tbuckley/cabot-search huggingface dataset:
Abstract 4354: CRISPR/Cas9 genome-wide gRNA library for target identification
Authors: Donato Tedesco, Paul Diehl, Mikhail Makhanov, Sylvain Baron, Dmitry Suchkov, Costa Frangou, Alex Chenchik
Journal: Cancer Research (2016)

Abstract Genome-wide loss-of-function screening is a fundamental method to identify genes responsible for driving biological responses, and complex pooled lentiviral-based libraries expressing large numbers of genetic disruptors, such as shRNAs, make large-scale cell screening practical. While RNAi-based approaches have proven to be an effective strategy for these screens, recent work suggests CRISPR technology offers an effective alternative. Although shRNA and sgRNA pooled library screens are similar in concept, the gene interruption with the two techniques occurs by a very different mechanism so some divergence may be expected when comparing results obtained using one method versus the other. To investigate the potential difference in the two methodologies, we performed parallel dropout viability screens to identify essential genes in a pair of primary isogenic CML cell lines using a CRISPR/Cas9 knockout library and an RNA interference (RNAi) library targeting the same set of 6,300 genes with the same number of targeted effectors (sgRNA or shRNA) for each gene. The results showed significant, but not complete, overlap in the essential genes identified by each assay in each cell line indicating that both approaches are effective to identify the majority of essential genes in a cell system. However, analysis did indicate that a small number of essential targets were only identified with CRISPR and certain unique targets seemed to show up only in the RNAi screen results. By combining data from the two screening methodologies, a consistent number of viability genes and pathways could be identified and subsequently validated by independent cell based assays at a very high confirmation rate. Citation Format: Donato Tedesco, Paul Diehl, Mikhail Makhanov, Sylvain Baron, Dmitry Suchkov, Costa Frangou, Alex Chenchik. CRISPR/Cas9 genome-wide gRNA library for target identification. [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 4354.
Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (<scp>ROPAC</scp>) of the European Society of Cardiology
Authors: Karen Sliwa, Iris M. van Hagen, Werner Budts, Lorna Swan, Gianfranco Sinagra, Maryanne Caruana, Manuel Vazquez Blanco, Lodewijk J. Wagenaar, Mark R. Johnson, Gary Webb, Roger Hall, Jolien W. Roos‐Hesselink
Journal: European Journal of Heart Failure (2016)
Phase Ib/II study of cancer stem cell (CSC) inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Carlos Becerra, Joe Stephenson, Derek J. Jonker, Allen Lee Cohn, Timothy R. Asmis, Tanios S. Bekaii-Saab, Paul R. Conkling, Lawrence E. Garbo, Heinz-Josef Lenz, Donald A. Richards, Alexander I. Spira, Sameh Mikhail, Rachel Anne Goodwin, Harry H. Yoon, Stephanie Hume, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2015)

