bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetically Silenced Candidate Tumor Suppressor Genes in Prostate Cancer: Identified by Modeling Methylation Stratification and Applied to Progression Prediction
Authors: Zhang Wensheng , Flemington Erik K. , Deng Hong-Wen , Zhang Kun 
Published: September 2018

Abstract

Background:
Recent studies have shown that epigenetic alterations, especially the hypermethylated promoters of tumor suppressor genes (TSGs), contribute to prostate cancer progression and metastasis. This article proposes a novel algorithm to identify epigenetically silenced TSGs (epi-TSGs) for prostate cancer.

Methods:
Our method is based on the perception that the promoter CpG island(s) of a typical epi-TSG has a stratified methylation profile over tumor samples. In other words, we assume that the methylation profile resembles the combination of a binary distribution of a driver mutation and a continuous distribution representing measurement noise and intratumor heterogeneity.

Results:
Applying the proposed algorithm and an existing method to The Cancer Genome Atlas prostate cancer data, we identify 57 candidate epi-TSGs. Over one third of these epi-TSGs have been reported to carry potential tumor suppression functions. The negative correlations between the expression levels and methylation levels of these genes are validated on external independent datasets. We further find that the expression profiling of these genes is a robust predictive signature for Gleason scores, with the AUC statistic ranging from 0.75 to 0.79. The identified signature also shows prediction strength for tumor progression stages, biochemical recurrences, and metastasis events.

Conclusions:
We propose a novel method for pinpointing candidate epi-TSGs in prostate cancer. The expression profiling of the identified epi-TSGs demonstrates significant prediction strength for tumor progression.

Impact:
The proposed epi-TSGs identification method can be adapted to other cancer types beyond prostate cancer. The identified clinically significant epi-TSGs would shed light on the carcinogenesis of prostate adenocarcinomas.
For Whom the Cell Tolls? Intratumoral Treatment Links Innate and Adaptive Immunity
Authors: Marquez-Rodas Ivan , Aznar María Angela , Calles Antonio , Melero Ignacio 
Published: September 2018

Abstract
Intratumoral immunotherapy can potentially modulate the tumor microenvironment (TME) and potentiate the effects of concomitant or sequential systemic immunotherapies. Intratumoral administration of different Toll-like receptor agonists, including TLR4, can potentiate these effects through innate and adaptive immunity connection.
See related article by Bhatia et al., p. 1185
СТАН КОМОРБІДНОЇ ПАТОЛОГІЇ У ХВОРИХ НА МОРБІДНЕ ОЖИРІННЯ
Authors: Todurov I. M. , Perekhrestenko O. V. , Kalashnikov O. O. , Kosyukhno S. V. , Yakimets V. M. , Plehutsa O. I. , Potapov O. A. 
Published: September 2018

Мета: покращити результати лікування хворих на морбідне ожиріння шляхом оцінки частоти розвитку та особливостей супутньої патології.Матеріали і методи. Проаналізовано результати передопераційного клініко-лабораторного та інструментального обстеження 205 хворих на морбідне ожиріння.Результати. Супутні захворювання діагностовано у 203 (99 %) хворих на морбідне ожиріння, включених у дослідження. В структурі супутньої патології переважали захворювання серцево-судинної системи у 135 (65,8 %) хворих, порушення вуглеводного – в 135 (65,8 %) пацієнтів та ліпідного обміну – в 161 (78,5 %) хворого, що віддзеркалюють патогенетичну сутність метаболічного синдрому та суттєво підвищують ризик передчасної смерті. Захворювання дихальної системи діагностовано у 63 (30,7 %) хворих, системи травлення – у 130 (63,4 %) пацієнтів.Висновки. Характерною особливістю хворих на морбідне ожиріння є висока частота, системність та, в більшості випадків, мультифокальність органних уражень, що вимагає системної реалізації мультидисциплінарного підходу для покращення результатів лікування означеної категорії пацієнтів.
USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis
Authors: Jean-Charles Pierre-Yves , Wu Jiao-Hui , Zhang Lisheng , Kaur Suneet , Nepliouev Igor , Stiber Jonathan A. , Brian Leigh , Qi Rui , Wertman Virginia , Shenoy Sudha K. , Freedman Neil J. 
Published: September 2018

Objective—
Signaling that activates NFκB (nuclear factor κB) in smooth muscle cells (SMCs) is integral to atherosclerosis and involves reversible ubiquitination that activates proteins downstream of proatherogenic receptors. Deubiquitination of these proteins is mediated by USP20 (ubiquitin-specific protease 20), among other deubiquitinases. We sought to determine whether USP20 activity in SMCs decreases atherosclerosis.

