bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Casein Kinase 1 Delta Sensitizes Pancreatic and Bladder Cancer Cells to Gemcitabine Treatment by Upregulating Deoxycytidine Kinase
Authors: Vena Francesca , Bayle Simon , Nieto Ainhoa , Quereda Victor , Aceti Massimiliano , Frydman Sylvia M. , Sansil Samer S. , Grant Wayne , Monastyrskyi Andrii , McDonald Patricia , Roush William R. , Teng Mingxiang , Duckett Derek 
Published: May 2020

Abstract
Although gemcitabine is the cornerstone of care for pancreatic ductal adenocarcinoma (PDA), patients lack durable responses and relapse is inevitable. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. This study evaluated casein kinase 1 delta (CK1δ) as a potential therapeutic target for PDA and bladder cancer, in which CK1δ is frequently overexpressed. We assessed the antitumor effects of genetically silencing or pharmacologically inhibiting CK1δ using our in-house CK1δ small-molecule inhibitor SR-3029, either alone or in combination with gemcitabine, on the proliferation and survival of pancreatic and bladder cancer cell lines and orthotopic mouse models. Genetic studies confirmed that silencing CK1δ or treatment with SR-3029 induced a significant upregulation of deoxycytidine kinase (dCK), a rate-limiting enzyme in gemcitabine metabolite activation. The combination of SR-3029 with gemcitabine induced synergistic antiproliferative activity and enhanced apoptosis in both pancreatic and bladder cancer cells. Furthermore, in an orthotopic pancreatic tumor model, we observed improved efficacy with combination treatment concomitant with increased dCK expression. This study demonstrates that CK1δ plays a role in gemcitabine metabolism, and that the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic PDA as well as other cancers with upregulated CK1δ expression.
Pathway-Specific Genome Editing of PI3K/mTOR Tumor Suppressor Genes Reveals that PTEN Loss Contributes to Cetuximab Resistance in Head and Neck Cancer
Authors: Izumi Hiroki , Wang Zhiyong , Goto Yusuke , Ando Toshinori , Wu Xingyu , Zhang Xuefeng , Li Hua , Johnson Daniel E. , Grandis Jennifer R. , Gutkind J. Silvio 
Published: May 2020

Abstract
Cetuximab, an mAb targeting EGFR, is a standard of care for the treatment for locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC). However, despite overexpression of EGFR in more than 90% of HNSCC lesions, most patients with HNSCC fail to respond to cetuximab treatment. In addition, there are no available biomarkers to predict sensitivity or resistance to cetuximab in the clinic. Here, we sought to advance precision medicine approaches for HNSCC by identifying PI3K/mTOR signaling network–specific cetuximab resistance mechanisms. We first analyzed the frequency of genomic alterations in genes involved in the PI3K/mTOR signaling circuitry in the HNSCC TCGA dataset. Experimentally, we took advantage of CRISPR/Cas9 genome editing approaches to systematically explore the contribution of genomic alterations in each tumor suppressor gene (TSG) controlling the PI3K–mTOR pathway to cetuximab resistance in HNSCC cases that do not exhibit PIK3CA mutations. Remarkably, we found that many HNSCC cases exhibit pathway-specific gene copy number loss of multiple TSGs that normally restrain PI3K/mTOR signaling. Among them, we found that both engineered and endogenous PTEN gene deletions can mediate resistance to cetuximab. Our findings suggest that PTEN gene copy number loss, which is highly prevalent in HNSCC, may result in sustained PI3K/mTOR signaling independent of EGFR, thereby representing a promising mechanistic biomarker predictive of cetuximab resistance in this cancer type. Further prospective studies are needed to investigate the impact of PTEN loss on cetuximab efficacy in the clinic.
Catheter Ablation Improves Mortality and Other Outcomes in Real‐World Patients With Atrial Fibrillation
Authors: Yang Pil‐Sung , Sung Jung‐Hoon , Jang Eunsun , Yu Hee Tae , Kim Tae‐Hoon , Uhm Jae‐Sun , Kim Jong‐Youn , Pak Hui‐Nam , Lee Moon‐Hyoung , Joung Boyoung 
Published: May 2020

Background

It is still controversial whether catheter ablation for atrial fibrillation (
AF
) improves survival and other outcomes in patients with AF. This study evaluated whether ablation reduces death and other events in nationwide real‐world Asian patients with
AF
.

