tbuckley/cabot-search huggingface dataset:
VIKTORY trial: Report on AZD1775/paclitaxel in TP53 mutation (+) GC, selumetinib/paclitaxel in ras aberrant GC, AZD5363/paclitaxel in PIK3CA mt and biomarker negative, savolitinib/docetaxel in met (+), and vistusertib/paclitaxel in RICTOR(+) GC.
Authors: Jeeyun Lee, Seung Tae Kim, Peter G. Mortimer, Simon J Hollingsworth, Elizabeth A. Harrington, Christopher Shepherd, Elaine Kilgour, Se Hoon Park, Hyuk Lee, Sung Yong Oh, Jung Hun Kang, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Kyoung-Mee Kim, Won Ki Kang
Journal: Journal of Clinical Oncology (2017)

4024 Background: The VIKTORY trial is a biomarker-based umbrella trial in GC. Methods: See table below. Results: From June 2014 to Jan 2017, 432 metastatic gastric cancer patients were enrolled. 124 (28.7%) were treated on one of the associated study protocols. At January 2017, 25 pts were allocated to selumetinib/paclitaxel arm, 25 to AZD1775/paclitaxel arm, 16 to AZD5363/paclitaxel arm, 16 to vistusertib/paclitaxel arm, 4 to savolitinib monotherapy, 19 to savolitinib/docetaxel arm, 19 to phase I AZD6738/paclitaxel arm. Initial efficacy signals have been seen in several arms (selumetinib/paclitaxel, 6 of 21 evaluable patients in PR). Correlative analyses between molecular signatures and treatment response are ongoing and will be presented at the meeting. For vistusertib/paclitaxel in the biomarker negative arm, we found RICTOR amplification as a promising predictive biomarker for response. Two (of three) GC patients with RICTOR amplification achieved PR to vistusertib/paclitaxel. Conclusions: This is one of the first attempts to undertake a biomarker-driven trial in metastatic GC. 28.7% of the patients were guided to one of the parallel arms based on molecular screening outcomes. We were able to identify potential molecular targets in the biomarker-negative arm, for further assessment in new protocols. Clinical trial information: 02299648. [Table: see text]
SU014813 is a novel multireceptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity
Authors: Dana D. Hu-Lowe, Maren Grazzini, Jeffrey Chen, Jingchuan Zhang, Wei-Zhu Zhong, Douglas Laird, Shem Patyna
Journal: Cancer Research (2005)

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3(FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813inhibited liganddependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813inhibited VEGFR-2, PDGFR- B, and FLT3phosphorylation in xenograft tumors in a doseand time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumorbearing mice compared with administration of either agent alone. In summary, SU14813inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774 – 82]
Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other Pathogenic Viruses
Authors: Franziska Schandock, Camilla Frich Riber, Annika Röcker, Janis A. Müller, Mirja Harms, Paulina Gajda, Kaja Zuwala, Anna H. F. Andersen, Kaja Borup Løvschall, Martin Tolstrup, Florian Kreppel, Jan Münch, Alexander N. Zelikin
Journal: Advanced Healthcare Materials (2017)

Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad-spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure-activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad-spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer-based antivirals and represent promising candidates for further development as preventive microbicides.
Clinical Features and Prognosis of Unselected Patients with AML and RAEB-2: Japan Adult Leukemia Study Group CS-07 Study
Authors: Yasushi Miyazaki, Sumihisa Honda, Toru Sakura, Kiyotoshi Imai, Masamitsu Yanada, Kensuke Usuki, Noriko Usui, Ken Takase, Yasutaka Aoyama, Masashi Sawa, Kazunori Ohnishi, Shigeki Ohtake, Hitoshi Kiyoi, Yukio Kobayashi, Tomoki Naoe
Journal: Blood (2016)
Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women
Authors: Roy M. Gulick, Timothy J. Wilkin, Ying Q. Chen, Raphael J. Landovitz, K. Rivet Amico, Alicia M. Young, Paul Richardson, Mark A. Marzinke, Craig W. Hendrix, Susan H. Eshleman, Ian McGowan, Leslie M. Cottle, Adriana Andrade, Cheryl Marcus, Karin L. Klingman, Wairimu Chege, Alex R. Rinehart, James F. Rooney, Philip Andrew, Robert A. Salata, Marc Siegel, Yukari C. Manabe, Ian Frank, Ken Ho, Jorge Santana, Joanne D. Stekler, Shobha Swaminathan, Marybeth McCauley, Sally Hodder, Kenneth H. Mayer
Journal: Annals of Internal Medicine (2017)

