tbuckley/cabot-search huggingface dataset:
Thin films of binary amorphous Zn-Zr alloys developed by magnetron co-sputtering for the production of degradable coronary stents: A preliminary study
Authors: Nathalie Annonay, Fatiha Challali, Marie-Noëlle Labour, Valérie Bockelée, A. Garcia-Sanchez, Florent Tetard, Marie-Paule Besland, Philippe Djemia, Frédéric Chaubet
Journal: Bioactive Materials (2018)
An Advance Care Planning Video Decision Support Tool for Nursing Home Residents With Advanced Dementia
Authors: Susan L. Mitchell, Michele L. Shaffer, Simon Cohen, Laura C. Hanson, Daniel Habtemariam, Angelo E. Volandes
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Better advance care planning (ACP) can help promote goal-directed care in patients with advanced dementia. <h3>Objectives</h3> To test whether an ACP video (vs usual care) has an effect on documented advance directives, level of care preferences, goals-of-care discussions, and burdensome treatments among nursing home residents with advanced dementia. <h3>Design, Setting, and Participants</h3> The Educational Video to Improve Nursing home Care in End-stage dementia (EVINCE) trial was a cluster randomized clinical trial conducted between February 2013 and July 2017, at 64 Boston-area nursing homes (32 facilities per arm). A total of 402 residents with advanced dementia and their proxies (intervention arm, n = 212; control arm, n = 190) were assessed quarterly for 12 months. <h3>Interventions</h3> A 12-minute ACP video for proxies with written communication of their preferred level of care (comfort, basic, or intensive) to the primary care team. <h3>Main Outcomes and Measures</h3> The primary outcome was the proportion of residents with do-not-hospitalize (DNH) directives by 6 months. Secondary outcomes included preference for comfort care, documented directives to withhold tube-feeding and intravenous hydration, documented goals-of-care discussions, and burdensome treatments (hospital transfers, tube-feeding, or parenteral therapy) per 1000 resident-days. Exploratory analyses examined associations between trial arm and documented advance directives when comfort care was preferred. <h3>Results</h3> The mean age of the 402 study residents was 86.7 years [range, 67-102 years]; 350 were white (87.1%) and 323 were female (80.3%), with DNH directives that by 6 months did not differ between arms (63% in both arms; adjusted odds ratio [AOR], 1.08; 95% CI, 0.69-1.69). Preferences for comfort care, directives to withhold intravenous hydration, and burdensome treatments did not differ between arms. Residents in intervention vs control facilities were more likely to have directives for no tube-feeding at 6 months (70.10% vs 61.90%; AOR, 1.79; 95% CI, 1.13-2.82) and all other time periods, and documented goals-of-care discussions at 3 months (16.10% vs 7.90%; AOR, 2.58; 95% CI, 1.20-5.54). When comfort care was preferred, residents in the intervention arm were more likely to have both DNH and no tube-feeding directives (72.20% vs 52.80%; AOR, 2.68; 95% CI, 2.68-5.85). <h3>Conclusions and Relevance</h3> An ACP video did not have an effect on preferences, DNH status, or burdensome treatments among residents with advanced dementia, but did increase directives to withhold tube-feeding. When proxies preferred comfort care, advance directives of residents in the intervention arm were more likely to align with that preference. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01774799
Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response
Authors: Thitinun Anusornvongchai, Masaomi Nangaku, Tzu-Ming Jao, Chia-Hsien Wu, Yu Ishimoto, Hiroshi Maekawa, Tetsuhiro Tanaka, Akira Shimizu, Masayuki Yamamoto, Norio Suzuki, Ryoji Sassa, Reiko Inagi
Journal: Kidney International (2018)

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.
A Secondary Mutation in<i>BRAF</i>Confers Resistance to RAF Inhibition in a<i>BRAF</i>V600E-Mutant Brain Tumor
Authors: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy N. Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc K. Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas
Journal: Cancer Discovery (2018)