4069 Background: BBI608, a first-in-class CSC inhibitor that works through inhibiting Stat3, has shown potent synergistic anti-tumor and anti-metastatic activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 + weekly paclitaxel was well tolerated and a RP2D of BBI608 500 mg BID was determined. Methods: Patients with advanced, pre-treated gastric and GEJ adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with advanced gastric/GEJ adenocarcinoma. Eligible patients received ≥ 1 line of prior treatment in the metastatic setting with a platinum + fluoropyrimidine/TS inhibitor. BBI608 was administered orally at 480 mg or 500 mg twice daily with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Results: 46 patients (87% Caucasian, 7% Black, 6% Asian) were enrolled in US and Canada; 10 (22%) had 1 line of prior therapy, 16 (35%) had 2 prior lines, and 20 (43%) had 3 or more prior lines. Common adverse events (AE) were grade 1 to 2 diarrhea, abdominal cramps, nausea, and vomiting. Grade 3 AE included vomiting (10%), diarrhea of 5 days or longer (7%), fatigue (7%), and abdominal cramps, nausea, dehydration (2% each). In 20 patients who had not received a taxane in the metastatic setting, the per-protocol ORR was 31% (5/16) and DCR was 75% (12/16); median PFS was 20.6 wks and mOS was 39.3 wks. In 26 patients who failed a prior taxane (median 3 prior lines), per-protocol ORR was 11% (2/19), and DCR was 68% (13/19); mPFS was 12.6 wks and mOS was 33.1 wks. In a subset of evaluated patients who received only 1 prior line of therapy without a taxane, the ORR was 50% (3/6) and the DCR was 83% (4/6). Conclusions: In this first known clinical study of a CSC inhibitor in gastric/GEJ adenocarcinoma, BBI608 and weekly paclitaxel were combined safely at the full-intended doses. Encouraging signs of anti-cancer activity were observed. A phase 3 study of BBI608 in combination with weekly paclitaxel in patients with gastric/GEJ cancer who had failed first line therapy is underway. Clinical trial information: NCT01325441.
Screening for <i>PIK3CA</i> mutations, PTEN loss, and <i>RAS</i>/<i>RAF</i> mutations in early-phase protocols with PI3K/mTOR pathway inhibitors.
Authors: F. Janku, I. Garrido-Laguna, J. J. Wheler, D. S. Hong, A. Naing, G. S. Falchook, S. Fu, S. L. Moulder, R. Luthra, J. J. Lee, A. M. Tsimberidou, R. Kurzrock
Journal: Journal of Clinical Oncology (2011)

10507 Background: Activating mutations of PIK3CA or loss of PTEN function result in increased PI3K/mTOR signaling and may predict sensitivity to drugs targeting the PI3K/mTOR pathway, while simultaneous mutations in the MAPK pathway (RAS, RAF) may mediate resistance. Methods: From 10/2008, 922 consecutive tumor samples from advanced cancer patients referred to the Clinical Center for Targeted Therapy were screened (CLIA-certified tests) for PIK3CA, KRAS, NRAS, BRAF mutations and PTEN loss (mutation or complete loss of staining on immunohistochemistry). Patients with tumors carrying PIK3CA mutations and/or PTEN loss were preferentially treated with agents targeting the PI3K/mTOR pathway. Results: Overall, 922 patients with diverse histologies were tested, and 157 (17%) had PIK3CA mutations (n=86, 9%), PTEN loss (n=67, 7%), or a simultaneous PIK3CA mutation and PTEN loss (n=4, <1%). Of these 157 patients, 86 (55%) were treated in clinical trials containing a PI3K/mTOR pathway inhibitor (median age, 56; median number of prior therapies, 3). Of these 86 patients, 54 (63%) had PIK3CA mutations, 29 (34%) PTEN loss, 3 (4%) simultaneous PIK3CA mutation and PTEN loss; and 18 (21%, 95% CI 0.14-0.31) patients achieved a partial response (PR). In contrast, patients without known PIK3CA mutations and/or PTEN loss treated on the same protocols had a PR rate of 6% (26/458; 95% CI 0.04-0.08, p<0.001). Patients with PIK3CA/PTEN testing of primary tumor had a similar PR rate of 20% compared to 23% in patients with PIK3CA/PTEN testing of metastatic tumor (p=0.8). Treated patients with wild-type KRAS had a higher PR rate of 31% compared to 6% in patients with simultaneous KRAS mutations (p=0.05). Conclusions: Heavily pretreated patients with PIK3CA mutations and/or PTEN loss and wild-type KRAS had a significantly higher PR rate (31%) on protocols incorporating PI3K/mTOR inhibitors compared to unselected patients on the same protocols (PR rate = 6%) or patients with PIK3CA mutations and/or PTEN loss and simultaneous KRAS mutations (PR rate = 6%). Our observations suggest that screening for PIK3CA mutations, PTEN loss and KRAS mutations is warranted in patients who are treated with PI3K/mTOR pathway inhibitors.
A Genetic Variant in the CD53 Gene Is Associated with Clinical Outcomes after Unrelated Bone Marrow Transplantation
Authors: Luis Jorge Espinoza, Keitaro Matsuo, Saki Toda, Yasuo Morishima, Makoto Onizuka, Koichi Kashiwase, Takahiro Fukuda, Yoshihisa Kodera, Shinji Nakao, Akiyoshi Takami
Journal: Blood (2014)
Chronic myelogenous leukemia in the era of tyrosine kinase inhibitors: Are there barriers to ideal care?
Authors: Isabelle Phuong Le, Anand B. Karnad, Christos Fountzilas, Yuanyuan Liang, Alex V. Mejia, Marcela Mazo- Canola, Selena Juarez Stuart, Elizabeth Ann Bowhay-Carnes, Jay C Shiao, Roy Liu, Praveena Iruku, Tamna Wangjam, Steven D. Weitman
Journal: Journal of Clinical Oncology (2015)

