tbuckley/cabot-search huggingface dataset:
Does risk of brain cancer increase with intracranial volume? A population-based case control study
Authors: Even Hovig Fyllingen, Tor Ivar Hansen, Asgeir Store Jakola, Asta Kristine Håberg, Øyvind Salvesen, Ole Solheim
Journal: Neuro-Oncology (2018)

Glioma is the most common primary brain tumor and is believed to arise from glial stem cells. Despite large efforts, there are limited established risk factors. It has been suggested that tissue with more stem cell divisions may exhibit higher risk of cancer due to chance alone. Assuming a positive correlation between the number of stem cell divisions in an organ and size of the same organ, we hypothesized that variation in intracranial volume, as a proxy for brain size, may be linked to risk of high-grade glioma. Intracranial volume was calculated from pretreatment 3D T1-weighted MRI brain scans from 124 patients with high-grade glioma and 995 general population–based controls. Binomial logistic regression analyses were performed to ascertain the effect of intracranial volume and sex on the likelihood that participants had high-grade glioma. An increase in intracranial volume of 100 mL was associated with an odds ratio of high-grade glioma of 1.69 (95% CI: 1.44‒1.98; P < 0.001). After adjusting for intracranial volume, female sex emerged as a risk factor for high-grade glioma (odds ratio for male sex = 0.56, 95% CI: 0.33‒0.93; P = 0.026). Intracranial volume is strongly associated with risk of high-grade glioma. After correcting for intracranial volume, risk of high-grade glioma was higher in women. The development of glioma is correlated to brain size and may to a large extent be a stochastic event related to the number of cells at risk.
Diploma in Medical Toxicology
Authors: David Menzies
Journal: BMJ (2007)

Credit: TONY CRADDOCK/SPL



FURTHER INFORMATION 

Ms Sue Coleman, Department of Pharmacology, Therapeutics and Toxicology, Cardiff University, Cardiff, Wales tel: 029 2074 6698; www.cardiff.ac.uk/nursing/medicine/pharmacology/ttc/pge/diptox/)

Anyone concerned with the treatment of poisoned patients, such as emergency physicians and occupational physicians. Doctors, nurses, pharmacists, and poisons information officers will also find it useful.

I did it during my first year as a registrar in emergency medicine in 2005-6.

To broaden my knowledge of clinical toxicology. …
A professor-cum-GP
Authors: Bruno Rushforth
Journal: BMJ (2009)

When I first met Mark Howson he was a fifth year medical student, with not long to go before starting work on the wards as a house officer. When his friends called him “Prof Mark” I thought they were making an affectionate joke about his academic prowess. It was only much later when I discovered that he had been a professor of physics with a young family but had decided on a radical career change, going back to university to retrain as a doctor
Abstract 14844: A Novel Anti-inflammatory Mechanism of High Density LipoproteinThrough Up-regulating Annexin A1 in Vascular Endothelial Cells
Authors: Lemin Zheng
Journal: Circulation (2016)

Introduction: High density lipoprotein (HDL) as well as annexin A1 has been reported to be associated with cardiovascular protection. However, the correlation between HDL and annexin A1 was still u...
Number of NHS redundancy payments over £100 000 rises by 50%
Authors: Helen Jaques
Journal: BMJ (2013)

The number of NHS staff who have received redundancy payments of more than £100 000 (€117 000; $155 000) has increased by more than 50% over the past year, the Department of Health’s annual accounts show.1