BRAFV600E hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence.Significance: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. Cancer Discov; 8(9); 1130-41. ©2018 AACR.See related commentary by Romano and Kwong, p. 1064This article is highlighted in the In This Issue feature, p. 1047.
Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism
Authors: Martin J. Shearer, Toshio Okano
Journal: Annual Review of Nutrition (2018)

Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in the maintenance of hemostasis. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we show how novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR. We also discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed.
Disentangling determinants of insecticide use to manage production, food security, and health risks in Cambodia and Vietnam: evidence from household surveys and risk-assessment experiments
Authors: Wei Zhang, Yanyan Liu, Andrew Bell
Journal: The Lancet Planetary Health (2018)

BackgroundInsect pest problems are among the main causes of crop yield losses in global agriculture. Insecticides protect households from food-security and income shocks, but can induce human health and environmental risks. Semi-subsistence farm households (SSFHs), which farm for both consumption and market, make decisions about crop management and output allocation to maximise food consumption, income, and health outcomes, depending on their risk preferences and other household and community characteristics. In this study, we aimed to disentangle the determinants of insecticide use by SSFHs and identify whether health consideration has had any effect on insecticide use.MethodsIn this econometric analysis, we used field data collected from household surveys and risk-assessment experiments in 2014 in Cambodia and Vietnam to analyse insecticide use among more than 1000 SSFHs.FindingsWe found that crops (except for rice) whose outputs were used to a greater degree for consumption were less likely to be sprayed with insecticides or were sprayed fewer times. Health-conscious households (as indicated by the use of modern-fuel cooking stoves and reported concern over food safety as a main reason for maintaining home gardens) consistently refrained from spraying, but this tendency diminished as output allocation shifted toward commercial use, suggesting a possible moral-hazard phenomenon. Farmers were more likely to apply insecticides to crops of high food security or dietary importance, such as rice, although the difference between fresh produce and grain produce in risk of insecticide residue exposure might also have contributed to the difference in insecticide use between rice and non-rice crops. The two samples from Cambodia and Vietnam had similarities regarding the deterring effect of health consideration and differences in other factors affecting insecticide use, such as risk preference, landholding size, household head's education level, and land tenure security.InterpretationWe identified both push and deterring factors for use of insecticides at household, plot, and crop levels. These factors varied between the samples from Cambodia and Vietnam, indicating the importance of addressing specific contexts. Although the extent of crop output used for consumption was negatively correlated with insecticide use, caution needs to be taken when drawing causal interpretation from this correlation because of the complexity in SSFH decision making. Improved understanding of these issues is essential to inform policies that address multiple sustainable development objectives cutting across poverty reduction, food security, health, and the environment.FundingCGIAR Fund Donors.
Long-term effectiveness and immunogenicity of quadrivalent HPV vaccine in young men: 10-year end-of study analysis.
Authors: Stephen Goldstone, Anna Giuliano, Joel Palefsky, Alain Luxembourg
Journal: Journal of Clinical Oncology (2018)

