tbuckley/cabot-search huggingface dataset:
Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults
Authors: Benjamin H. Han, David Sutin, Jeff D. Williamson, Barry R. Davis, Linda B. Piller, Hannah Pervin, Sara L. Pressel, Caroline S. Blaum
Journal: JAMA Internal Medicine (2017)

While statin therapy for primary cardiovascular prevention has been associated with reductions in cardiovascular morbidity, the effect on all-cause mortality has been variable. There is little evidence to guide the use of statins for primary prevention in adults 75 years and older.To examine statin treatment among adults aged 65 to 74 years and 75 years and older when used for primary prevention in the Lipid-Lowering Trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).Post hoc secondary data analyses were conducted of participants 65 years and older without evidence of atherosclerotic cardiovascular disease; 2867 ambulatory adults with hypertension and without baseline atherosclerotic cardiovascular disease were included. The ALLHAT-LLT was conducted from February 1994 to March 2002 at 513 clinical sites.Pravastatin sodium (40 mg/d) vs usual care (UC).The primary outcome in the ALLHAT-LLT was all-cause mortality. Secondary outcomes included cause-specific mortality and nonfatal myocardial infarction or fatal coronary heart disease combined (coronary heart disease events).There were 1467 participants (mean [SD] age, 71.3 [5.2] years) in the pravastatin group (48.0% [n = 704] female) and 1400 participants (mean [SD] age, 71.2 [5.2] years) in the UC group (50.8% [n = 711] female). The baseline mean (SD) low-density lipoprotein cholesterol levels were 147.7 (19.8) mg/dL in the pravastatin group and 147.6 (19.4) mg/dL in the UC group; by year 6, the mean (SD) low-density lipoprotein cholesterol levels were 109.1 (35.4) mg/dL in the pravastatin group and 128.8 (27.5) mg/dL in the UC group. At year 6, of the participants assigned to pravastatin, 42 of 253 (16.6%) were not taking any statin; 71.0% in the UC group were not taking any statin. The hazard ratios for all-cause mortality in the pravastatin group vs the UC group were 1.18 (95% CI, 0.97-1.42; P = .09) for all adults 65 years and older, 1.08 (95% CI, 0.85-1.37; P = .55) for adults aged 65 to 74 years, and 1.34 (95% CI, 0.98-1.84; P = .07) for adults 75 years and older. Coronary heart disease event rates were not significantly different among the groups. In multivariable regression, the results remained nonsignificant, and there was no significant interaction between treatment group and age.No benefit was found when pravastatin was given for primary prevention to older adults with moderate hyperlipidemia and hypertension, and a nonsignificant direction toward increased all-cause mortality with pravastatin was observed among adults 75 years and older.clinicaltrials.gov Identifier: NCT00000542.
MEDU-02. DIFFERENTIAL EXPRESSION OF FOLATE RECEPTOR 1 IN MEDULLOBLASTOMA AND ITS RELATIONSHIP TO CLINICOPATHOLOGICAL CHARACTERISTICS AND TARGETED THERAPY
Authors: Hailong Liu, Chunjiang Yu, Qianwen Sun, Yongmei Song, Youliang Sun, Yongqiang Liu, Yuduo Guo, Weihai Ning, Yanming Qu, Hongyu Yuan
Journal: Neuro-Oncology (2017)

Medulloblastoma is the most common malignant CNS tumor of childhood. High expression of folate receptor 1 (Folr1) was observed in some malignant epithelial tumors. However its expression and the role for clinicopathological significance and targeted therapeutic potential in MB still remain unclear. Currently we have detected the expression of Folr1 in MB and identified its clinical, pathological and radiological values to be considered as a biomarker for diagnosis of MB. Then we studied the targeted treatment of MB with Folr1 targeted cytarabine (Folr1-Ara-C) both in vitro and in vivo. Folr1 were overexpressed in MB, while the level correlated with pathological subtypes. Folr1 expression was positively correlated with CSF spreading, Ki-67, MMP9, pathological subtypes and serum Folr1. Factors of age, CSF spreading, Ki-67, MMP9, strong Folr1 expression and pathological subtypes were found to be the independent prognostic values for patients with MB. Serum Folr1 showed rational sensitivity and specificity in demonstrating histological types. Folr1-Ara-C led to changes in cellular proliferation and invasion with down-regulation of MMPs proteins and activation of apoptosis in vitro. Using mouse xenografts, Folr1-Ara-C suppressed tumor growth and improved survival by MRI and PET/CT. Immunohistochemical analysis showed decreased Ki-67 and MMP9 index suggesting the effects on proliferation and invasion in vivo. Folr1 may be considered as a predictive candidate for histological types and serum Folr1 may be a novel non-invasive biomarker. The application of Folr1-Ara-C contributed to be one kind of targeted therapies for MB.
GENE-03. MICRORNAS PROFILE IN PAEDIATRIC GBMS
Authors: Laura Giunti, Martina Da Ros, Anna Lisa Iorio, Alberto Magi, Benedetta Mazzinghi, Sabrina Giglio, Iacopo Sardi
Journal: Neuro-Oncology (2017)