In 2012-13, the department paid out a total of 958 redundancy packages worth more than £100 000, a rise of 54% from 628 such agreements in 2011-12. Overall the department spent nearly £445m on …
Preclinical evaluation of BET-bromodomain inhibitor TEN-010 as monotherapy and combination therapy in MYC-driven neuroblastoma
Authors: K.A. Firle, A. Szymansky, M.J. Witthauer, H. Dorado-Garcia, J. Toedling, K. Schoenbeck, A.G. Henssen, F. Hertwig, A. Eggert, J.H. Schulte
Journal: Annals of Oncology (2018)
INCREMENTAL VALUE OF RIGHT VENTRICULAR STRAIN AND 3D ECHO COMPARED TO CONVENTIONAL ECHO APPROACHES FOR DETECTION OF CARDIAC MRI (CMR) EVIDENCED RIGHT VENTRICULAR DYSFUNCTION IN ISCHEMIC MITRAL REGURGITATION
Authors: Javid Alakbarli, Farhan Raza, Tara Shah, Meridith P. Pollie, Athena Poppas, Richard B. Devereux, Jonathan W. Weinsaft, Jiwon Kim
Journal: Journal of the American College of Cardiology (2018)
AXIAL SARCOPENIA, SUBCUTANEOUS, ABDOMINAL VISCERAL AND PERICARDIAL ADIPOSITY IN HEART FAILURE WITH PRESERVED AND REDUCED EJECTION FRACTION
Authors: Julio A. Chirinos, Jessica Kim, Sowmya Gaddam, Jagan Vanjarapu, Dheera Tamvada, Bilal Ansari, Arpita Suri, Anique Mustafa, Scott Akers
Journal: Journal of the American College of Cardiology (2018)
Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase
Authors: Jiang-Kai Dong, Hui-Min Lei, Qian Liang, Ya-Bin Tang, Ye Zhou, Yang Wang, Shengzhe Zhang, Wen-Bin Li, Yunguang Tong, Guanglei Zhuang, Liang Zhang, Hong-Zhuan Chen, Liang Zhu, Ying Shen
Journal: Theranostics (2018)

How to improve the efficacy and reverse the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of lung adenocarcinoma with EGFR-activating mutation.Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis over-expressed in various types of cancer including lung cancer.Elevated PHGDH expression is correlated with a worse overall survival in clinical lung adenocarcinoma patients.Here we investigated the role of PHGDH in lung adenocarcinoma with the acquisition of resistance to erlotinib.Methods: The necessary genes required for the acquired erlotinib resistance in lung adenocarcinoma cells were screened out by RNA-Seq analysis.Then the protein and mRNA levels of PHGDH were confirmed by immunoblotting and qRT-PCR in the erlotinib resistant cells.The effects of PHGDH inhibition or overexpression on erlotinib resistance were examined using cell culture and tumor xenograft mouse models respectively.To explore mechanism, the ROS level and DNA damage marker, γH2AX, were tested by DCFH-DA staining and immunofluorescence after PHGDH inhibition. Results:We found that PHGDH level was significantly increased in the lung adenocarcinoma PC9ER4 and HCC827ER9 cells that acquired resistance to erlotinib.Perturbation of PHGDH by siPHGDH transfection or NCT-503, a small molecular PHGDH inhibitor, synergistically augmented the tumoricidal effect and restored sensitivity to erlotinib in cell lines and xenografts.Over-expression of PHGDH caused xenografts resistant to erlotinib.Furthermore, multiple DNA damage repair pathways related genes were changed by PHGDH depletion specifically in erlotinib resistant cells.ROS stress and DNA damage marker γH2AX were enhanced by siPHGDH and NCT-503, which was reversed by NAC.Conclusion: Our study indicated that PHGDH inhibition has potential therapeutic value in lung adenocarcinoma with the acquired resistance to EGFR-TKIs.
THE COURSE OF PATIENTS WITH CHEST PAIN AND NO EVIDENCE OF HEART DISEASE: A 20 YEAR FOLLOW-UP STUDY
Authors: Abel E. Moreyra, Waseem Shami, Stavros Zinonos, Nora M. Cosgrove, Alex Gold, John B. Kostis, Javier Cabrera, Mihir Trivedi, William J. Kostis
Journal: Journal of the American College of Cardiology (2018)
Phase I/II study of hypofractionated intensity modulated radiotherapy (IMRT) for prostate cancer including simultaneously integrated boost (SIB).
Authors: Michael G. Chang, Siddharth Saraiya, Nitai Mukhopadhyay, Mitchell Anscher
Journal: Journal of Clinical Oncology (2016)