1553 Background: The quadrivalent human papillomavirus (qHPV) vaccine prevented HPV6/11/16/18-related persistent infection and external genital lesions in young men in an international, randomized, placebo-controlled pivotal efficacy study. We report the end-of-study analysis of a long-term follow up (LTFU) extension study that assessed the effectiveness and immunogenicity of the qHPV vaccine through 10 years after the first dose. Methods: In the 3-year base study, young men (16-26 years old) were randomized 1:1 to receive a 3-dose regimen of qHPV vaccine or placebo; we report results from those who received 3 doses of qHPV vaccine in the base study and participated in the LTFU. The entire study population was assessed annually in the 7-year LTFU for HPV6/11-related genital warts and HPV6/11/16/18-related external genital lesions (EGL), and a subpopulation was assessed for HPV6/11/16/18-related anal intraepithelial neoplasia (AIN) or anal cancer. Persistence of anti-HPV6/11/16/18 antibodies was evaluated from serum samples collected 48-72 months (first LTFU visit) and 10 years post-Dose 1. Results: A total of 917 participants were followed for effectiveness for up to 11.5 years (median: 9.5 years) post-Dose 3. There were no new cases of HPV6/11-related genital warts, HPV6/11/16/18-related EGL, or HPV6/11/16/18-related high-grade AIN during the LTFU (Years 3 to 10 of the study) in the per-protocol population. One case of low-grade AIN (AIN1) with positive PCR results for HPV6 and HPV58 was reported. Seropositivity rates assessed by competitive Luminex immunoassay (cLIA) were > 97% at Month 7 (1 month post-Dose 3); remained high over time for HPV6, 11, and 16; and decreased over time for HPV18 (40.2% at Month 120 by cLIA). Seropositivity rates at Month 120 assessed by IgG Luminex immunoassay (a more sensitive assay) were > 90% for all 4 HPV types. Conclusions: The qHPV vaccine provides durable protection from vaccine-type–related anogenital disease and elicits persistent HPV antibody responses through 10 years post-vaccination onset in 16-26–year-old men. Clinical trial information: NCT00090285.
Immune cell profiling of melanoma metastases from patients treated with TriMixDC-MEL dendritic cell therapy in combination with ipilimumab.
Authors: Kelly Schats, Emily A. Van Vre, Isolde Debyser, Arno Vandenbroeck, Yanina Jansen, Teofila Seremet, Koen Marien, Erik Fransen, Dorien Schrijvers, Wim Van Criekinge, Kris Thielemans, Bart Neyns, Ingrid De Meester, Mark Kockx
Journal: Journal of Clinical Oncology (2017)

e21030 Background: Ipilimumab has proven clinical benefit in a subset of melanoma patients. Previously a high rate of durable complete response was shown with the combination of ipilumumab and TriMixDC-MEL therapy (Wilgenhof et al. JCO 2016). Methods: Melanoma metastases were collected from patients, before initiation of combined ipilimumab and dendritic cell (TrimixDC-MEL) therapy [NCT01302496]. Formalin-fixed, paraffin-embedded samples were available from 24 patients of which 6 had durable benefit (DB) and 18 had no clinical benefit (NB). Serial 4µm slides were stained with immunohistochemistry (IHC) for immune response markers. Semi-automated analysis (Definiens software) was applied to estimate the tumor area stained for CD8, CD20, CD163, OX40, ICOS and LAG3, % of FOXP3 positive T-cells and IRF1-positive tumor nuclei. H-scores were calculated for IDO, STING and MHC-I on tumor cells (TC). A qualified pathologist scored the % PD-L1 on TC and immune cells (IC). In addition, RNA was extracted (n = 19) and analyzed using the NanoString nCounter Pan Cancer immune profiling panel. Results: The IHC and NanoString variables were tested for predictive response, as single marker using logistic regression and the area under the curve (AUC) values. The top 15 biomarkers for either IHC or NanoString are listed in the table below (AUC in descending order). Gene Ontology analysis (GOstat) of Nanostring markers revealed over-representation of genes involved in the response to other organisms (GO: 0051707) and viruses (GO: 0009615) in DB patients. Conclusions: This study identified a set of potentially new predictive biomarkers, including virus response related genes, for DB following ipilimumab plus TriMixDC-MEL therapy. Further prospective validation is warranted. [Table: see text]
Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients
Authors: Melek Simsek, Berrie Meijer, Dewkoemar Ramsoekh, Gerd Bouma, Egbert-Jan van der Wouden, Bert den Hartog, Annemarie C. de Vries, Frank Hoentjen, Gerard Dijkstra, Sybrand Y. de Boer, Jeroen M. Jansen, Andrea E. van der Meulen, Ruud Beukers, Menno A. Brink, Toos Steinhauser, Bas Oldenburg, Lennard P. Gilissen, Ton H. Naber, Marc A. Verhagen, Nanne K.H. de Boer, Chris J.J. Mulder
Journal: Clinical Gastroenterology and Hepatology (2018)
연구논문 : 만성 바이러스간질환에서 간섬유화의 다양한 비침습 혈청표지자검사의 비교
Authors: 김선민 ( Sun Min Kim ), 손주현 ( Joo Hyun Sohn ), 김태엽 ( Tae Yeob Kim ), 노영욱 ( Young Wook Roh ), 은창수 ( Chang Soo Eun ), 전용철 ( Yong Cheol Jeon ), 한동수 ( Dong Soo Han ), 오영하 ( Young Ha Oh )
Journal: Clinical and Molecular Hepatology (2009)