MicroRNAs are a novel class of gene regulators and are involved in several physiologic cellular mechanisms, anti-viral defense, cancer and drug sensitivity/resistance of several tumors. Recently, specific microRNA expression profiles have been identified in Glioblastoma Multiforme (GBM), but there are only limited data on the role of microRNA in pediatric GBM (pGBM). In this study we explored the expression profile of 377 microRNAs in 3 pGBM versus a pool of 5 no-tumor pediatric cerebral cortex using TaqMan® Human MicroRNA Array v2.0, Applied Biosystems. We identified a set of microRNAs differentially expressed: miR-490, miR-876-3p and miR-876-5p, miR-448 (under expressed) and miR-501-3p (overexpressed). Through Bioinformatic analysis of this set of miRNAs, we predicted a series of hypothetical target genes: GRIA1, SORL1, NUCKS1, SOX11, SAP30L, HTT, PXMP4, THRB, PSD3, SPN, AGPAT4, USP31, GRIK3, POM121L8P, TNRC6B, SNX29, HIPK2, RIMKLA, ZNF738, LOC388692. We individually validated the expression of all of these genes in 3 pGBM and in 3 cell lines of human GBM (U87MG, A172 and T98G). Interestingly, drug resistant T98G cell line showed an over expression of NUCKS1 (nuclear, casein kinase and cyclin-dependent kinase substrate 1), a cell cycle-related protein that plays an important role in cell proliferation and cell progression. NUCKS1 is overexpressed in many tumors but its precise role in cancer development remains unknown. On the basis of this preliminary report it could be of paramount importance to investigate the role of miR-501-3p and NUCKS1 in the multidrug resistance mechanism of pediatric brain tumors.
Whole-genome resequencing of 292 pigeonpea accessions identifies genomic regions associated with domestication and agronomic traits
Authors: Rajeev K Varshney, Rachit K Saxena, Hari D Upadhyaya, Aamir W Khan, Yue Yu, Changhoon Kim, Abhishek Rathore, Dongseon Kim, Jihun Kim, Shaun An, Vinay Kumar, Ghanta Anuradha, Kalinati Narasimhan Yamini, Wei Zhang, Sonnappa Muniswamy, Jong-So Kim, R Varma Penmetsa, Eric von Wettberg, Swapan K Datta
Journal: Nature Genetics (2017)
Results from two phase III studies of bortezomib (BTZ) consolidation vs observation (OBS) post-transplant in patients (pts) with newly diagnosed multiple myeloma (NDMM).
Authors: Christian Straka, Martin Vogel, Jürgen Müller, Martin Kropff, Bernd Metzner, Christian Langer, Herbert Sayer, Wolfram Jung, Heinz Albert Dürk, Hannes Wandt, Florian Bassermann, Martin Gramatzki, Wolf Rösler, Stefan Knop, Hans-Heinrich Wolf, Wolfram Brugger, Monika Martha Engelhardt, Thomas Fischer, Hermann Einsele
Journal: Journal of Clinical Oncology (2015)