Background: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). Objective: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. Design: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114) Setting: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. Participants: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. Intervention: MVC only, MVC–emtricitabine (FTC), MVC–tenofovir disoproxil fumarate (TDF), and TDF–FTC (control). Measurements: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. Results: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC–FTC), 9 (MVC–TDF), and 8 (TDF–FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC–TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. Limitations: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. Conclusion: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF–FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. Primary Funding Source: National Institutes of Health.
A comparison of the resection rate for cold and hot snare polypectomy for 4–9 mm colorectal polyps: a multicentre randomised controlled trial (CRESCENT study)
Authors: Takuji Kawamura, Yoji Takeuchi, Satoshi Asai, Isao Yokota, Eisuke Akamine, Minoru Kato, Takuji Akamatsu, Kazuhiro Tada, Yoriaki Komeda, Mineo Iwatate, Ken Kawakami, Michiko Nishikawa, Daisuke Watanabe, Atsushi Yamauchi, Norimasa Fukata, Masaaki Shimatani, Makoto Ooi, Koichi Fujita, Yasushi Sano, Hiroshi Kashida, Satoru Hirose, Hiroyoshi Iwagami, Noriya Uedo, Satoshi Teramukai, Kiyohito Tanaka
Journal: Gut (2017)

Objective To investigate the success rate of cold snare polypectomy (CSP) for complete resection of 4–9 mm colorectal adenomatous polyps compared with that of hot snare polypectomy (HSP). Design A prospective, multicentre, randomised controlled, parallel, non-inferiority trial conducted in 12 Japanese endoscopy units. Endoscopically diagnosed sessile adenomatous polyps, 4–9 mm in size, were randomly assigned to the CSP or HSP group. After complete removal of the polyp using the allocated technique, biopsy specimens from the resection margin after polypectomy were obtained. The primary endpoint was the complete resection rate, defined as no evidence of adenomatous tissue in the biopsied specimens, among all pathologically confirmed adenomatous polyps. Results A total of 796 eligible polyps were detected in 538 of 912 patients screened for eligibility between September 2015 and August 2016. The complete resection rate for CSP was 98.2% compared with 97.4% for HSP. The non-inferiority of CSP for complete resection compared with HSP was confirmed by the +0.8% (90% CI −1.0 to 2.7) complete resection rate (non-inferiority p&lt;0.0001). Postoperative bleeding requiring endoscopic haemostasis occurred only in the HSP group (0.5%, 2 of 402 polyps). Conclusions The complete resection rate for CSP is not inferior to that for HSP. CSP can be one of the standard techniques for 4–9 mm colorectal polyps. (Study registration: UMIN000018328)
Abstract 299: Natural Product Derivative Bio Promotes Recovery After Myocardial Infarction via Unique Modulation of the Cardiac Microenvironment
Authors: Yong Sook Kim, Wan Seok Kang, Ju Hee Kang, Youngkeun Ahn
Journal: Circulation Research (2016)

Rationale: Myocardial infarction (MI) induces cardiac remodeling, which is regulated by the cardiac microenvironment and results in scarring and loss of cardiac function. Targeting the microenvironment represents a novel therapeutic approach. Objective: To investigate the therapeutic effect of a natural compound derivative, BIO [(2’Z,3’E)-6-Bromoindirubin-3′-oxime], on cardiac microenvironment cells and remodeling post-MI. Methods and Results: Using a series of co-culture studies, BIO was shown to induce proliferation in cardiomyocytes and, conversely, inhibit proliferation in cardiac fibroblasts. In addition, BIO produced anti-fibrotic effects in the fibroblasts, such as reduced motility and expression changes in fibrosis-related factors. In macrophages, BIO inhibited the expression of pro-inflammatory inducible nitric oxide synthase. Interestingly, BIO modulated molecular crosstalk between cardiac fibroblasts and differentiating macrophages to increase expression of anti-inflammatory M2 macrophage markers. In the optically transparent zebrafish-based model of heart failure, BIO induced cardiomyocyte proliferation to recover survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel, potential therapeutic effects of BIO on remodeling. We characterized these novel effects of BIO as differential modulation of p27 expression and potent induction of interleukin-10 in microenvironment cells. In rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed a greater presence of anti-inflammatory M2 macrophages in the infarction zone. BIO treatment also reduced serum levels of pro-fibrotic interleukin-6. Conclusions: BIO differentially activates signaling pathways in cardiomyocytes, cardiac fibroblasts and cardiac macrophages to reduce fibrosis, increase cardiomyocyte proliferation and promote recovery post-MI.
Traffic-Related Air Pollution and All-Cause Mortality during Tuberculosis Treatment in California
Authors: Robert J. Blount, Lisa Pascopella, Donald G. Catanzaro, Pennan M. Barry, Paul B. English, Mark R. Segal, Jennifer Flood, Dan Meltzer, Brenda Jones, John Balmes, Payam Nahid
Journal: Environmental Health Perspectives (2017)