e18046 Background: Tyrosine kinase inhibitors (TKI) have revolutionized treatment of chronic myelogenous leukemia (CML) with excellent survival outcomes and response rates. Our institution serves a significant portion of South Texas, a population facing serious cancer health disparities. We therefore reviewed the treatment outcomes of our patients to evaluate for barriers to ideal CML care. Methods: Retrospective chart review of patients with CML treated with TKI as first line therapy from 2002-2014 at an academic cancer institution. Major molecular response (MMR) rates at 12 months, 24 months, and last documented disease status were recorded. Response rates and disease status were analyzed by ethnicity, age, gender, language barrier, participation in clinical trials, and type of TKI used in first line. Results: Using Fisher’s exact test, we included 51 patients in the analysis. Mean age was 44.6 years. 49% (n = 25) were Hispanics and 56.9% (n = 29) were female. 66.7% (n = 34) received imatinib and 33.3% (n = 17) received dasatinb/nilotinib as first line therapy. 37.2% (n = 19) were younger than 40 years. 15% (n = 8) had language barrier. 11.7% (n = 6) were enrolled in clinical trials. 23.5% (n = 12) and 44.9% (n = 22) achieved MMR at 12 and 24 months (comparable to historical data). There was no significant difference in MMR rates at 12 months, 24 months and last documented disease status in Hispanics vs. non-Hispanics, patients older vs. younger than 40 years old, patients with and without language barrier, and between different genders. MMR rates at 12 months was significantly lower in patients treated with imatinib vs. dasatinib/nilotinib as first line (10 vs. 53%, p = 0.001). MMR rate at 12 and 24 months was significantly higher in patients enrolled vs. not enrolled in clinical trials (83 vs. 15%, p = 0.002, 100 vs. 45%, p = 0.023). Conclusions: Our preliminary data shows similar outcomes with our patients compared to historical data. Patient who were enrolled in clinical studies had better MMR rates at 12 and 24 months likely secondary to extensive education about their disease and close follow-ups. This warrants further investigation with prospective studies.
Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus
Authors: Jean-Luc Faillie, Oriana H. Yu, Hui Yin, Dominique Hillaire-Buys, Alan Barkun, Laurent Azoulay
Journal: JAMA Internal Medicine (2016)

The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association.To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes.A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014.Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs.Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs.During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02).The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.
Abstract 4877: Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy
Authors: Shengyang Liu, Taoliangshan Tao, Yue Liang, Hongli Guo, Xiaogang Ye, Zhiheng Wu, Fang Bao, Heping Yang, Yaxian Cai, Gangjing Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Xiaolei Liu, Jiangang Du, Ping Qin, Yuanfei Ma, Panhu Zhu, Yajun Yu, Chen Ma, Pei Wang, Liping Zhao, Yuxun Wang, Daxin Gao, Qun Li
Journal: Cancer Research (2016)