8511 Background: Following ASCT, consolidation therapy including novel agents can improve outcomes in pts with MM. Here we report the combined outcomes of two large randomized phase III studies investigating BTZ consolidation or OBS in pts with NDMM. Methods: MMY3012 (NCT00416273; 222 pts aged ≤ 60 yrs) and MMY3013 (NCT00416208; 158 pts aged 61–75 yrs) recruited adults with NDMM who underwent induction therapy followed by ASCT. Pts were randomized 1:1 to receive BTZ consolidation (1.6 mg/m² days 1, 8, 15, 22; 4 x 35-day cycles) or OBS, 60–120 days after ASCT. Primary endpoint was progression-free survival (PFS) from start of induction; secondary endpoints included response rate, overall survival (OS), and safety. Results: In 371 pts, median age was 59 yrs (35–76); 62% were male, 14%/84% were Durie-Salmon stage II / III. 37% of the 278 pts assessed for cytogenetics were classified as high-risk. 50% of pts had received prior BTZ; the most common induction regimen was VCD (40%). Others included dexamethasone/idarubicin (14%), dexamethasone (13%), and VAD (9%). Outcomes are shown in the table (median follow-up 42 mos). Conclusions: A higher proportion of pts had a response of ≥ VGPR after BTZ consolidation than OBS. PFS was significantly improved by ~6 mos, but there was no improvement in OS, likely related to the use of effective salvage options. Subgroups that seemed to benefit from BTZ consolidation were pts with < VGPR and those with high-risk cytogenetics. The BTZ dosing regimen was generally well-tolerated. Clinical trial information: NCT00416208 and NCT00416273. BTZ (N = 186) OBS (N = 185) HR (95% CI) P-value Best response ≥ VGPR before consolidation, n (%) 102 (55) 109 (59) Best response ≥ VGPR after consolidation, n/N* (%) 109/177 (62) 86/180 (48) Median PFS, mos† 33.6 27.8 0.70 (0.55, 0.90) 0.0058 Pts with < VGPR‡ 33.3 24.5 0.58 (0.39, 0.88) 0.0089 Pts with high-risk cytogenetics‡§ 30.6 24.2 0.66 (0.41, 1.05) 0.074 Median OS, mos NR NR 0.94 (0.64, 1.39) 0.75 TEAE, % 95 94 Diarrhea 43 8 Nausea 33 5 Vomiting 27 3 Fatigue 24 9 Discontinuations due to AE, % 15 0 SAE, % 11 17 Deaths, % 25 30 *Response-evaluable pts; †Cox proportional hazards regression model; ‡Univariate Cox regression; §del13q, t(4;14), del17p.
A population-based analysis of the impact of physicians on cancer screening.
Authors: Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

1572 Background: Despite its ability to reduce morbidity and mortality, participation in cancer screening continues to be suboptimal. Our aims were to 1) characterize the frequency of breast (BR), colorectal (CR), cervical (CV) and prostate (PR) cancer screening in a US population-based setting, 2) describe the clinical factors associated with screening uptake, and 3) examine the effect of patient contact with their physicians and the quality of these interactions in modifying screening behavior. Methods: Average risk patients considered eligible for cancer screening were identified from the US Health Information National Trends Survey. We developed a scoring system based on patient-reported patterns of care to characterize the quality of their interactions with physicians. Determinants of screening were assessed with multivariate logistic regression analyses and joint effects models that accounted for the frequency and quality of contact with physicians were developed to explore their influence on screening. Results: A total of 7,327 patients were included. In each of the BR (n=1,696), CR (n=2,377), CV (n=2,240) and PR (n=1,014) cancer cohorts, screening rates were suboptimal at 72%, 69%, 76% and 61%, respectively. Advanced age, family history of any cancers, high income earners, individuals who visited their physicians frequently and those who rated the interactions with their physicians highly were generally more likely to have undergone screening (Table). Joint effects models revealed that the quality rather than the frequency of physician contact was a stronger predictor of screening, but the odds of screening were greatest for patients who experienced both frequent and high quality interactions with their physicians. Conclusions: Participation in cancer screening remains poor. Contact with physicians and the quality of this interaction were associated with screening behavior. Interventions to improve these provider-related factors may optimize screening. Odds ratios for cancer screening. BR CR CV PR Advanced age 0.99 1.05* 0.96 1.06* Family history 1.26* 1.17 1.10 1.82* High income 1.08 1.22* 1.18* 1.22* Frequent visits with MD 1.41* 1.36* 1.06 1.39* Good quality interactions with MD 1.87* 1.27* 1.67* 1.19 *means p < 0.05.
Tandem gait performance following concussion
Authors: Jessie R Oldham, Melissa S DiFabio, Ryan M DeWolf, Thomas W Kaminski, Thomas A Buckley
Journal: British Journal of Sports Medicine (2017)