Background: Ambient air pollution and tuberculosis (TB) have an impact on public health worldwide, yet associations between the two remain uncertain. Objective: We determined the impact of residential traffic on mortality during treatment of active TB. Methods: From 2000–2012, we enrolled 32,875 patients in California with active TB and followed them throughout treatment. We obtained patient data from the California Tuberculosis Registry and calculated traffic volumes and traffic densities in 100- to 400-m radius buffers around residential addresses. We used Cox models to determine mortality hazard ratios, controlling for demographic, socioeconomic, and clinical potential confounders. We categorized traffic exposures as quintiles and determined trends using Wald tests. Results: Participants contributed 22,576 person-years at risk. There were 2,305 deaths during treatment for a crude mortality rate of 1,021 deaths per 10,000 person-years. Traffic volumes and traffic densities in all buffers around patient residences were associated with increased mortality during TB treatment, although the findings were not statistically significant in all buffers. As the buffer size decreased, fifth-quintile mortality hazards increased, and trends across quintiles of traffic exposure became more statistically significant. Increasing quintiles of nearest-road traffic volumes in the 100-m buffer were associated with 3%, 14%, 19%, and 28% increased risk of death during TB treatment [first quintile, referent; second quintile hazard ratio (HR)=1.03 [95% confidence interval (CI): 0.86, 1.25]; third quintile HR=1.14 (95% CI: 0.95, 1.37); fourth quintile HR=1.19 (95% CI: 0.99, 1.43); fifth quintile HR=1.28 (95% CI: 1.07, 1.53), respectively; p-trend=0.002]. Conclusions: Residential proximity to road traffic volumes and traffic density were associated with increased all-cause mortality in patients undergoing treatment for active tuberculosis even after adjusting for multiple demographic, socioeconomic, and clinical factors, suggesting that TB patients are susceptible to the adverse health effects of traffic-related air pollution. https://doi.org/10.1289/EHP1699
Primary non-Hodgkin’s lymphoma of the thoracic spine: A case report with a review of the literature.
Authors: Muran Man, Qinghua Liu
Journal: Journal of Clinical Oncology (2017)

e19039 Background: Primary non-Hodgkin lymphomas of thoracic vertebra are rare, hard to confirm the diagnosis and with unfavorable prognosis. It is characterized by pain, asthenia, numbness, motor disturbances, etc. However, these symptoms don’t have their specificity. Biopsies are needed to confirm the diagnosis. Methods: A 37-year- old man presented with 3 months lumbar region pains and 4 days motor disturbances before he was admitted. The lumbar spine MRI showed lumbar disc herniation with no spinal compression. The thoracic spine MRI revealed altered vertebra signal and compressed marrow in the T10 vertebra. After the posterior tumor reduction and decompression and internal fixation of T10, the histopathology and immunohistochemistry was consistent with diffuse large B cell lymphoma. After surgery, treatment of chemotherapy (ECHOP, RCHOP) in combination with radiotherapy (T8-T12, L5-S1, 45Gy/25F) were followed. Results: Six-year follow-up MRI showed no relapses, metastasis and instability. The patient currently has the self-care ability which could deal with the everyday activities. Conclusions: Primary non-Hodgkin lymphoma originated in the thoracic vertebra is rare, easily to be misdiagnosed. To learn more about the diagnoses and to do the needle biopsy as early as possible would be beneficial to improve the survival rate and the quality of patients’ lives. Key words: Non-Hodgkin Lymphoma, Thoracic Vertebra, Case Report
A multi-center phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401).
Authors: Sandra P. D'Angelo, Michelle R. Mahoney, Brian Andrew Van Tine, James N Atkins, Mohammed M. Milhem, William D. Tap, Cristina R. Antonescu, Laura E. Horvath, Gary K. Schwartz, Howard Streicher
Journal: Journal of Clinical Oncology (2017)