Approach and Results—

To address this question, we used male
Ldlr
−/−
mice without (control) or with SMC-specific expression of murine USP20 (SMC-USP20-transgenic) or its dominant-negative (DN; C154S/H643Q) mutant (SMC-DN-USP20-transgenic). Before the appearance of intimal macrophages, NFκB activation in aortic medial SMCs was greater in SMC-DN-USP20-transgenic than in control mice. After 16 weeks on a Western diet, SMC-DN-USP20-transgenic mice had 46% greater brachiocephalic artery atheroma area than control mice. Congruently, aortic atherosclerosis assessed en face was 21% greater than control in SMC-DN-USP20-transgenic mice and 13% less than control in SMC-USP20-transgenic mice. In response to TNF (tumor necrosis factor), SMCs from SMC-DN-USP20-transgenic mice showed ≈3-fold greater NFκB activation than control SMCs. Silencing USP20 in SMCs with siRNA (small interfering RNA) augmented NFκB activation by ≈50% in response to either TNF or IL-1β (interleukin-1β). Coimmunoprecipitation experiments revealed that USP20 associates with several components of the TNFR1 (TNF receptor-1) signaling pathway, including RIPK1 (receptor-interacting protein kinase 1), a critical checkpoint in TNF-induced NFκB activation and inflammation. TNF evoked ≈2-fold more RIPK1 ubiquitination in SMC-DN-USP20-transgenic than in control SMCs, and RIPK1 was deubiquitinated by purified USP20 in vitro.

Conclusions—
USP20 attenuates TNF- and IL-1β–evoked atherogenic signaling in SMCs, by deubiquitinating RIPK1, among other signaling intermediates.
NBEAL2 (Neurobeachin-Like 2) Is Required for Retention of Cargo Proteins by α-Granules During Their Production by Megakaryocytes
Authors: Lo Richard W. , Li Ling , Leung Richard , Pluthero Fred G. , Kahr Walter H.A. 
Published: September 2018

Objective—
Human and mouse megakaryocytes lacking NBEAL2 (neurobeachin-like 2) produce platelets where α-granules lack protein cargo. This cargo is mostly megakaryocyte-synthesized, but some proteins, including FGN (fibrinogen), are endocytosed. In this study, we examined the trafficking of both types of cargo within primary megakaryocytes cultured from normal and NBEAL2-null mice, to determine the role of NBEAL2 in α-granule maturation. We also examined the interaction of NBEAL2 with the granule-associated protein P-selectin in human megakaryocytes and platelets.

Approach and Results—
Fluorescence microscopy was used to compare uptake of labeled FGN by normal and NBEAL2-null mouse megakaryocytes, which was similar in both. NBEAL2-null cells, however, showed decreased FGN retention, and studies with biotinylated protein showed rapid loss rather than increased degradation. Intracellular tracking via fluorescence microscopy revealed that in normal megakaryocytes, endocytosed FGN sequentially associated with compartments expressing RAB5 (Ras-related protein in brain 5), RAB7 (Ras-related protein in brain 7), and P-selectin, where it was retained. A similar initial pattern was observed in NBEAL2-null megakaryocytes, but then FGN passed from the P-selectin compartment to RAB11 (Ras-related protein in brain 11)-associated endosomes before release. Megakaryocyte-synthesized VWF (Von Willebrand factor) was observed to follow the same route out of NBEAL2-null cells. Immunofluorescence microscopy revealed intracellular colocalization of NBEAL2 with P-selectin in human megakaryocytes, proplatelets, and platelets. Native NBEAL2 and P-selectin were coimmunoprecipitated from platelets and megakaryocytes.