Objective To examine post-concussion tandem gait (TG) performance. Design Prospective Longitudinal. Setting Research Laboratory. Subjects Twenty-two NCAA Division I student-athletes: twelve diagnosed with sport-related concussions (Age: 20.3 ± 1.2 years; Height: 180.1 ± 12.4 cm; Weight: 80.5 ± 21.0 kg), and ten healthy controls (Age: 19 ± 1.2 years; Height: 176.3 ± 8.4 cm; Weight: 71.9 ± 9.4 kg). Intervention TG was performed in accordance with the SCAT3. Participants walked heel-to-toe down a 3-metre line and back as quickly as possible four times. All participants were tested prior to the season. The concussed group was re-tested acutely (&lt;48 hours) post-concussion; controls were re-tested at 4 months. An MDC value, or the smallest meaningful change, was calculated from the controls, and the data were compared using a 2 × 2 (group × time) ANOVA. Outcome measures Fastest time to complete TG. Main results The MDC was 0.38 seconds. There was no significant interaction (p=0.08), but there was a main effect for time (p=0.04); Post-concussion, the mean time increased by 2.3 seconds (10.6 ± 2.0 seconds and 12.9 ± 3.7) and 10 of the 12 participants exceeded the MDC. The control mean increased by 0.3 seconds (11.5 ± 1.2 seconds and 11.8 ± 0.5 seconds), which was less than the MDC. Conclusions Following concussion, there was a group increase of 2.3 seconds. Ten of the twelve student-athletes exceeded the MDC of TG acutely post-concussion, which differs from other clinical tests, such as the BESS, where the average number of errors following concussion falls below the MDC. This suggests TG might be a more stable test of post-concussion postural control. Competing interests None.
Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract
Authors: Laurence Heidet, Vincent Morinière, Charline Henry, Lara De Tomasi, Madeline Louise Reilly, Camille Humbert, Olivier Alibeu, Cécile Fourrage, Christine Bole-Feysot, Patrick Nitschké, Frédéric Tores, Marc Bras, Marc Jeanpierre, Christine Pietrement, Dominique Gaillard, Marie Gonzales, Robert Novo, Elise Schaefer, Joëlle Roume, Jelena Martinovic, Valérie Malan, Rémi Salomon, Sophie Saunier, Corinne Antignac, Cécile Jeanpierre
Journal: Journal of the American Society of Nephrology (2017)

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.
Gefitinib effectiveness in an head and neck squamous cell carcinoma in vitro model
Authors: Sinto Sebastian, Amalia Azzariti, Letizia Porcelli, Grazia M. Simone, Massimo Tommasino, Angelo Paradiso
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4749 

EGFR (epidermal growth factor receptor) is frequently altered in head and neck squamous cell carcinoma (HNSCC) leading to the hypothesis that it could be a suitable target for antitumoral therapy. First clinical trials of EGFR inhibitors, in single and combinatorial modalities, have demonstrated the feasibility of these approaches. The availability in our laboratory of a panel of twelve HNSCC cell lines, already characterised for major tumour suppressors (p53, p63, p73, fhit, and PTEN) and drug resistance protein (ABCG2), provided us with the possibility to study the activity and mechanism of the EGFR inhibitor, gefitinib (IRESSA), in oral cancer. Gefitinib activity was evaluated on cell growth inhibition and apoptosis induction, together with analysis of molecular pathways underlying the observed phenotypic effects. Gefitinib inhibited cell growth, with IC50s ranging between 0.06μM and 33μM, and induced apoptosis (15% increase of annexin V positive cells after 3 days of gefitinib exposure). In all cell lines, gefitinib induced a 10% accumulation of cells in G0/G1 phase that could explain its cytostatic activity. Moreover, it did not modulate EGFR, Akt and Erk1/2, conversely, it progressively inhibited its specific target, p-EGFR, as a function of drug time exposure. The analysis of the phosphorylated forms of the downstream effectors, Akt and Erk1/2, showed that in all cell lines the inhibition of the survival pathway (p-Akt) was more evident than the proliferation one (p-Erk1/2). However, no evidence of a clear relationship between target modulation and drug efficacy was observed. Our study confirms the possibility of utilising EGFR inhibitors in oral cancer patients and strongly suggests that further studies look at the capability of EGFR inhibitors to modulate other EGFR controlled pathways and other TK receptor pathways. IRESSA is a trademark of the AstraZeneca group of companies. Supported by AIRC funds 2005.
Suicides among junior doctors in the NHS
Authors: Rachel Clarke, Martin McKee
Journal: BMJ (2017)

Suicide should be included among work related causes of death

On 12 February 2016, Rose Polge, a foundation doctor at Torbay Hospital in south west England, disappeared.1 Her body was found in the sea almost two months later. At the inquest, the coroner concluded that she had taken her own life by walking into the sea.

