tbuckley/cabot-search huggingface dataset:
Phase I study of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors.
Authors: David W. Cescon, Aaron Richard Hansen, Albiruni Ryan Abdul Razak, Lee-Anne Stayner, John Frederick Hilton, Daniel John Renouf, Trisha Denny, Graham Fletcher, Tak W Mak, Mark R Bray, Philippe L Bedard
Journal: Journal of Clinical Oncology (2017)

TPS2619 Background: TTK (MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. TTK is overexpressed in several tumor types, which may contribute to survival and proliferation of aneuploid cells, and higher expression correlates with adverse outcomes. The Campbell Family Therapeutics Group at the University Health Network (UHN) has developed CFI-402257, a potent (Ki = 0.09 nM, IC50 = 1.2 nM), highly selective and orally active inhibitor of TTK, with negligible activity towards 265 other kinases. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 at tolerated doses in several cell line (breast, colorectal) and patient-derived (ovarian) xenograft models. Pharmacodynamic effects including reduction in phospho-histone H3 were observed. In syngeneic mouse colorectal cancer models, CFI-402257 + PD-1 immune checkpoint blockade demonstrated greater activity than either agent alone, and resulted in tumor regressions and immunity to rechallenge. Methods: This multi-center Phase I dose escalation study (3+3 design) will determine the safety, tolerability and maximum tolerated dose (MTD) of CFI-402257 administered as daily continuous oral treatment. Secondary and correlative endpoints include plasma PK, antitumor activity, and molecular features associated with response or clinical benefit. An expansion cohort (n = 12) will be enrolled at the MTD. Key inclusion criteria: adult patients with advanced solid tumors, measurable disease (RECIST 1.1), adequate organ function and performance status (ECOG 0-1). Exclusion criteria: uncontrolled medical illness, CNS metastases (unless stable x 3 months). CFI-402257 will be dosed once daily on a continuous schedule in 28-day cycles, beginning at 5 mg/day with planned escalation to 56 mg/day. DL1 completed enrolment 01/2017 and accrual is ongoing. Phase II studies are planned (Stand Up to Cancer Canada Breast Cancer Dream Team). Funding: UHN, CIRM. Clinical trial information: NCT02792465.
Abstract 20492: Long Term Outcomes After Surgical Repair of Tetralogy of Fallot (TOF): A Study From the Pediatric Cardiac Care Consortium (PCCC)
Authors: Clayton Smith, Michael Kelleman, Courtney McCracken, Andreas Kalogeropoulos, Cassandra Sung, Matthew Oster, Logan Spector, James Moller, Lazaros Kochilas
Journal: Circulation (2016)

Introduction:  TOF can exist either in simple (without association with other lesions) or in complex form when associated with absent pulmonary valve (TOF-APV), complete atrioventricular canal (TOF-CCAVC) or pulmonary atresia (TOF-PA). Surgical repair is feasible in all forms, but risks for long term outcomes can be different depending on the substrate of the TOF. We examined the long term vital status and risk of transplantation of patients registered in PCCC with repaired TOF.   Methods:  We identified 3,841 and 1,878 patients surviving after simple and complex TOF repair between 1982 and 2003. Of these 3,302 and 1,619 respectively had direct identifiers sufficient for submission to the National Death Index (NDI) and United Network for Shared Organs (UNOS) datasets to determine vital and transplant status through 2014. Kaplan Meier (KM) transplant-free survival curves and hazard of mortality were calculated for comparisons between groups.   Results:  275 deaths (8.3%) occurred in simple TOF and 199 (19.0%) in complex TOF during a median follow-up period of 19.4 years (IQR: 14.9-24.4 years). There were 11 heart transplants in simple TOF and 11 transplants (7 heart, 3 heart-lung and 1 lung) for complex TOF. Each complex cohort had a higher hazard of mortality than simple TOF: TOF-APV 3.27 (95% CI: 2.39-4.49, p   Conclusions:  20 year transplant-free survival for patients with repaired simple and complex TOF reaches 91.7% and 81% respectively. These results provide a conservative estimate of expected outcomes for these groups of patients. In depth analysis is underway for risk factors and specific diagnoses affecting mortality.
Mapping under-5 and neonatal mortality in Africa, 2000–15: a baseline analysis for the Sustainable Development Goals
Authors: Nick Golding, Roy Burstein, Joshua Longbottom, Annie J Browne, Nancy Fullman, Aaron Osgood-Zimmerman, Lucas Earl, Samir Bhatt, Ewan Cameron, Daniel C Casey, Laura Dwyer-Lindgren, Tamer H Farag, Abraham D Flaxman, Maya S Fraser, Peter W Gething, Harry S Gibson, Nicholas Graetz, L Kendall Krause, Xie Rachel Kulikoff, Stephen S Lim, Bonnie Mappin, Chloe Morozoff, Robert C Reiner, Amber Sligar, David L Smith, Haidong Wang, Daniel J Weiss, Christopher J L Murray, Catherine L Moyes, Simon I Hay
Journal: The Lancet (2017)