목적: 만성 바이러스간질환에서 병의 경과와 예후를 평가하고 치료반응을 예측함에 있어 간섬유화의 진단은 중요하다. 최근 간섬유화 평가에 표준방법이지만 침습적 간생검을 대신하여 여러 가지 비침습적 진단법이 이용되고 있고, 또한 새로운 검사법들이 개발되고 있다. 저자들은 만성 B형 및 C형간염 환자를 대상으로 임상에서 광범위하게 흔히 시행하는 혈액검사와 임상 소견을 이용한 아래와 같은 진단법들만으로 간섬유화를 얼마나 정확하게 평가할 수 있는지 알아보고, 단일 검사로 간섬유화를 평가하는 데 유용하다고 알려져 있는 hyaluronic acid(HA)와 IV형 콜라겐 농도와 비교하여 그 임상적 유용성을 평가하였다. 대상과 방법: 2002년 3월부터 2007년 2월까지 만성 바이러스간 질환으로 간생검을 시행받은 225명의 환자(HBV 180명, HCV 43명, HBV+HCV 2명)를 대상으로 분석하였다. 간생검을 시행하는 날에 말초혈액검사, 혈액응고검사, 혈청생화학검사를 시행하고, 혈중 HA, IV형 콜라겐 농도를 측정하였다. 간섬유화의 정도는 F0(섬유화가 없음), F1(문맥역 섬유화), F2(문맥주변부 섬유화), F3(섬유성 격막) 및 F4(간경변증)의 4단계로 구분하였다. 대상 환자를 F0-1, F2-4 혹은 F0-2, F3-4의 두 집단으로 분류하여 두 집단을 구분하고자 할 때 AAR(AST/ALT ratio), API(age-platelet index), APRI(AST to platelet index), CDS(cirrhosis discriminant score), platelet count, HA, IV형 콜라겐의 예측능을 area under the receiver operating characteristic curve (AUROC)값을 이용하여 비교하였다. 결과: 대상환자의 섬유화의 단계는 F0 집단은 17명, F1 집단은 40명, F2 집단은 61명, F3 집단은 74명, F4 집단은 33명이었다. 의미 있는 간섬유화를 F2 이상으로 판단할 때, 의미 있는 섬유화의 예측에 대한 AUROC 값은 APRI=0.822, CDS=0.776, platelet count=0.773, API=0.756, HA=0.749, IV형 콜라겐=0.718, AAR=0.642 순이었고, F3 이상의 광범위한 섬유화 예측에 대한 AUROC값은 CDS=0.835, platelet count=0.795, API=0.794, HA=0.766, AAR=0.711, IV형 콜라겐=0.697, APRI=0.691 순으로 관찰되었다. 결론: 만성 바이러스간질환에서 간섬유화를 평가하는 데 임상 소견 및 혈액검사를 이용한 방법들이 비침습적 진단법 중 단독 검사로도 유용한 것으로 알려져 있는 혈중 HA와 IV형 콜라겐 농도와 비교하여 우월하거나 대등하였다. 특히 APRI는 다른 인자들에 비해 F2 이상의 의미 있는 섬유화를 예측하는 데 가장 유용하였고, CDS는 F3 이상의 광범위한 섬유화를 예측하는 데 가장 유용하였다.
Cancer and non-cancer pain opioid utilization in Medicare and Medicaid populations.
Authors: Catherine J. Datto, Yiqun Hu, Eric Wittbrodt, Perry G. Fine
Journal: Journal of Clinical Oncology (2018)