Abstract Indoleamine-2,3-dioxygenase (IDO1) is an immune regulatory enzyme that oxidizes tryptophan to kynurenine. IDO1 is overexpressed in numerous tumor cells that block T-cell activation, induce T-cell apoptosis and increase regulatory T cells, which create an environment in which tumor-specific cytotoxic T lymphocytes are no longer able to attack a patient's cancer cells. IDO1 inhibition reverses the immune suppression at the tumor site and allows the generation of an effective anticancer immune response. Preclinical and clinical studies have shown that IDO1 inhibitors increase the anticancer immune response and dramatically increase the efficacy of various therapeutic agents especially the immune checkpoint antibodies targeting PD-1, PD-L1 and CTLA-4. Via structure-based design, we have discovered a series of novel and potent IDO1 inhibitors that demonstrate strong IDO1 on-target activity with IC50 values ranging from 10 nM to 50 nM against human IDO1 enzyme. These compounds potently inhibit IDO1 in tumor-bearing mice as well as in Hela cells with lower single-digit to lower double digit nM IC50. The lead compound selected for clinical development shows good ADME profile, low serum binding, and good efficacy in various murine animal models when dosed orally and subcutaneously alone or in combination with immune checkpoint inhibitors. Preclinical evaluation of the compound will be presented in details. Citation Format: Shengyang Liu, Taoliangshan Tao, Yue Liang, Hongli Guo, Xiaogang Ye, Zhiheng Wu, Fang Bao, Heping Yang, Yaxian Cai, Gangjing Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Xiaolei Liu, Jiangang Du, Ping Qin, Yuanfei Ma, Panhu Zhu, Yajun Yu, Chen Ma, Pei Wang, Liping Zhao, Yuxun Wang, Daxin Gao, Qun Li. Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy. [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 4877.
Multiplex Quantitative Real-Time PCR for the Detection of t(14;18) Translocations with Breakpoints within 5 Different Regions of the BCL-2 Gene: MBR, 3′MBR, mcr, 5′mcr, icr.
Authors: Frank Schüler, Sandra C. Dölken, Carsten Hirt, Gottfried Dolken
Journal: Blood (2005)
Tackles, tears and troubles… a South African Sports Medicine Association perspective
Authors: Jon Patricios
Journal: British Journal of Sports Medicine (2016)

Rugby Sevens returns to the Olympics this August after an absence of over 90 years. South African Seabelo Senatla, pictured on the cover, is one of a number of international Rugby Sevens players with poetic-sounding names. Akira Ioane (New Zealand), Nathan Hirayama (Canada), Collins Injera (Kenya) and Savenaca Rawaca (Fiji) have titles of similar allure for rugby commentators. The truly international reach, fast pace and tempo of the sport vilify the Olympic motto of ‘ Citius, Altius, Fortius ’. However, the debates surrounding the risks of collision sport, the discussions around injury epidemiology and prevention as well as the ubiquitous grey cloud of doping are unlikely to evaporate in the midst of Olympic euphoria. This South African Sports Medicine Association (SASMA)-led BJSM edition scrutinises these aspects of sport.

The contentious call by a group of UK-based ‘health experts’ for a ban on tackling in school rugby1 has provoked much print and social media …
Abstract 2612: Zinc inhibits Orai1-mediated Ca2+ signals and proliferation in esophageal cancer cells
Authors: Sangyong Choi, Chaochu Cui, Yanhong Luo, Jae-Kyun Ko, Jianjie Ma, Liwu Fu, Irina Korichneva, Zui Pan
Journal: Cancer Research (2016)

