). Of some/frequent users, the most common reasons were for letting people know about the diagnosis (69%), getting advice about treatments (56%), and for dealing with negative feelings/emotions (46%). Less common reasons were for sharing opinions about doctors (31%) or deciding on doctors (22%). More frequent users more often reported a deliberative decision process and had higher decision satisfaction (P<0.05) than never users. Conclusions: The substantial use of OC and SM for treatment decision and care support suggests growing opportunities to incorporate these modes into clinical practice. Future research should address optimal ways to incorporate these modes of engagement to improve experiences for all patients. Funding: NCI P01CA163233 Use of OC or SM for treatment decision or care support (%) Never Some Frequent < 45 37 29 33 45-54 54 22 23 55-64 60 18 21 65+ 75 13 12 P<0.001
First-in-human, open label, multicenter phase I of IPH4102, first-in-class humanized anti-KIR3DL2 monoclonal antibody, in relapsed/refractory cutaneous T-cell lymphomas.
Authors: Martine Bagot, Madeleine Duvic, Maarten Vermeer, Pierluigi Porcu, Sean Whittaker, Caroline Ram-Wolff, Christine Paiva, Anne Marie-Cardine, Cecile Bonnafous, Carine Paturel, Frederique Moriette, Robert Albert Zerbib, Armand Bensussan, Helene Sicard, Korinna Pilz, Youn H. Kim
Journal: Journal of Clinical Oncology (2016)

TPS2591 Background: KIR3DL2 is consistently expressed in all subtypes of Cutaneous T-cell Lymphomas (CTCL), irrespectively of disease clinical stage, with the greatest expression in Sézary Syndrome (SS) and transformed Mycosis Fungoides (MF), two subsets with high unmet need. KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptor (KIRs) family expressed on minor populations of NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It depletes selectively KIR3DL2-expressing cells. Its modes of action include Antibody-Dependent Cell-Cytoxicity (ADCC) and –Phagocytosis (ADCP). IPH4102 has potent efficacy in non-clinical models, in particular ex vivo autologous assays using primary CTCL cells. Methods: IPH4102-101 (NCT02593045) is a first-in-Human Phase I study of single-agent IPH4102 in relapsed/refractory CTCL. The study has two sequential parts, a dose-escalation followed by cohort expansion. The primary objective is to assess the safety and tolerability of increasing doses by characterizing dose-limiting toxicity (DLT) and adverse events. A 3+3 design with accelerated titration is employed. IPH4102 first Human dose and subsequent dose-levels were selected based on a MABEL strategy and PK/PD modeling. The dose-escalation portion aims to determine the maximal tolerated dose (MTD) or recommended Phase 2 dose (RP2D). Secondary objectives include PK, immunogenicity and signals of anti-neoplastic clinical activity. Exploratory objectives include identification of biomarkers of IPH4102 activity in skin lesions and on malignant blood cells when present. Eligible CTCL patients must have received at least 2 lines of systemic therapy. Centrally assessed KIR3DL2 expression in at least one involved organ is also required. In the expansion portion, two CTCL subtype-specific cohorts will include 20 additional patients to further explore the MTD or RP2D. CTCL subtypes will be selected according to dose-escalation findings. Enrollment into study IPH4102-101 started in November 2015. Cohorts 1-3 have been completed without DLT. Enrolment to cohort 4 started in January 2016. Clinical trial information: NCT02593045.
High Thymidine Kinase Activity and CD5 Positivity Predict Poor Prognosis Of DLBCL Treated With R-CHOP
Authors: Kazuhito Suzuki, Yasuhito Terui, Masahiro Yokoyama, Noriko Nishimura, Naoko Tsuyama, Kengo Takeuchi, Noriko Usui, Keisuke Aiba, Kiyohiko Hatake
Journal: Blood (2013)
Abstract 1220: A novel PTK7-targeted antibody-drug conjugate eliminates tumor-initiating cells and induces sustained tumor regressions
Authors: Marc Isaac Damelin, Alex Bankovich, Jeff Bernstein, Justin Lucas, Liang Chen, Sam Williams, Albert Park, Jorge Aguilar, Elana Ernstoff, Manoj Charati, Russell Dushin, Amy Jackson-Fisher, Monette Aujay, Christina Lee, Hanna Ramoth, Milly Milton, Johannes Hampl, Sasha Lazetic, Virginia Pulito, Douglas Armellino, Edward Rosfjord, Magali Guffroy, Hadi Falahatpisheh, Lindsay King, Frank Barletta, Robert Stull, Marybeth Pysz, Paul Escarpe, David Liu, Orit Foord, Brenda Gibson, Eric Powell, Christopher O’Donnell, Xiaohua Xin, Hans Peter Gerber, Puja Sapra, Scott Dylla
Journal: Cancer Research (2016)