139 Background: Limited data exist comparing opioid use patterns in Medicare and Medicaid patients with cancer-related (CP) and non-cancer-related pain (NCP). Methods: A retrospective analysis of Medicare and Medicaid claims data (MarketScan Research Databases) investigated opioid use patterns in patients with CP and NCP. Adults (age ≥18 yr) with ≥1 pharmacy claim for an opioid (index date), continuous plan eligibility for 6 months pre- and 12 months post-index date, and duration of opioid use of ≥4 weeks were identified. CP patients were identified by medical claim for a cancer diagnosis within 30 days before index date. Results: A total of 4,009 Medicare and 551 Medicaid patients with CP and 98,631 Medicare and 25,163 Medicaid patients with NCP were analyzed. The most common cancer diagnoses were breast, lung, prostate, and colorectal. Medicare patients with CP and NCP had similar mean age; in the Medicaid cohort, patients with CP were older than those with NCP. In the Medicare cohort, NCP patients were more likely to be women; sex distribution was similar among Medicaid patients. Higher rates of comorbidity in the CP cohorts were observed in both datasets. Median index and post-index opioid doses were consistent between the CP and NCP cohorts. The post-index pattern of change in opioid dose was consistent between CP and NCP in both Medicare and Medicaid patients. The most common pattern observed was up to a doubling of index dose. Conclusions: Similar opioid utilization patterns in Medicare and Medicaid populations, including dose escalation, were observed regardless of pain etiology (cancer or non-cancer). [Table: see text]
A phase II trial of an adenovirus/PSA vaccine for prostate cancer
Authors: D. M. Lubaroff, D. A. Vaena, R. D. Williams, F. N. Joudi, M. C. Smith, P. S. Zehr, J. Eastman, K. Griffith, T. M. Madsen, K. Johnson
Journal: Journal of Clinical Oncology (2009)

3065 Background: Our phase I adenovirus/PSA vaccine trial has proven the vaccine is safe. We are conducting a phase II clinical trial with two separate protocols for patients with recurrent or hormone-refractory prostate cancer assessing toxicity, immune responses, and change in PSA levels. Methods: In Protocol 1 men with recurrent prostate cancer after definitive initial treatment were randomized to arm A (vaccine injection alone at days 0, 30, and 60) or arm B (vaccine injection 14 days after initiation of androgen deprivation therapy). In Protocol 2 men with hormone-refractory disease receive the vaccine alone at days 0, 30, and 60. Each injection consists of 108 pfu of Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Twenty-five patients will be enrolled in arms A and B in Protocol 1 and 32 in Protocol 2. Results: To date 10 patients have completed 3 monthly injections and have been followed a median of 5 months. Median patient age is 70 years (range 61–84), and median enrollment PSA levels are 0.79 ng/ml (range 0.24–3.93) in Protocol 1 and 5.47 ng/ml (range 0.29–11.17) in Protocol 2. Preliminary results show 86% in both protocols demonstrating anti-PSA T cell responses above preinjection levels. 25% have stable serum PSA levels, 50% have decreased levels, and 25% have increased levels. 11% have stable serum prostatic acid phosphatase (PAP) levels, 56% have decreased levels, and 33% have increased levels. Conclusions: These early results from the first few months of this phase II trial demonstrate the induction of anti-PSA T-cell responses in a high percentage of the vaccinated patients and stabilization or declines in serum PSA and PAP levels. No serious vaccine-related toxicities have been identified. No significant financial relationships to disclose.