During the Millennium Development Goal (MDG) era, many countries in Africa achieved marked reductions in under-5 and neonatal mortality. Yet the pace of progress toward these goals substantially varied at the national level, demonstrating an essential need for tracking even more local trends in child mortality. With the adoption of the Sustainable Development Goals (SDGs) in 2015, which established ambitious targets for improving child survival by 2030, optimal intervention planning and targeting will require understanding of trends and rates of progress at a higher spatial resolution. In this study, we aimed to generate high-resolution estimates of under-5 and neonatal all-cause mortality across 46 countries in Africa.
HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors
Authors: Makoto Taniguchi, Maria B. Carreira, Yonatan A. Cooper, Ana-Clara Bobadilla, Jasper A. Heinsbroek, Nobuya Koike, Erin B. Larson, Evan A. Balmuth, Brandon W. Hughes, Rachel D. Penrod, Jaswinder Kumar, Laura N. Smith, Daniel Guzman, Joseph S. Takahashi, Tae-Kyung Kim, Peter W. Kalivas, David W. Self, Yingxi Lin, Christopher W. Cowan
Journal: Neuron (2017)
Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma
Authors: Jeroen Depreeuw, Ellen Stelloo, Elisabeth M. Osse, Carien L. Creutzberg, Remi A. Nout, Matthieu Moisse, Diego A. Garcia-Dios, Michael Dewaele, Karen Willekens, Jean-Christophe Marine, Xavier Matias-Guiu, Frédéric Amant, Diether Lambrechts, Tjalling Bosse
Journal: Clinical Cancer Research (2017)

Purpose: Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the "nonspecific molecular profile" (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs).Experimental Design: SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy.Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26-3.59; P = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17-4.70; P = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without MDM4 amplification. Vice versa, increasing MDM4 expression in nonamplified cell lines stimulated cell proliferation.Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region. Clin Cancer Res; 23(23); 7232-41. ©2017 AACR.
<i>Mycobacterium avium</i> complex infection: phenotypes and outcomes
Authors: Michael R. Loebinger
Journal: European Respiratory Journal (2017)

Nontuberculous mycobacteria (NTM) pulmonary disease is becoming increasingly recognised as an emerging healthcare issue. Multiple studies have demonstrated an increasing prevalence throughout the world, with evidence of significant associated morbidity, mortality and healthcare costs [1, 2]. The most prevalent and important group leading to pulmonary disease is the Mycobacterium avium complex (MAC), which includes the Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium chimaera species. These organisms are ubiquitous in the environment and, unlike Mycobacterium tuberculosis , isolation of NTM from respiratory samples does not necessarily equate to pulmonary disease. Furthermore, even radiological evidence of pulmonary disease does not always necessitate treatment [3]. The judicious use of treatment for pulmonary NTM disease is related, in part, to the long (>1 year) courses of multiple antibiotics needed for treatment. In addition to problems with tolerance of the antibiotic regimens, treatment failure is common. There has been a wide range (13–86%) of reported treatment success rates in the literature for pulmonary NTM disease [4, 5], influenced by disease severity, treatment regimen, microbial resistance and definition of success. A recent meta-analysis of 16 studies involving 1462 patients on macrolide containing regimes reported a treatment success rate, defined by sustained culture conversion, of 60% [6]. The outcome of infection by Mycobacterium avium complex reflects clinical phenotypes <http://ow.ly/sV8z30erYON>
A randomized, open-label, two-arm phase II trial comparing the efficacy of sequential ipilimumab (ipi) versus best supportive care (BSC) following first-line (1L) chemotherapy in patients with unresectable, locally advanced/metastatic (A/M) gastric or gastro-esophageal junction (G/GEJ) cancer.
Authors: Markus H. Moehler, Jae Yong Cho, Yeul Hong Kim, Jin Won Kim, Maria Di Bartolomeo, Jaffer A. Ajani, Kensei Yamaguchi, Agnes Balogh, Maria Teresa Kong-Sanchez, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2016)