67 Background: The purpose of this study is to evaluate the toxicity of hypofractionationed H- IMRT treatment including SIB IMRT when pelvic nodes were covered. Additionally, we assessed early treatment efficacy through PSA control (biochemical failure defined as PSA more than nadir + 2 ng/mL). Methods: Men with localized prostate cancer were enrolled in a phase I/II trial to receive H-IMRT to the prostate, seminal vesicles)(SV) and pelvic lymph nodes (LN) using simultaneous integrated boost (SIB) method. Low risk (LR) patients received 69.4 Gy to the prostate only in 29 fractions. The intermediate (IR) and high risk (HR) patients received 72 Gy to the prostate, 54 Gy to the proximal 1 cm SV, and 50.4 Gy to the pelvic LN when risk of LN involvement &gt;15% by Roach formula. Treatment was given in 30 fractions using intraprostatic fiducials and daily image guidance. PTV expansion for prostate and SV was 0.3 mm posteriorly and 0.7 cm in all other directions. The IR and HR patients received androgen deprivation therapy (3 years for HR patients, and 6 months for IR patients). Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated according to CTCAE v3.0. Results: 55 men (29 African American and 26 white) were enrolled on trial with 20% LR, 41% IR and 39% HR disease (NCCN criteria). The median age was 55 with median follow-up time of 37.9 months. 26 patients received pelvic nodal SIB-IMRT. Toxicity is reported in the table. The biochemical control rate for the cohort was 91% at 3 years. Patients with pelvic LN IMRT experienced grade 2+ acute GI toxicity 38% vs 21% in the non-nodal IMRT group. (p= 0.25 by chi-square test). Conclusions: Hypofractionated SIB-IMRT can be delivered safely. Late grade III GI and GU toxicity for our cohort were 0% and 3.6% respectively. Our prospective trial shows acceptable toxicity with moderate hypofractionation in treating prostate cancer while maintaining good PSA control. Clinical trial information: NCT01117935. [Table: see text]
Phase Ib study of ramucirumab and irinotecan for metastatic gastric cancer previously treated with fluoropyrimidine with/without platina and taxane.
Authors: Tamotsu Sagawa, Hironaga Satake, Koshi Fujikawa, Yukimasa Hatachi, Hisateru Yasui, Masahito Kotaka, Takeshi Kato, Akihito Tsuji
Journal: Journal of Clinical Oncology (2018)

155 Background: Optimal salvage line chemotherapy for previously heavily treated advanced/ metastatic gastric cancer (AGC) is unknown, but treated with irinotecan in Japan. Ramucirumab, a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2, is the first molecularly targeted agent proven to be effective in second-line therapy for AGC in combination with chemotherapy. Furthermore, combination chemotherapy with ramucirumab and irinotecan based regimen (FOLFIRI) is recognized as one of the promising regimens for metastatic colorectal cancer. To date, however, use of the ramucirumab plus irinotean regimen for AGC patients has not been investigated, and recommended doses (RD) of ramucirumab plus irinotecan for patients with AGC therefore remain unknown. The aim of this study was to determine the maximum tolerated dose (MTD) and RD for systemic chemotherapy with rumucirumab plus irinotecan for AGC previously treated with fluoropyrimidine with/without platina and taxane. Methods: Patients received systemic chemotherapy with ramucirumab (8mg/kg) and irinotecan on day 1, repeated every 2 weeks. A decrease in irinotecan dose was planned from start level 1 (irinotecan 150mg/m 2 ). This trial was registered with the University Hospital Medical Network (UMIN no. 000018606). Results: Six patients were enrolled from August 2015 to September 2017. MTD was not reached at level 1. Irinotecan 150 mg/m 2 in combination with ramucirumab 8mg/kg could be administered with acceptable toxicity, and all patients were treated at these doses. No DLT was observed at Level 1. No treatment-related death was observed. Adverse events of grade 3/4 were neutropenia (17%), anemia (17%), hyponatremia (17%), hypertension (17%). Five of the six patients were evaluable for efficacy based on the RECIST criteria, and response rate and disease control rate were 20% and 100%, respectively. Conclusions: Salvage chemotherapy with a ramucirumab plus irinotecan regimen was well tolerable for patients with previously heavily treated AGC. RD was defined as ramucirumab 8 mg/kg in combination with irinotecan 150 mg/m 2 /day. Clinical trial information: 000018606.
Should universal distribution of high dose vitamin A to children cease?
Authors: JB Mason, CS Benn, HPS Sachdev, Keith P West, Amanda C Palmer, Alfred Sommer
Journal: BMJ (2018)

Up to $500m a year could be put to better use by stopping ineffective and potentially harmful supplementation programmes in poorer countries, say <b>JB Mason</b>, <b>CS Benn</b>, and <b>HPS Sachdev</b>; but <b>Keith P West Jr</b>, <b>Amanda C Palmer,</b> and <b>Alfred Sommer</b> disagree, saying that such programmes have been proved to save millions of lives and should be withdrawn only when robust evidence permits
White NHS staff are more likely to secure jobs
Authors: Abi Rimmer
Journal: BMJ (2017)

The Workforce Race Equality Standard 2017 gathers data from all NHS trusts in England and covers 1.3 million staff members, of whom 425 000 identified as being from a black and minority ethnic (BME) background.1 Data on staff members were not broken down by profession.