Abstract Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor regrowth and metastasis. Here we identify Protein Tyrosine Kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase, as an antigen that is enriched on TICs in low-passage patient-derived xenografts (PDX) of TNBC, NSCLC and other tumor types. An anti-PTK7 antibody-drug conjugate (ADC) was generated from a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker and the Aur0101 auristatin microtubule inhibitor. The anti-PTK7 ADC induced sustained regressions of TNBC, NSCLC and ovarian cancer PDX, with improved activity over standard-of-care chemotherapy, and reduced the frequency of TICs as determined by serial transplantation experiments. Moreover, the ADC may have additional mechanisms of action, including an anti-angiogenic effect, that promote anti-tumor immune responses. Together these preclinical results indicate the potential of the anti-PTK7 ADC to improve the long-term survival of cancer patients. The ADC is currently being tested in a Phase 1 clinical trial, from which interim results will be presented. Citation Format: Marc Isaac Damelin, Alex Bankovich, Jeff Bernstein, Justin Lucas, Liang Chen, Sam Williams, Albert Park, Jorge Aguilar, Elana Ernstoff, Manoj Charati, Russell Dushin, Amy Jackson-Fisher, Monette Aujay, Christina Lee, Hanna Ramoth, Milly Milton, Johannes Hampl, Sasha Lazetic, Virginia Pulito, Douglas Armellino, Edward Rosfjord, Magali Guffroy, Hadi Falahatpisheh, Lindsay King, Frank Barletta, Robert Stull, Marybeth Pysz, Paul Escarpe, David Liu, Orit Foord, Brenda Gibson, Eric Powell, Christopher O’Donnell, Xiaohua Xin, Hans Peter Gerber, Puja Sapra, Scott Dylla. A novel PTK7-targeted antibody-drug conjugate eliminates tumor-initiating cells and induces sustained tumor regressions. [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 1220.
Abstract 4847: Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents
Authors: Mingming Zhang, Ui Joung Youn, Gabriella Miklossy, Supakit Wongwiwatthananukit, James Turkson, Leng Chee Chang, Dianqing Sun
Journal: Cancer Research (2016)

Abstract Clinically, natural product has played a pivotal role in anticancer drug discovery and development. Cancer chemotherapy and/or radiotherapy due to glioma treatment are not ideal, frequently cause unwanted adverse effects, and justify further research and development of alternative, novel, safe, and effective agents. In our continued efforts to identify new signal transducer and activator of transcription 3 (STAT3) and antiglioma agents with enhanced efficacy and specificity, we have initiated a collaborative and multidisciplinary natural product drug discovery project and the goal was to isolate, semisynthesize, and evaluate the potential of Vernonia cinerea-derived phytochemicals as STAT3 inhibitors with therapeutic remedy of human glioma and may be even more effective than the existing ones. To date, our preliminary studies have been conducted and resulted in the discovery of a class of sesquiterpene lactone hirsutinolide series with an á,â-unsaturated-ã-lactone ring as new STAT3 inhibitors. Specifically, on the basis of encouraging biological data and to expand the existing structure activity relationship (SAR) of isolated natural hirsutinolide analogues, chemical modifications were performed using conventional Steglich esterification protocol to produce a series of semisynthetic hirsutinolide derivatives in moderate to high yields. Thus far, biological evaluation revealed that several semisynthetic analogues showed low micromolar inhibitory activities against constitutively-active STAT3 and malignant glioma phenotype. SAR showed that a bulky and lipophilic ester functionality at position 13 is essential for STAT3 inhibition as well as whole cell based anticancer activity. A lipophilic side chain at position 8 also plays an important role in anticancer activity and may contribute a detrimental effect on specificity. In addition, the methoxy group at position 1 enhances the cell-type specificity and selectivity. Finally, selected promising lead candidates also demonstrated in vivo efficacy following oral gavage delivery, inhibiting human glioma tumor growth in subcutaneous mouse xenografts. Together, natural and chemically modified hirsutinolide-type sesquiterpene lactones represent a promising natural product class of new anticancer agents for the treatment of malignant human glioma. Citation Format: Mingming Zhang, Ui Joung Youn, Gabriella Miklossy, Supakit Wongwiwatthananukit, James Turkson, Leng Chee Chang, Dianqing Sun. Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents. [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 4847.
Abstract CT134: Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma
Authors: Alain Algazi, Katy K. Tsai, Kathryn T. Takamura, Lawrence Chen, Chris Twitty, Mary Dwyer, Samantha Greaney, Tu Diep, Robert H. Pierce, Mai H. Le, Lawrence Fong, Adil Daud
Journal: Cancer Research (2016)