Conclusions—
NBEAL2 is not required for FGN uptake by megakaryocytes. NBEAL2 is required for the retention of both endocytosed and megakaryocyte-synthesized proteins by maturing α-granules, and possibly by platelet-borne granules. This function may involve interaction of NBEAL2 with P-selectin.
Small GTPase Rap1A/B Is Required for Lymphatic Development and Adrenomedullin-Induced Stabilization of Lymphatic Endothelial Junctions
Authors: Xu Wenjing , Wittchen Erika S. , Hoopes Samantha L. , Stefanini Lucia , Burridge Keith , Caron Kathleen M. 
Published: September 2018

Objective—

Maintenance of lymphatic permeability is essential for normal lymphatic function during adulthood, but the precise signaling pathways that control lymphatic junctions during development are not fully elucidated. The G
s
-coupled AM (adrenomedullin) signaling pathway is required for embryonic lymphangiogenesis and the maintenance of lymphatic junctions during adulthood. Thus, we sought to elucidate the downstream effectors mediating junctional stabilization in lymphatic endothelial cells.

Approach and Results—

We knocked-down both
Rap1A
and
Rap1B
isoforms in human neonatal dermal lymphatic cells (human lymphatic endothelial cells) and genetically deleted the
mRap1
gene in lymphatic endothelial cells by producing 2 independent, conditional
Rap1a/b
knockout mouse lines.
Rap1A/B
knockdown caused disrupted junctional formation with hyperpermeability and impaired AM-induced lymphatic junctional tightening, as well as rescue of histamine-induced junctional disruption. Less than 60% of lymphatic-
Rap1a/b
knockout embryos survived to E13.5 exhibiting interstitial edema, blood-filled lymphatics, disrupted lymphovenous valves, and defective lymphangiogenesis. Consistently, inducible lymphatic-
Rap1a/b
deletion in adult animals prevented AM-rescue of histamine-induced lymphatic leakage and dilation.

Conclusions—
Rap1 (Ras-related protein) serves as the dominant effector downstream of AM to stabilize lymphatic junctions. Rap1 is required for maintaining lymphatic permeability and driving normal lymphatic development.
Spearcon Sequences for Monitoring Multiple Patients: Laboratory Investigation Comparing Two Auditory Display Designs
Authors: Li Simon Y. W. , Tse Man-Kei , Brecknell Birgit , Sanderson Penelope M. 
Published: September 2018

Objective: The aim was to compare the effectiveness of two auditory displays, implemented with spearcons (time-compressed speech), for monitoring multiple patients. Background: Sequences of sounds can convey information about patients’ vital signs, such as oxygen saturation (SpO2) and heart rate (HR). We tested whether participants could monitor five patients using spearcon-based sound sequences. Method: A 2 × 3 within-subjects design was used. The first factor was interface, with two levels: the ALL interface used spearcons to convey vital signs for all five patients, whereas the ABN (abnormal) interface represented patients who had normal vital signs with a low-pitched single-tone sound and patients who had at least one abnormal vital sign with spearcons. The second factor was the number of patients who had at least one abnormal vital sign: there were one, two, or three such patients in each monitoring sequence. Participants were 40 nonclinicians. Results: Participants identified abnormal patients’ SpO2 and HR levels and located abnormal patients in the sound sequence more accurately with the ABN interface than the ALL interface. Accuracy declined as the number of abnormal patients increased. Participants associated ABN with easier identification of vital signs, resulting in higher ratings of confidence and pleasantness compared with ALL. Conclusion: Sequences of spearcons may support effective eyes-free monitoring of multiple patients. Application: Sequences of spearcons may be useful in monitoring multiple patients and the underlying design principles may extend to monitoring in other domains such as industrial process control or control of multiple autonomous vehicles.
Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression
Authors: Zhou Yanling , Zheng Wei , Liu Weijian , Wang Chengyu , Zhan Yanni , Li Hanqiu , Chen Lijian , Li Mingding , Ning Yuping 
Published: September 2018