4011 Background: Pts with advanced gastric cancer have a poor prognosis with median overall survival (OS) of ~1 yr. Ipi is a monoclonal antibody that enhances T-cell activation and T-effector cell tumor infiltration and activity by inhibiting CTLA-4 receptor interaction with its ligands. This study (NCT01585987) evaluated efficacy of ipi vs BSC as sequential/maintenance therapy in pts with unresectable locally A/M G/GEJ cancer following 1L chemotherapy with platinum plus fluoropyrimidine. Methods: Eligible pts ≥18 years without progressive disease (PD) following 1L chemotherapy were randomized to ipi 10 mg/kg Q3W for 4 doses then ipi 10 mg/kg Q12W for up to 3 yrs, or BSC. Primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints were PFS by modified WHO criteria (mWHO) and OS. Post-interim analysis (IA), the study was stopped. Updated OS are presented. Results: Of 143 pts screened, 57 were randomized to each arm. At the IA, improvement in irPFS with ipi vs BSC was not observed (HR=1.44 [80% CI: 1.09, 1.91], p=0.097). Treatment-related adverse events (AEs) occurred in 41/57 (72%) of ipi pts and 25/45 (56%) pts on active BSC. The most frequent ipi-related AEs of any grade were pruritus (32%), diarrhea (25%), fatigue (23%), and rash (18%), with no gastrointestinal perforations in the ipi arm. Conclusions: The irPFS was similar and median OS for both arms was approximately 1 yr. AEs were consistent with other ipi studies. These results suggest ipi in combination with chemotherapy warrants further study in pts with A/M G/GEJ cancer. Clinical trial information: NCT01585987.Survival. Ipi (n=57) BSC (n=57) p-value HR (80% CI) irPFSa Events, n (%) 51 (90) 40 (70) 0.097 1.44 (1.09–1.91) Median (mos) 95% CI 2.9 1.6–5.2 4.9 3.5–6.5 PFS by mWHOa Events, n (%) 52 (91) 40 (70) 0.034 1.59 (1.20–2.10) Median (mos) 95% CI 2.7 1.4–3.0 4.9 3.5–6.1 OSa Events, n (%) 25 (44) 25 (44) 0.643 0.87 (0.60–1.27) Median (mos) 95% CI 16.8 11.8–23.1 12.1 9.3–NE OSb Events, n (%) 36 (63) 30 (53) Median (mos) 95% CI 12.7 10.5–18.9 12.1 9.3–NE aat IA bat study end; NE, not estimable.
Imaging for hip-related groin pain: don’t be hip-notised by the findings
Authors: Kieran O’Sullivan, Ben Darlow, Peter O’Sullivan, Bruce B Forster, Michael P Reiman, Adam Weir
Journal: British Journal of Sports Medicine (2017)

Awareness of femoroacetabular impingement (FAI) syndrome, acetabular labral tears and chondral lesions as potential causes of hip-related groin pain has increased considerably due to advances in imaging and arthroscopic surgery. Consequently, hip imaging and surgery rates have grown rapidly.1 However, there is no strong evidence of improved clinical outcomes with arthroscopic interventions. Although imaging findings are only diagnostic for FAI syndrome when they exist together with clinical signs and symptoms , imaging remains the main criterion for FAI surgery.2 Most patients (71%) are willing to undergo surgery based solely on their physician’s recommendation.3 We question whether such reliance on imaging can be justified. Does it have risks (eg, radiation, downstream testing, costs) and may it lead to suboptimal management of hip-related groin pain?

People with both large cam morphology and reduced hip internal rotation are 25 times more likely to develop future hip osteoarthritis (OA).4 While such high odd ratios cannot be ignored, many with such morphology do not develop …
Statin therapy for skeletal dysplasia
Authors: Akihiro Yamashita, Miho Morioka, Hiromi Kishi, Takeshi Kimura, Yasuhito Yahara, Minoru Okada, Kaori Fujita, Hideaki Sawai, Shiro Ikegawa, Noriyuki Tsumaki
Journal: Nature Reviews Endocrinology (2014)
Trends in the characteristics, dose-limiting toxicities and efficacy of phase I oncology trials: The Cancer Research UK experience.
Authors: Han Hsi Wong, Claire Barton, Gary Acton, Robert McLeod, Rachel Darby-Dowman, Janette McQuillan, Helen Turner, Susan Wan, Zoe Backholer, Jane Peters, Sarah E. R. Halford
Journal: Journal of Clinical Oncology (2015)