Her death attracted media attention, partly because it occurred at the height of the junior doctors’ dispute over their new contract, but also because she had expressed concern about the pressures in the NHS, leaving a note that mentioned the secretary of state, Jeremy Hunt. Polge’s mother linked her daughter’s suicide directly to her conditions of work, stating on her Just Giving page: “Exhaustion because of long hours, work related anxiety, despair at her future in medicine and the news of the imposition of the new contract on junior doctors (announced [the day before Rose died]) were definite contributors to this awful and final decision.”2

Concern about suicides among junior doctors …
OC-087 Clinical evaluation of oesophageal mucosal integrity and acid sensitivity in patients with NERD. A study using basal impedance and assessment of mucosal recovery after acid challenge: Abstract OC-087 Figure 1
Authors: P Woodland, M Al-Zinaty, I Bravi, J Jafari, D Sifrim
Journal: Gut (2012)

<h3>Introduction</h3> Patients with NERD have no erosions but impaired oesophageal mucosal integrity, that is, dilated intercellular spaces. It has been proposed that such microscopic changes can underlie symptoms in NERD, however, the relationship between impaired mucosal integrity and acid perception is unclear. Thus far, oesophageal mucosal integrity has been studied in vitro. Recently, oesophageal impedance basal values have been suggested as an in vivo surrogate to assess mucosal integrity in man. Low basal impedance is seen in patients with higher oesophageal acid exposure, and improves after PPI treatment. Oesophageal mucosal integrity, as expressed by basal impedance, is probably a dynamic process reflecting (1) the damaging effect of repeated acid reflux events and (2) the mucosal capacity to recover integrity. We hypothesised that there may be a relationship between mucosal integrity, recovery capacity and acid perception. We <b>aimed</b> to study the relationship between the dynamic properties of oesophageal mucosal integrity after acid challenge and symptom perception in patients with reflux symptoms. <h3>Methods</h3> We studied 53 patients with typical reflux symptoms and no oesophagitis. A combined pH-MII catheter was inserted, and baseline distal oesophageal mucosal impedance measured for 15 min (and continuously thereafter). We performed a 10 min mid-oesophageal perfusion (10 ml/min) of a neutral solution. After a 10 min rest period an acid perfusion was performed with pH1 solution. Symptoms were recorded with a visual analogue scale. Impedance recovery was observed for 2 h post-acid perfusion in ambulatory conditions. Subjects then completed a 24 h reflux study. <h3>Results</h3> There was significant inter-individual variability in pre-perfusion impedance baselines (mean 2059Ω, range 462–5388). Neutral perfusion caused a drop in impedance that recovered fully in 10 min. Acid perfusion caused a drop in impedance that was slow to recover. The mean impedance recovery rate was 7.5 Ω/min (25th–75th percentile=3.1–10.9). 32 of 53 patients perceived heartburn during acid perfusion. Patients with slower impedance recovery (&lt;25th percentile, n=12) had lower basal impedance (mean±SEM 1331Ω±256 vs 3325Ω±325, p&lt;0.01), higher 24 h acid exposure (5.2%±1.0 vs 1.7%±0.3, p&lt;0.01), and more often acid sensitivity (10/12 vs 5/13, p&lt;0.05) than those with faster impedance recovery (&gt;75th percentile, n=13). <h3>Conclusion</h3> A continuous impaired mucosal integrity (low impedance) might be a consequence of repeated reflux episodes with slow recovery. There is a link between mucosal integrity, recovery capacity and symptom perception. Low basal impedance and slow recovery after acid challenge are associated with increased acid sensitivity. <h3>Competing interests</h3> None declared.
Item-based selection is in good shape in visual compound search: A view from electrophysiology
Authors: Thomas Töllner, Dragan Rangelov
Journal: Behavioral and Brain Sciences (2017)

Abstract We argue that although the framework put forward by Hulleman &amp; Olivers (H&amp;O) can successfully explain much of visual search behaviour, it appears limited to tasks without precise target identification demands. In particular, we contend that the unit of selection may be larger than a single item in standard detection tasks, whereas the unit may mandatorily be item-based in compound tasks.