White applicants who have been shortlisted for a role are …
Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)
Authors: Ulrik M. Mogensen, Jianjian Gong, Pardeep S. Jhund, Li Shen, Lars Køber, Akshay S. Desai, Martin P. Lefkowitz, Milton Packer, Jean L. Rouleau, Scott D. Solomon, Brian L. Claggett, Karl Swedberg, Michael R. Zile, Guenther Mueller‐Velten, John J.V. McMurray
Journal: European Journal of Heart Failure (2018)

Aims Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM‐HF, using a variety of statistical approaches advocated for this type of analysis. Methods and results In PARADIGM‐HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67–0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71–0.89], the LWYY method (RR 0.78, 95% CI 0.68–0.90), and the joint frailty model (HR 0.75, 95% CI 0.66–0.86) (all P &lt; 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. Conclusions In PARADIGM‐HF, approximately one third of patients with a primary endpoint (time‐to‐first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.
Neuregulin-1 attenuates stress-induced vascular senescence
Authors: Hadis Shakeri, Andreas B Gevaert, Dorien M Schrijvers, Guido R Y De Meyer, Gilles W De Keulenaer, Pieter-Jan D F Guns, Katrien Lemmens, Vincent F Segers
Journal: Cardiovascular Research (2018)

Cardiovascular ageing is a key determinant of life expectancy. Cellular senescence, a state of irreversible cell cycle arrest, is an important contributor to ageing due to the accumulation of damaged cells. Targeting cellular senescence could prevent age-related cardiovascular diseases. In this study, we investigated the effects of neuregulin-1 (NRG-1), an epidermal growth factor with cardioprotective and anti-atherosclerotic effects, on cellular senescence.Senescence was induced in cultured rat aortic endothelial cells (ECs) and aortic smooth muscle cells (SMCs) by 2 h exposure to 30 µM hydrogen peroxide (H2O2). Cellular senescence was confirmed after 72 h using senescence-associated-β-galactosidase staining (SA-β-gal), cell surface area, and western blot analyses of SA pathways (acetyl-p53, p21). Recombinant human NRG-1 (rhNRG-1, 20 ng/mL) significantly reduced H2O2-induced senescence, as shown by a lower number of SA-β-gal positive cells, smaller surface area and lower expression of acetyl-p53. In C57BL/6 male mice rendered diabetic with streptozotocin (STZ), rhNRG-1 attenuated cellular senescence in aortic ECs and SMCs. Next, we created mice with SMC-specific knockdown of the NRG-1 receptor ErbB4. Aortic SMCs isolated from SMC-specific ErbB4 deficient mice (ErbB4f/+ SM22α-Cre+) showed earlier cellular senescence in vitro compared with wild-type (ErbB4+/+ SM22α-Cre+) SMCs. Furthermore, when rendered diabetic with STZ, ErbB4f/+ SM22α-Cre+ male mice showed significantly more vascular senescence than their diabetic wild-type littermates and had increased mortality.This study is the first to explore the role of NRG-1 in vascular senescence. Our data demonstrate that NRG-1 markedly inhibits stress-induced premature senescence in vascular cells in vitro and in the aorta of diabetic mice in vivo. Consistently, deficiency in the NRG-1 receptor ErbB4 provokes cellular senescence in vitro as well as in vivo.
Genetic Mosaicism and Cancer: Cause and Effect
Authors: Anatoly V. Lichtenstein
Journal: Cancer Research (2018)

Abstract Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Here, I suggest that a progressively deteriorating microenvironment (“soil”) generates the cancerous “seed” and favors its development. Cancer Res; 78(6); 1375–8. ©2018 AACR.
Value of bone scan index for predicting overall survival among patients treated with radium-223 for bone metastatic castration-resistant prostate cancer.
Authors: Shuko Yoneyama, Yasuhide Miyoshi, Sohgo Tsutsumi, Takashi Kawahara, Yusuke Hattori, Yumiko Yokomizo, Narihiko Hayashi, Masahiro Yao, Hiroji Uemura
Journal: Journal of Clinical Oncology (2018)