2534 Background: Phase I oncology trials are crucial in cancer drug development and have evolved over the years. We examined the trends in trial characteristics, dose-limiting toxicities (DLTs) and efficacy, and questioned whether the concepts of DLT and maximum-tolerated dose (MTD) were still helpful. Methods: Cancer Research UK Centre for Drug Development (CRUK CDD) sponsors phase I trials across the UK. We reviewed our experience of adult trials between 1995 and 2013. Results: Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n = 603) and 2004-2013 (25 trials, n = 750). From 1995-2003 to 2004-2013, there was a shift towards studying biological and targeted agents. Patients in the later years tended to be older, had a greater disease burden and were more likely to have received prior treatment, although baseline haematology and biochemistry test results were no worse. The incidence of DLTs was similar in both year groups (10.1% vs 11.5%; risk of death 0.7% vs 0.3%). DLTs such as neuropathy, stomatitis and thrombocytopenia were less common in the later trials, while the frequency of elevated liver enzymes was greater. Non-classical DLTs also emerged in the later trials, including hypertension, hypophosphatemia, cardiac and ophthalmic toxicities. Of a total of 219 DLT events, only four fell outside the protocol-defined criteria for a DLT. The overall disease control rate increased from 27.9% in 1995-2003 to 36.0% in 2004-2013 (P = 0.0033) due to improved disease stabilisation, and there was a trend towards a lower rate of progressive disease as best response (51.0% vs 46.3%, P > 0.05). Objective response rates as high as 33.3% (radioimmunotherapy in lymphoma) were observed, and were both disease- and agent-dependent. Doses at or above the MTD were associated with response to cytotoxics and radioimmunotherapy but not to other targeted agents. Conclusions: CRUK CDD phase I oncology trials continue to provide clinical benefit to participants while minimising toxicities, and DLT remains a helpful concept. However, pharmacodynamic rather than MTD endpoints are becoming increasingly important in defining the dose for subsequent trials.
A genome-wide association study of LCH identifies a variant in SMAD6 associated with susceptibility
Authors: Erin C. Peckham-Gregory, Rikhia Chakraborty, Michael E. Scheurer, John W. Belmont, Harshal Abhyankar, Amel G. Sengal, Brooks P. Scull, Olive Eckstein, Daniel J. Zinn, Louisa Mayer, Albert Shih, Miriam Merad, D. Williams Parsons, Kenneth L. McClain, Philip J. Lupo, Carl E. Allen
Journal: Blood (2017)
Irradiance, as well as body site and timing of readings, is important in determining ultraviolet A minimal erythema dose
Authors: E. Eadie, S.H. Ibbotson, R.S. Dawe
Journal: British Journal of Dermatology (2017)

Irradiance, as well as body site and timing of readings, is important in determining ultraviolet A minimal erythemal dose. (Response to Gambichler et al. July BJD)

Gambichler et al. demonstrated that, in their population, using a 25 mWcm−2 ultraviolet A-1 (UVA-1) source the median 24-hour delayed minimal erythema dose (MED) on the inner forearm was > 130 Jcm−2.1 This differs from the 20 Jcm−2 to 28 Jcm−2 median MED reported from our centre.2

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Experimental Roentgen Injury. III. Tissue and Cellular, Changes Brought about with Single Massive Doses of Radiation
Authors: Paul S. Henshaw
Journal: JNCI Journal of the National Cancer Institute (1944)

Journal Article Experimental Roentgen Injury. III. Tissue and Cellular, Changes Brought about with Single Massive Doses of Radiation Get access Paul S. Henshaw Paul S. Henshaw senior radiobiologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 5, April 1944, Pages 503–512, https://doi.org/10.1093/jnci/4.5.503 Published: 01 April 1944
Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer
Authors: Mayada A. Aljehani, John W. Morgan, Laurel A. Guthrie, Brice Jabo, Majed Ramadan, Khaled Bahjri, Sharon S. Lum, Matthew Selleck, Mark E. Reeves, Carlos Garberoglio, Maheswari Senthil
Journal: JAMA Surgery (2017)

Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT.To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC.This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1, 2004, through December 31, 2014. Patients were stratified by tumor origin in the left vs right sides.Treatment with SC or SC plus bevacizumab or cetuximab.Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed.A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001).Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.
mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation
Authors: Kaushal Asrani, Akshay Sood, Alba Torres, Dan Georgess, Pornima Phatak, Harsimar Kaur, Amber Dubin, C. Conover Talbot, Loubna Elhelu, Andrew J. Ewald, Bo Xiao, Paul Worley, Tamara L. Lotan
Journal: Journal of Clinical Investigation (2017)

Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation. In mice with mTORC1 loss of function, we found that Rho kinase (ROCK) signaling was constitutively activated, resulting in increased cytoskeletal tension and impaired cell-cell adhesion. Inhibition or silencing of ROCK1 was sufficient to rescue keratinocyte adhesion and biochemical differentiation in these mice. mTORC1 loss of function also resulted in marked feedback upregulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension, and cell adhesion, underscoring the complexity of signaling feedback following mTORC1 inhibition.