tbuckley/cabot-search huggingface dataset:
Mortality in people with mental disorders in the Czech Republic: a nationwide, register-based cohort study
Authors: Dzmitry Krupchanka, Karolína Mladá, Petr Winkler, Yasser Khazaal, Emiliano Albanese
Journal: The Lancet Public Health (2018)

BackgroundThe region of central and eastern Europe is estimated to have high rates of premature mortality due to mental disorders. However, epidemiological evidence is scarce and insufficient to inform policy actions and health system development. We aimed to assess mortality associated with mental disorders in the Czech Republic.MethodsWe did a nationwide, register-based, retrospective cohort study using routinely collected health data from two nationwide registries in the Czech Republic: the register of inpatient discharges (from Jan 1, 1994, to Dec 31, 2013) and the causes of death registry (from Jan 1, 1994, to Dec 31, 2014). We first identified all individuals discharged from mental health institutions with WHO International Classification of Diseases tenth edition (ICD-10) diagnoses of mental and behavioural disorders (from 1994 to 2013). We then did a deterministic individual-level linkage of these data with all-cause mortality data for the whole period (1994–2014). Standardised mortality ratios (SMRs) and 95% CIs were calculated for the year 2014, comparing deaths in people with mental and behavioural disorders discharged from psychiatric hospitals with deaths in the general population.FindingsThe final study population comprised 283 618 individuals. 3819 of these individuals died in 2014, corresponding to a mortality risk more than two times higher than that of the general population (SMR estimate 2·2; 95% CI 2·2–2·3). Differences in SMR estimates across diagnostic groups were substantial, with the highest SMR for substance use disorders (3·5; 95% CI 3·4–3·7) followed by schizophrenia, schizotypal, and delusional disorders (2·3; 2·1–2·5), personality disorders (2·3; 2·0–2·6), neurotic, stress-related, and somatoform disorders (1·8; 1·6–1·9), and mood (affective) disorders (1·6; 1·5–1·7).InterpretationMortality among people with mental disorders in the Czech Republic is markedly higher than in the general population. Our findings should stimulate and inform policy in the central and eastern Europe region, as well as ongoing national mental health-care reforms in the Czech Republic.FundingCzech Ministry of Education, Youth and Sports.
Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054
Authors: Yiwen Li, Carmine Carpenito, George Wang, David Surguladze, Amelie Forest, Maria Malabunga, Mary Murphy, Yiwei Zhang, Andreas Sonyi, Darin Chin, Douglas Burtrum, Ivan Inigo, Anthony Pennello, Leyi Shen, Laurent Malherbe, Xinlei Chen, Gerald Hall, Jaafar N. Haidar, Dale L. Ludwig, Ruslan D. Novosiadly, Michael Kalos
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. <h3>Results</h3> Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways. <h3>Conclusions</h3> LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.
Skin cancer treatment effectiveness is improved by iontophoresis of EGFR-targeted liposomes containing 5-FU compared with subcutaneous injection
Authors: Raquel Petrilli, Josimar O. Eloy, Fabiano P. Saggioro, Deise L. Chesca, Marina Claro de Souza, Marcos V.S. Dias, Luis L.P. daSilva, Robert J. Lee, Renata F.V. Lopez
Journal: Journal of Controlled Release (2018)
5-day dosing schedule of temozolomide in relapsed sensitive or refractory small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase (MGMT) analysis in a phase II trial.
Authors: Alexander Edward Dela Cruz Drilon, Kadota Kyuichi, Kety H Huberman, Camelia S. Sima, John Joseph Fiore, Helena Alexandra Yu, Anna M. Varghese, Dyana K. Sumner, William D Travis, Adriana Heguy, Michelle S. Ginsberg, Andrei Holodny, Timothy An-thy Chan, Naiyer A. Rizvi, Christopher G. Azzoli, Gregory J. Riely, Mark G. Kris, Lee M. Krug, Maria Catherine Pietanza
Journal: Journal of Clinical Oncology (2012)