11007 Background: Patients (pts) with metastatic sarcoma (SAR) have limited options. Nivolumab(N), a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety &amp; efficacy in other tumors. Pembrolizumab demonstrated a response rate (RR) of 12% in SAR pts. We evaluated N, independently from N+I, in SAR pts. Methods: This open-label multi-center phase II study enrolled pts failing prior regimens. Randomized (non-comparative) pts received either N3 [N (3 mg/kg q2W)] or N3+I1 [N(3 mg/kg Q3W x4, then Q2W) &amp; [I(1 mg/kg q3W x4)]. Treatment continued beyond progressive disease (PD) in 1 st 12 weeks. 5 confirmed responses in 38 evaluable pts yielded 90% power (0.05 1-sided alpha) to detect a 20% (vs 5%) confirmed RR. Other endpoints: adverse events (AEs), progression-free, overall survival (PFS, OS), and correlative studies including PD-L1 expression by IHC, mutational burden/neoantigen analysis, TCR clonality and TIL characterization. Results: 85 pts (43 - N3; 42 - N3+I1) were enrolled [mean age 54 yrs (21–81), 52% female). No significant differences in histological subtypes across cohorts: 36% LMS, 4% LPS, 10% UPS/MFH, 6% synovial, 5% bone, 5% Ewing’s, and 34% other. Pts were refractory to 1(20%), 2(22%), and ≥3 (58%) regimens. Grade 3-4 treatment related adverse events (TRAE) occurred in 7% (N3) and 14% (N3+I1) and 0 Gr 5 TRAEs. 8% of pts stopped due to AEs (2% N3, 14% N3+I1). 2/3 confirmed responses on N3, with 2 ongoing (range 1.1-3.2 months). 6/7 confirmed responses (2 complete) on N3+N1, with 5 ongoing (range 6-13 months). Responses occurred in 7 histologies. See Table for pt outcomes. Conclusions: N + I showed acceptable safety and encouraging antitumor activity with most responses ongoing across multiple SAR histologies, passing efficacy criteria. There was minimal activity observed with N alone. Increased TRAEs were observed in N3+I1. Correlative analyses ongoing. NCT02500797. Support: U10CA180821, U10CA180882, Conquer Cancer Foundation, BMS. Clinical trial information: NCT02500797. [Table: see text]
Clinical Implications of Echocardiographic Phenotypes of Patients With Diabetes Mellitus
Authors: Laura Ernande, Etienne Audureau, Christine L. Jellis, Cyrille Bergerot, Corneliu Henegar, Daigo Sawaki, Gabor Czibik, Chiara Volpi, Florence Canoui-Poitrine, Hélène Thibault, Julien Ternacle, Philippe Moulin, Thomas H. Marwick, Geneviève Derumeaux
Journal: Journal of the American College of Cardiology (2017)
Skp2-Mediated Stabilization of MTH1 Promotes Survival of Melanoma Cells upon Oxidative Stress
Authors: Jia Yu Wang, Guang Zhi Liu, James S. Wilmott, Ting La, Yu Chen Feng, Hamed Yari, Xu Guang Yan, Rick F. Thorne, Richard A. Scolyer, Xu Dong Zhang, Lei Jin
Journal: Cancer Research (2017)

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res; 77(22); 6226-39. ©2017 AACR.
Breathlessness despite optimal pathophysiological treatment: on the relevance of being chronic
Authors: Miriam J. Johnson, Janelle Yorke, John Hansen-Flaschen, Robert Lansing, Magnus Ekström, David C. Currow
Journal: European Respiratory Journal (2017)

With regard to the letter from Morélot-Panzini and colleagues in response to our Perspective [1], it is good to see support for the concept of a clinical syndrome and its potential in raising awareness of the needs of such patients in the minds of all clinicians; we welcome the ongoing discussion. It serves to highlight the importance of this neglected patient group and clinical topic, as well as the process for how an internationally agreed name and definition in English can be translated both linguistically and culturally in non-English-speaking countries. This letter highlights the thought processes that will need to occur in each translation of the concept. In seeing this work already occurring, our Perspective [1] has already achieved one of its aims. Chronic breathlessness syndrome, an international name, should be translated for non-English-speaking countries <http://ow.ly/vvFT30erPmC>