Abstract Background: Intratumoral electroporation of plasmid IL-12 (IT-pIL12-EP) induces tumor infiltrating lymphocytes (TILs) and anti-tumor immunity in melanoma as described in previous Phase 1 and 2 clinical trials. PD-1 and PD-L1 antibodies induce durable tumor responses in advanced melanoma, however responses to these agents are far less common in tumors lacking significant numbers of TILs. Therefore, in this retrospective study, patients were evaluated for response to anti-PD-1/PD-L1 therapies post IT-pIL12-EP. Methods: A multi-center, Phase 2 trial of IT-pIL12-EP was conducted in patients with stage III/IV melanoma. Upon disease progression or treatment discontinuation with IT-pIL12-EP, many patients received subsequent PD-1/PD-L1 inhibitors. Patients with documented follow up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis. Results: We evaluated 34 patients enrolled and treated with IT-pIL12-EP monotherapy at a single center, of which, 14 patients went on to receive a systemic PD-1/PD-L1 inhibitor and were evaluable for PD-1/PD-L1 best overall response (BOR). The PD-1/PD-L1-associated BOR was 9/14 (64%) with CR in 5 patients (36%), PR in 4 (29%), SD in 2 (14%), and PD in 3 (21%). Eight of these evaluable patients received a systemic PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP. Of these 8 patients, a BOR of 75% was observed (50% CR and 25% PR). Conclusion: Patients who received IT-pIL12-EP and later went on to receive a PD-1/PD-L1 inhibitor demonstrated a high PD-1/PD-L1-associated response rate (64% CR+PR). Interestingly, patients who received a PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP had a BOR of 75% (CR+PR). These data suggest that IT-pIL12-EP may prime for responses to PD-1 blockade. Patient tumor samples are being evaluated for TIL status and gene expression analysis to determine the mechanism of IT-pIL12-EP priming. A prospective clinical trial combining IT-pIL12-EP and pembrolizumab in advanced melanoma is ongoing at the University of California San Francisco. NCT01502293 Citation Format: Alain Algazi, Katy K. Tsai, Kathryn T. Takamura, Lawrence Chen, Chris Twitty, Mary Dwyer, Samantha Greaney, Tu Diep, Robert H. Pierce, Mai H. Le, Lawrence Fong, Adil Daud. Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma. [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 CT134.
Insurance claims related to opioid dependence have risen by 3200%, US study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Private health insurance claims for opioid dependence in the United States rose more than 3200% from 2007 to 2014, an analysis of privately billed healthcare claims has shown.1 The study was conducted by FAIR Health, a New York City based non-profit corporation that maintains a database of over 20 billion privately billed healthcare claims and provides healthcare cost data and analysis to government agencies, insurers, providers, and consumers.

The US is currently experiencing a major epidemic of opioid dependence, misuse, and deaths resulting from overdose. The US Centers for Disease Control and Prevention noted that since 1999 the number of overdose deaths from opioids, including prescription opioids and heroin, …
Natural language processing and the Now-or-Never bottleneck
Authors: Carlos Gómez-Rodríguez
Journal: Behavioral and Brain Sciences (2016)

Abstract Researchers, motivated by the need to improve the efficiency of natural language processing tools to handle web-scale data, have recently arrived at models that remarkably match the expected features of human language processing under the Now-or-Never bottleneck framework. This provides additional support for said framework and highlights the research potential in the interaction between applied computational linguistics and cognitive science.
Treatment with Pegylated Interferon Alpha 2a in Combination with the Bcl-Xl Inhibitor ABT-737 Specifically Targets JAK2V617F Positive Hematopoietic Progenitor Cells From Patients with Polycythemia Vera.
Authors: Min Lu, Wei Zhang, Daniel Yoo, Dmitriy Berenzon, Yan Li, Xiaoli Wang, Adam Austin, John Mascarenhas, Mingjiang Xu, Ronald Hoffman
Journal: Blood (2009)