Abstract Intracellular Ca2+ signals, including oscillations, regulate proliferation, migration, and other cellular events in cancer cells. Zinc (Zn), an essential micronutrient, has been studied for its chemopreventive effects in several cancers, including esophageal cancer. Although there is a growing research interest in the cross-talk between Ca2+ and Zn signaling, it remains elusive as to how Zn prevents tumor growth and whether Ca2+ signaling is involved. Our previous report demonstrated that Orai1, a store-operated Ca2+ entry (SOCE) channel, is highly expressed in esophageal squamous cell carcinoma (ESCC) compared to normal tissues, and that the elevated expression of Orai1 is strongly associated with poor prognosis in patients. In the current study, we show that physiological levels of Zn can significantly suppress cell proliferation in KYSE-150, a human ESCC cell line. We also show that Zn is able to inhibit Orai1-mediated SOCE and intracellular Ca2+ oscillations, both which are known as proliferation signals. Based on the topology information of Orai1, we hypothesized that the histidine residue in linker region between transmembrane 1 and 2 of Orai1 (H113) as well as three cysteine residues may play a critical role in Zn-inhibitory effects. Using a point mutation approach, we exhibit that the Zn-inhibitory effects on both SOCE and cell proliferation are vanished in KYSE-150 cells containing Orai1 H113A mutant. Furthermore, KYSE-150 cells expressing Orai1 with any mutation in cysteine residues (C126A, C143A and C195A) display significant loss of Zn-inhibitory functions. These results indicate that the four amino acid residues are likely to be involved in Zn-inhibitory effects on SOCE and cell proliferation. Taken together, our data suggest that dietary Zn may inhibit Orai1-mediated SOCE and intracellular Ca2+ signaling, which in turn suppresses cell proliferation in ESCC. Further studies are required to search for novel and effective prevention strategies as well as therapeutic options targeting on Zn and Ca2+ signaling in ESCC. Citation Format: Sangyong Choi, Chaochu Cui, Yanhong Luo, Jae-Kyun Ko, Jianjie Ma, Liwu Fu, Irina Korichneva, Zui Pan. Zinc inhibits Orai1-mediated Ca2+ signals and proliferation in esophageal cancer cells. [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 2612.
Multidisciplinary cancer conferences as a forum for early identification of patients who can benefit from palliative care.
Authors: Frances Catriona Wright, Hardeep Johal, Marnie MacKinnon, Erin Arthurs
Journal: Journal of Clinical Oncology (2015)

148 Background: Introducing palliative care early in the cancer journey results in a better quality of life, less aggressive care and longer survival compared to patients receiving standard care. The INTEGRATE Project goal is to identify and manage patients who can benefit from palliative care using the UK Gold Standards Framework Surprise Question (would you be surprised if this person died within the next year?). Multidisciplinary cancer conferences (MCCs) are scheduled meetings for oncology teams to prospectively discuss patient diagnostic tests and treatment options, which were leveraged for the INTEGRATE Project. Methods: A pilot study to test the efficacy of the Surprise Question at MCCs and implementation of a palliative model of care has been implemented in 3 academic and 1 non-academic cancer centres. A survey was completed to identify provider comfort levels in providing palliative care. All sites completed Pallium Canada’s LEAP Onco module, which equips providers with skills to provide primary level palliative care. Patients identified at MCCs received advance care planning, symptom management, referrals and standardized reporting to primary care. Results: Four disease sites (Lung, GI, CNS and Head &amp; Neck) are participating. A baseline survey showed over 50% of providers had no training in palliative care. 161 providers participated in LEAP Onco. Implementation of the Surprise Question at MCCs began in February 2015. Two months of implementation identified 39 patients at the CNS, Lung and GI disease sites out of 108 of patients reviewed. At the CNS MCC, 100% glioblastoma patients were identified. The Lung and GI disease sites had lower identification rates (27% and 10%, respectively). Identified patients will have their healthcare utilization (referrals to community providers, billing patterns, ER visits) analyzed to determine impact of this project. Implementation continues until 2016. Conclusions: MCCs appear to be an excellent forum for identifying patients who can benefit from a palliative approach to care within the CNS, Lung and GI site groups. Further data is being collected to inform provincial recommendations for broader implementation of palliative care in Ontario.