7052 Background: MGMT promoter methylation and loss of MGMT activity are associated with improved sensitivity to alkylating agents. We recently reported that the oral alkylating agent temozolomide is active in 2nd- and 3rd-line treatment of relapsed SCLC at 75mg/m 2 /day for 21 out of 28 days (Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing schedule of temozolomide in a second cohort of patients and analyze MGMT activity in both cohorts of patients on the same study. Methods: Patients with disease progression after 1 or 2 prior chemotherapy regimens received temozolomide at 200mg/m 2 /day for 5 out of 28 days (n=25). Those with sensitive (S-SCLC, n=16) and refractory (R-SCLC, n=9) disease were enrolled to assess safety. Available tumor tissue from patients treated according to either schedule was assessed for MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry (IHC). Results: An overall response rate of 12% was noted (3 partial responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 3 cycles. Median progression-free survival and overall survival for all patients were 1.3 months and 7.9 months, respectively. Grade ≥3 thrombocytopenia and neutropenia was observed in 20% with a shorter mean duration of myelosuppression compared to the 21-day schedule. Results from MGMT evaluation of tumor samples from both dosing schedules were combined. Promoter methylation of MGMT was not significantly associated with response (p=0.23). However, patients that lacked MGMT expression by IHC had a higher response rate compared to those with MGMT-positive tumors (43% vs. 13%, p = 0.052; see table). Conclusions: The 5-day dosing schedule of temozolomide is both active and safe in patients with relapsed SCLC. A strong trend toward increased response was demonstrated in patients with MGMT-negative tumors compared to patients with MGMT-positive tumors by IHC. A trial combining temozolomide with the PARP inhibitor, ABT888, is planned. [Table: see text]
Identifying challenges to breast cancer care coordination at urban community-based primary care clinics.
Authors: Tamara Hamlish, Zakiya N Moton, Zuoli Zhang, Dana Sohmer, Olufunmilayo I. Olopade, Daniel Johnson, Susan Hong
Journal: Journal of Clinical Oncology (2018)

83 Background: Primary care providers (PCPs) are well positioned to play a significant role in improving cancer care in the U.S. and achieving the Institute of Medicine (IOM) recommendation for patient-centered, coordinated, comprehensive cancer care across the care continuum. This is particularly important in underserved communities where fragmented care contributes to widening disparities in cancer mortality. However, PCPs can face considerable challenges delivering cancer care. This research examines challenges to breast cancer survivorship (BCS) care coordination at federally qualified health centers (FQHCs). Methods: We conducted a chart review at five Chicago FQHCs to assess BCS-related follow-up care provided by PCPs. We reviewed patient electronic medical records for documentation of breast cancer-related health information by the PCP and for documentation from cancer specialists, including consultant notes, pathology reports, and treatment histories. Based on BC ICD -9 codes we identified 109 patients who had a BC diagnosis within five years and a primary care visit at one of the five FQHCS within 2 years. Results: The patient population was primarily comprised of African Americans (81%), with 16% Hispanic, and 4% Asian or non-Hispanic White. Mean age at diagnosis was 55 years with 30% diagnosed &lt; 50 years. Medicaid (59%) was the most common health insurance. More than half of the patients had ≥1 chronic disease. Critical clinical BC information was missing from patient medical records, including BC pathology (65%), mammogram (60%), last clinical breast examination (49%), and cancer specialist notes (45%). Documentation of family history and genetic counseling were missing from 76% and 98% of the records, respectively. Conclusions: Our data indicate that PCPs at FQHCs currently have a limited role in delivering IOM recommended patient-centered, coordinated, comprehensive cancer care across the care continuum. The research results underscore a need for improvement in two key areas: 1) support for PCPs to build capacity in BCS care and 2) enhanced communication and care coordination between cancer specialists and PCPS in order to make PCPs an active part of the BCS care team.
A Study of Illness in a Group of Cleveland Families
Authors: Sidney Katz, George F. Badger, William S. Jordan, Herbert B. Rosenbaum, John H. Dingle
Journal: New England Journal of Medicine (1954)

A CONTROLLED study was recently undertaken to evaluate the effect of relatively small, daily doses of an antibiotic, oxytetracycline hydrochloride,** in the prevention and treatment of common upper respiratory illnesses in a group of Cleveland families.1 The small doses used were associated with an unexpectedly large number of reactions, requiring discontinuance of the study after a week. It is the purpose of this paper to report the frequency and nature of these reactions, as determined by comparison of the occurrence of symptoms in the experimental and control groups.MethodsThe general methods used in the study of this group of . . .
Dietary modifications for bowel dysfunction in rectal cancer survivors: The Altering Intake, Managing Symptoms (AIMS) intervention study.
Authors: Virginia Sun, Tracy E Crane, Samantha D Slack, Angela Yung, Sarah Wright, Stephen Sentovich, Kurt Melstrom, Marwan Fakih, Robert S. Krouse, Cynthia A. Thomson
Journal: Journal of Clinical Oncology (2018)