216 Background: The objective of this study was to evaluate the bone scan index (BSI) as a prognostic biomarker for overall survival (OS) among patients treated with radium-223 (Ra-223) for bone metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 42 men who had been treated with Ra-223 for bone metastatic CRPC between 2012 and 2017 and investigated correlations between the baseline clinical factors of age, time to CRPC, previous use of docetaxel, PSA, Gleason score, alkaline phosphatase (ALP), and BSI and OS by multivariate analysis using the Cox proportional hazard model. We also analyzed the correlations between OS and absolute BSI value or BSI change from baseline after 12 weeks of treatment. Continuous variables were classified as dichotomous. Results: The median age, PSA, and time to CRPC were 75.5 years, 42.8 ng/mL, and 11.2 months, respectively. The median observation period was 11.7 months. Twenty-five (59.5 %) of the 42 patients had completed six cycles of Ra-223 treatment. Twenty-two patients (52.4 %) had died, including 20 (47.6 %) of cancer, by the time of analysis. The median OS in the entire cohort was 20.7 months. Multivariate analysis also showed that only BSI (≥1.5 vs. &lt; 1.5, HR 3.72, 95% CI 1.17–11.79, p = 0.026) was significantly correlated with OS. The BSI had decreased in 16 (51.6%) of the 31 patients who had undergone bone scans after 12 weeks of treatment . Multivariate analysis showed that absolute BSI value after 12 weeks treatment was significantly correlated with OS (BSI (≥2.0 vs. &lt; 2.0%, HR 13.07, 95% CI 2.61–65.53, p = 0.002). No correlation was found between BSI change from baseline after 12 weeks and OS. Conclusions: According to multivariate analysis, both baseline BSI and PSA were significant prognostic factors for OS among men treated with Ra-223. Absolute BSI value after 12 weeks of Ra-223 treatment was also found to be an independent prognostic factor for OS.
First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study).
Authors: Bastian von Tresckow, Stefan Gundermann, Dennis A. Eichenauer, Walter Erich Aulitzky, Mariele Göbeler, Cyrus Sayehli, Liza Bacchus, Bernhard Hauns, Anna Mais, Bernd Hentsch, Hella Kohlhof, Rolf Krauss, Babett Krauss, Roland Baumgartner, Daniel Vitt, Andreas Engert
Journal: Journal of Clinical Oncology (2014)

8559 Background: 4SC-202 is a specific inhibitor of protein deacetylases HDAC1, 2 and 3 and lysine specific demethylase LSD1 (KDM1A). Enzymatic inhibition leads to transcriptional repression of Wnt and Hedgehog signaling. 4SC-202 provokes the inhibition of stemness-related properties of cancer cells and affects their viability. Methods: Patients with advanced hematological malignancies including AML, ALL, CLL, MM, MDS or lymphoma were orally dosed either once daily (QD) or twice daily (BID) from days 1 to 14, or BID continuously, in a 21-day cycle. Dose escalation followed a 3+3 design. Study objectives include safety, tolerability and pharmacokinetics (PK), determination of MTD and DLT as well as optimization of dosing. Biomarker program includes measuring of HDAC inhibition, total lysine acetylation and gene expression profiling. Additionally, the anti-tumor effect of 4SC-202 was evaluated. Dose escalation part is completed and data allow for reliable evaluation. Further patients will be enrolled to establish the MTD at prior dose levels. Results: 24 patients were treated at 7 dose levels of 25/50/100/200/400mg QD and 200mg BID (N=3, each), and 200mg BID continuous dosing (N=6). Treatment was very well tolerated by heavily pre-treated patients up to the highest dose group. Possibly drug-related AE were less frequent, e.g. low-grade GI complaints such as nausea. Higher-grade hematological toxicity e.g. leading to treatment changes was not observed. Elevation of liver enzymes was observed at 200mg BID during continuous dosing. Two objective responses (PR & CR, unconfirmed) were observed. 75% of patients went into follow-up treatment due to stable disease. Median time on treatment was 98 days with 3 patients treated > 400 days. Plasma exposure reached one digit µM concentrations over 24h. Modulation of Wnt pathway gene-signature was observed in blood samples, as well as HDAC inhibition and lysine acetylation. Conclusions: 4SC-202 could be safely administered up to 200mg BID. Anti-cancer activity could be demonstrated by two patients achieving PR and CR, respectively, and long term stabilization of several patients. The mode of action of 4SC-202 is demonstrated by biomarker response. Clinical trial information: NCT01344707.
Interferon-γ induces distinct mRNA and protein profiles in acute and chronic myeloid leukemia
Authors: Jayakumar Vadakekolathu, Rhonda Meredith, Paul Martin Ross, Sarah Wagner, Stephen Reeder, Gokhan Demirkan, Jamie R. Kuhar, Graham R. Ball, A. Graham Pockley, Sergio Rutella
Journal: Blood (2017)