Background: Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, whether repeated ketamine infusions would cause short-and long-term neurocognitive impairments was not clear. Our aims were to investigate the neurocognitive effects of six ketamine infusions and to examine the association between these infusions and the antidepressant response in patients with unipolar and bipolar depression. Methods: Six intravenous infusions of ketamine (0.5 mg/kg) over a 12-day period were administered to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and four domains of neurocognition, including speed of processing, working memory, visual learning and verbal learning, were assessed at baseline, one day following the last infusion and again two weeks post-infusion. Results: Significant improvements were found on speed of processing ( F=9.344, p<0.001) and verbal learning ( F=5.647, p=0.004) in a linear mixed model. The Sobel test showed significant indirect effects between time and improvement in speed of processing (Sobel test=3.573, p<0.001) as well as improvement in verbal learning (Sobel test=6.649, p<0.001), which were both significantly mediated by change in depressive symptoms. Logistic regression analysis showed ketamine responders had better visual learning at baseline than non-responders (B=0.118, p<0.001). Conclusions: Our findings suggest that neurocognitive function would not deteriorate after six ketamine infusions, while verbal learning and speed of processing improved over 13 days and 26 days of observation, respectively. However, this change was mainly accounted for by improvements in severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusions.
Enoxaparin 20 mg for thromboprophylaxis in severe renal impairment
Authors: Karaoui Lamis R. , Tawil Samah , Salameh Pascale , Chamoun Nibal 
Published: September 2018

Objective This study was performed to evaluate the efficacy of daily subcutaneous enoxaparin 20 mg in patients with renal failure. Methods This retrospective cohort study included nonsurgical patients aged ≥18 years with a creatinine clearance rate of <30 mL/minute who were prescribed enoxaparin 20 mg subcutaneously (SC) daily for ≥3 days. The main outcome measures were the occurrence of a venous thromboembolic event (VTE) and bleeding events. Results One hundred sixty patients were identified. VTE occurred in 9 patients (5.6%), and bleeding events occurred in 37 (23.1%). Multivariable analysis showed that an age of >75 years was significantly associated with an increased risk of bleeding, while a creatinine clearance rate of 15 to 29 mL/minute was significantly associated with a lower risk of bleeding. Conclusion In patients with renal failure, enoxaparin 20 mg SC daily resulted in a 5.6% incidence of VTE, which is similar to the previously published acceptable incidence of VTE in patients with normal renal function receiving enoxaparin 40 mg SC daily. The incidence of major bleeding events was 10%, which is lower than that previously published in the literature.
Impact of Patient Language on Emergency Medical Service Use and Prenotification for Acute Ischemic Stroke
Authors: Rostanski Sara K. , Kummer Benjamin R. , Miller Eliza C. , Marshall Randolph S. , Williams Olajide , Willey Joshua Z. 
Published: September 2018

Background and Purpose: Use of emergency medical services (EMS) is associated with decreased door-to-needle time in acute ischemic stroke (AIS). Whether patient language affects EMS utilization and prenotification in AIS has been understudied. We sought to characterize EMS use and prenotification by patient language among intravenous tissue plasminogen activator (IV-tPA) tissue plasminogen (IV-tPA) treated patients at a single center with a large Spanish-speaking patient population. Methods: We performed a retrospective analysis of all patients who received IV-tPA in our emergency department between July 2011 and June 2016. Baseline characteristics, EMS use, and prenotification were compared between English- and Spanish-speaking patients. Logistic regression was used to measure the association between patient language and EMS use. Results: Of 391 patients who received IV-tPA, 208 (53%) primarily spoke English and 174 (45%) primarily spoke Spanish. Demographic and clinical factors including National Institutes of Health Stroke Scale (NIHSS) did not differ between language groups. Emergency medical services use was higher among Spanish-speaking patients (82% vs 70%; P < .01). Prenotification did not differ by language (61% vs 63%; P = .8). In a multivariable model adjusted for age, sex, and NIHSS, Spanish speakers remained more likely to use EMS (odds ratio: 1.8, 95% confidence interval: 1.1-3.0). Conclusion: Emergency medical services usage was higher in Spanish speakers compared to English speakers among AIS patients treated with IV-tPA; however, prenotification rates did not differ. Future studies should evaluate differences in EMS utilization according to primary language and ethnicity.
Cerebrospinal Fluid in Posterior Reversible Encephalopathy Syndrome: Implications of Elevated Protein and Pleocytosis
Authors: Ellis Colin A. , McClelland Andrew C. , Mohan Suyash , Kuo Emory , Kasner Scott E. , Zhang Cen , Khankhanian Pouya , Balu Ramani 
Published: September 2018