141 Background: Rectal cancer survivors often experience persistent long-term effects of treatment. Functional deficits, such as bowel dysfunction, are associated with poor quality of life (QOL). There is a lack of evidence-based interventions to address bowel dysfunction symptoms in rectal cancer survivors. The purpose of this abstract is to describe the development and design of the Altering Intake, Managing Symptoms (AIMS) intervention to manage bowel dysfunction in rectal cancer survivors. Methods: Survivors with stage I-III rectosigmoid colon or rectal cancer who are 6 months post-treatment, &gt; 21 years, and English-speaking are eligible to participate. The AIMS intervention is a ten (30-40 minute) session, 4 month, telephone-based intervention delivered by trained health coaches. Outcome measures are assessed at baseline, 4 and 6 months, and include the MSKCC Bowel Function Tool, the COH-QOL-CRC, and adherence to cancer survivorship diet guidelines. Results: Based on the Chronic Care Self-Management Model (CCM), the AIMS intervention applies social cognitive theory to improve self-efficacy and self-management of bowel symptoms by coaching survivors to modify their diets to attenuate symptoms and enhance diet quality. Motivational interviewing-based behavioral approaches are applied, such as goal setting, self-monitoring, identification of barriers, and problem-solving. Monitoring of diet health involves review of 24 hour dietary recalls in conjunction with food and symptom diaries to promote survivor-directed behavior change resulting in improved bowel health. Conclusions: The AIMS intervention is among the first and few to address diet behavior changes for symptom management in rectal cancer survivors. It has the potential to positively impact the quality of long-term rectal cancer survivorship by integrating classic behavior change theories for cancer symptom management. Findings from the study will inform the design and development of future multi-institutional Phase II and III randomized trials. Clinical trial information: NCT03063918.
Factors affecting use of ballistics gelatin in laboratory studies of bacterial contamination in projectile wounds
Authors: Jessica J. Evans, Aaron Bost, Karim H. Muci-Küchler, Linda C. DeVeaux
Journal: Military Medical Research (2018)

Ballistics gelatin is a common tissue surrogate used in bacterial contamination models for projectile wounds. Although these studies have demonstrated that bacteria are transferred from the surface of the gelatin to the wound track by a projectile, quantifiable results have been inconsistent and not repeatable in successive tests. In this study, five areas of a typical contamination model in which bacterial recovery or survival are affected were identified for optimization. The first was a contaminated "skin" surrogate, where the novel use of vacuum filtration of a bacterial culture and buffer onto filter paper was employed. The other possibly problematic areas of the bacterial distribution model included the determination of bacterial survival when the contamination model is dried, survival in solid and molten gelatin, and the effect of high-intensity lights used for recording high-speed video. Vacuum filtration of bacteria and buffer resulted in a consistent bacterial distribution and recovery. The use of phosphate buffer M9 (pH 7) aided in neutralizing the ballistics gelatin and improving bacterial survival in solid gelatin. Additionally, the use of high-intensity lights to record high-speed video and the use of a 42°C water bath to melt the gelatin were found to be bactericidal for gram-positive and gram-negative bacteria. Multiple areas of a typical contamination model in which bacterial survival may be impeded were identified, and methods were proposed to improve survival in each area. These methods may be used to optimize the results of bacterial contamination models for medical applications, such as understanding the progression of infection in penetrating wounds and to identify possible sources of contamination for forensic purposes.
<i>Vital Signs:</i>Trends in State Suicide Rates — United States, 1999–2016 and Circumstances Contributing to Suicide — 27 States, 2015
Authors: Deborah M. Stone, Thomas R. Simon, Katherine A. Fowler, Scott R. Kegler, Keming Yuan, Kristin M. Holland, Asha Z. Ivey-Stephenson, Alex E. Crosby
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Suicide rates in the United States have risen nearly 30% since 1999, and mental health conditions are one of several factors contributing to suicide. Examining state-level trends in suicide and the multiple circumstances contributing to it can inform comprehensive state suicide prevention planning.Trends in age-adjusted suicide rates among persons aged ≥10 years, by state and sex, across six consecutive 3-year periods (1999-2016), were assessed using data from the National Vital Statistics System for 50 states and the District of Columbia. Data from the National Violent Death Reporting System, covering 27 states in 2015, were used to examine contributing circumstances among decedents with and without known mental health conditions.During 1999-2016, suicide rates increased significantly in 44 states, with 25 states experiencing increases >30%. Rates increased significantly among males and females in 34 and 43 states, respectively. Fifty-four percent of decedents in 27 states in 2015 did not have a known mental health condition. Among decedents with available information, several circumstances were significantly more likely among those without known mental health conditions than among those with mental health conditions, including relationship problems/loss (45.1% versus 39.6%), life stressors (50.5% versus 47.2%), and recent/impending crises (32.9% versus 26.0%), but these circumstances were common across groups.Suicide rates increased significantly across most states during 1999-2016. Various circumstances contributed to suicides among persons with and without known mental health conditions.States can use a comprehensive evidence-based public health approach to prevent suicide risk before it occurs, identify and support persons at risk, prevent reattempts, and help friends and family members in the aftermath of a suicide.
Characterization and validation of potential therapeutic targets based on the molecular signature of patient-derived xenografts in gastric cancer
Authors: Zuhua Chen, Wenwen Huang, Tiantian Tian, Wanchun Zang, Jingyuan Wang, Zhentao Liu, Zhongwu Li, Yumei Lai, Zhi Jiang, Jing Gao, Lin Shen
Journal: Journal of Hematology & Oncology (2018)

Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC). The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry. The antitumor activities of several targeted drugs were investigated in the PDX models. Furthermore, response biomarkers were explored. Each PDX model had individual histopathological and molecular features, and recurrent alterations in the MAPK, ErbB, VEGF, mTOR, and cell cycle signaling pathways were major events in these PDX models. Several potential drug targets, such as EGFR, MET, and CCNE1, were selected and validated in this study. Volitinib demonstrated strong antitumor activity in PDX models with MET and phosphorylated MET (pMET) overexpression. The EGFR monoclonal antibodies BK011 and cetuximab inhibited tumor growth in a PDX model with EGFR amplification. Afatinib inhibited tumor growth in the PDX models with EGFR amplification, EGFR overexpression, or HER2 amplification. Apatinib was more sensitive in the PDX models with high microvessel density. The CDK1/2/9 inhibitor AZD5438 had superior anti-tumor activity in two models with higher copy number of CCNE1. PDX models with defined molecular signature are useful for preclinical studies with targeted drugs, and the results should be validated in larger studies with PDX models or in clinical trials.
Next-generation targeted sequencing (NGTS) investigating <i>CDK4</i> as a prognostic driver in pure invasive lobular breast carcinoma (ILC): Preliminary results in early-stage patients (pts) stratified according to a validated clinico-pathological model.
Authors: Luisa Carbognin, Michele Simbolo, Caterina Vicentini, Isabella Sperduti, Anna Caliò, Francesco Schettini, Maria Vittoria Dieci, Gaia Griguolo, Sara Pilotto, Rolando Nortilli, Giovanni Paolo Pollini, Grazia Arpino, Valentina Guarneri, Sabino De Placido, Pier Franco Conte, Erminia Manfrin, Matteo Brunelli, Aldo Scarpa, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2018)

542 Background: The aim of this analysis was to investigate the distribution of molecular abnormalities and their potential role as therapeutic targets (with particular regard to CDK4/6 alterations) in resected ILC pts, grouped according to prognosis. Methods: Clinico-pathological multi-center data of early-stage pure ILC pts were correlated to disease-free survival (DFS). A continuous score was derived according to multivariate Hazard Ratios, to develop a 3-class model. The model was validated in an external pts’ cohort. Mutational and Copy Number Variation (CNV) analyses by NGTS, including 26 genes, were performed for pts at Poor and Good Prognosis (PP/GP). Quantitative-PCR analysis was applied for CNV validation; IHC for CDK6 was accomplished. Fisher’s exact test and Peto Odds Ratio (OR) were adopted for comparison. Results: Data from 773 pts (Training/Validation Set [TS/VS]: 491/282) were gathered. At multivariate analysis, T-size and N-status were independent predictors for DFS. A significant difference between pts at low/intermediate/high risk was found (10-yrs DFS: 76.3%/67.6%/39.8%, respectively, p < 0.0001) in the TS. The model discriminated DFS in the VS (p < 0.0001). According to the developed model, 20 PP and 14 GP pts underwent molecular analysis. In PP group, CDH1 was the most mutated gene (50.0%) followed by PIK3CA (35.0%). MAP3K1 (10.0%), ERBB2 and PTEN were mutated with low frequency (6.1%), only in the PP group. With regard to CNV, CDH1 loss (55.0%) were the most frequent event, followed by gain in ESR1, FGFR1 and CDK4 (35.0%), which was present exclusively in PP group (p = 0.03) and validated by quantitative-PCR. Moreover, CDK4 gain reported a significant higher chance to be associated with PP (OR = 7.98, 95%CI 1.51-42.1, p = 0.014). CDK6 overexpression showed a trend toward an association with PP (OR = 3.29, 95%CI 0.56-19.25, p = 0.18). Conclusions: These preliminary data first suggest that CDK4 gain is potentially associated with PP. The potential druggable of this alteration deserves further clinical investigations in the context of ILC.
Serum metabolites are associated with all-cause mortality in chronic kidney disease
Authors: Jiun-Ruey Hu, Josef Coresh, Lesley A. Inker, Andrew S. Levey, Zihe Zheng, Casey M. Rebholz, Adrienne Tin, Lawrence J. Appel, Jingsha Chen, Mark J. Sarnak, Morgan E. Grams
Journal: Kidney International (2018)