Background and Purpose: Patients with posterior reversible encephalopathy syndrome (PRES) sometimes undergo analysis of cerebrospinal fluid (CSF) to exclude alternative diagnoses. This study’s objectives were to describe the CSF characteristics in patients with PRES and to identify clinical and radiologic findings associated with distinct CSF abnormalities. Methods: We identified a retrospective cohort of patients with PRES. We compared clinical and radiographic characteristics of those who did versus did not undergo lumbar puncture, described the observed range of CSF findings, and analyzed clinical and radiographic features associated with specific CSF abnormalities. Results: A total of 188 patients were included. Patients with (n = 77) and without (n = 111) CSF analysis had similar clinical and radiographic characteristics. Cerebrospinal fluid protein was elevated in 46 (60%) of 77, with median CSF protein 53 mg/dL (upper limit of normal 45 mg/dL). Protein elevation was significantly associated with radiographic severity ( P = .0058) but not with seizure, time from symptom onset, radiographic evidence of diffusion restriction, or contrast enhancement. Five (7%) patients had elevated CSF white blood cells, all of whom had infarction and/or hemorrhage on neuroimaging, and 4 of whom had eclampsia. Conclusion: The CSF of most patients with PRES shows a mild protein elevation commensurate with radiographic severity. Cerebrospinal fluid pleocytosis may mark a distinct subtype of PRES with predisposition toward infarction and/or hemorrhage. These findings help clinicians interpret CSF findings in these patients and generate new hypotheses about the pathophysiology of this syndrome.
Editor’s Choice- Impact of insulin-treated diabetes on cardiovascular outcomes following high-risk myocardial infarction
Authors: Rossello Xavier , Ferreira João Pedro , McMurray John JV , Aguilar David , Pfeffer Marc A , Pitt Bertram , Dickstein Kenneth , Girerd Nicolas , Rossignol Patrick , Zannad Faiez ,   for the High-Risk Myocardial Infarction Database Initiative
Published: September 2018

Background: Diabetes is associated with poor cardiovascular outcomes, and insulin-treated patients usually have a worse prognosis than non-insulin-treated subjects. The relationship between insulin treatment and outcomes in high-risk myocardial infarction patients has not been described in a large dataset. Methods: To investigate the association between insulin-treated diabetes and long-term cardiovascular outcomes in patients with high-risk myocardial infarction, we used adjusted Cox models to compare cardiovascular mortality and hospitalisation among 28,771 patients grouped by diabetes status and insulin treatment from four randomised clinical trials (VALIANT, EPHESUS, OPTIMAAL, CAPRICORN) of acute myocardial infarction complicated by heart failure and/or left ventricular systolic dysfunction. Results: After an approximately 2-year follow-up, patients with no diabetes (21,386 subjects, 74.3%), non-insulin-treated diabetes (4977 patients, 17.3%) and insulin-treated diabetes (2409 subjects, 8.4%) had an incremental yearly mortality risk (15.8%, 21.3% and 28.1%, respectively). Insulin-treated diabetes patients presented with a higher cardiovascular burden and comorbidities. After adjustment for 18 baseline covariates, patients with non-insulin-treated and insulin-treated diabetes were at higher risk of cardiovascular death (hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.13–1.38 and HR 1.49, 95% CI 1.31–1.69, respectively; P for comparison of non-insulin-treated vs. insulin-treated diabetes =0.016) and cardiovascular hospitalisation (HR 1.33, 95% CI 1.25–1.41 and HR 1.16, 95% CI 1.11–1.22, respectively) compared to patients without diabetes. These results remained consistent after further adjustment for medications and left ventricular ejection fraction. Conclusions: Insulin-treated diabetes patients had higher event rates than diabetes patients taking oral treatments and patients without diabetes. However, insulin-treated diabetes patients had more comorbidities and atherosclerotic disease, precluding any causality suggestion between insulin treatment and outcomes. This high-risk population may require specific and/or more intense cardiovascular protective therapies.