Methods and Results

From the Korean National Health Insurance Service database, 194 928 adult patients (aged ≥18 years) with newly diagnosed
AF
were treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between January 1, 2005, and December 1, 2015. Among these patients, this study included 9185 with ablation and 18 770 with medical therapy. The time at risk was counted from the first medical therapy, and ablation was analyzed as a time‐varying covariate. Inverse probability of treatment weighting was used to correct for differences between the groups. After weighting, the 2 cohorts had similar background characteristics. During a median (25th, 75th percentiles) follow‐up of 43 (19, 81) months, ablation of
AF
was associated with lower incidence and risk of composite outcome, including death, heart failure admission, and stroke/systemic embolism (2.5 and 6.4 per 100 person‐years, respectively; hazard ratio [HR], 0.47; 95%
CI
, 0.43–0.52;
P
<0.001), all‐cause death (1.0 and 3.6 per 100 person‐years; HR, 0.41; 95%
CI,
0.36–0.47;
P
<0.001), heart failure admission (0.7 and 1.9 per 100 person‐years; HR, 0.43; 95%
CI,
0.37–0.50), and ischemic stroke/systemic embolism (1.1 and 2.8 per 100 person‐years; HR, 0.39; 95%
CI,
0.34–0.44) than medical therapy.

Conclusions

Ablation may be associated with lower risk of death, heart failure admission, and ischemic stroke/systemic embolism in real‐world Asian patients with
AF
.
Neuropsychological Status and Structural Brain Imaging in Adults With Simple Congenital Heart Defects Closed in Childhood
Authors: Asschenfeldt Benjamin , Evald Lars , Heiberg Johan , Salvig Camilla , Østergaard Leif , Dalby Rikke Beese , Eskildsen Simon Fristed , Hjortdal Vibeke Elisabeth 
Published: May 2020

Background
Neurodevelopmental impairments are common in survivors of complex congenital heart defects (CHD). We report neuropsychological and brain imaging assessments in adults operated for isolated septal defects.

Methods and Results

Patients (mean age 25.6 yrs) who underwent childhood surgery for isolated atrial septal defect (n=34) or ventricular septal defect (n=32), and healthy matched peers (n=40), underwent a standard battery of neuropsychological tests and a 3.0T brain magnetic resonance imaging scan. Patient intelligence was affected with lower scores on Full‐Scale intelligence quotient (
P
<0.001), Verbal Comprehension (
P
<0.001), Perceptual Reasoning (
P
=0.007), and Working Memory (
P
<0.001) compared with controls. Also, the CHD group had poorer visuospatial abilities (Immediate Recall,
P
=0.033; Delayed Recall,
P
=0.018), verbal memory (Trial 1,
P
=0.015; Total Learning,
P
<0.001; Delayed Recall,
P
=0.007), executive function (Executive Composite Score,
P
<0.001), and social recognition (Reading the Mind in the Eyes Test,
P
=0.002) compared with controls. Self‐reported levels of executive dysfunction, attention deficits and hyperactivity behavior, and social cognition dysfunction were higher in the CHD group compared with population means and controls. We found similar global and regional morphometric brain volumes and a similar frequency of brain magnetic resonance imaging abnormalities in the 2 groups. The CHD group had a high occurrence of psychiatric disease and a larger need for special teaching during school age.

Conclusions
Children operated for simple CHD demonstrate poorer neurodevelopmental outcomes in adulthood when compared with healthy controls and expected population means.

REGISTRATION

URL:
https://www.clini​caltr​ials.gov
. Unique identifier: NCT03871881.
Wide Complex Tachycardia Differentiation: A Reappraisal of the State‐of‐the‐Art
Authors: Kashou Anthony H. , Noseworthy Peter A. , DeSimone Christopher V. , Deshmukh Abhishek J. , Asirvatham Samuel J. , May Adam M. 
Published: May 2020

Abstract
The primary goal of the initial ECG evaluation of every wide complex tachycardia is to determine whether the tachyarrhythmia has a ventricular or supraventricular origin. The answer to this question drives immediate patient care decisions, ensuing clinical workup, and long‐term management strategies. Thus, the importance of arriving at the correct diagnosis cannot be understated and has naturally spurred rigorous research, which has brought forth an ever‐expanding abundance of manually applied and automated methods to differentiate wide complex tachycardias. In this review, we provide an in‐depth analysis of traditional and more contemporary methods to differentiate ventricular tachycardia and supraventricular wide complex tachycardia. In doing so, we: (1) review hallmark wide complex tachycardia differentiation criteria, (2) examine the conceptual and structural design of standard wide complex tachycardia differentiation methods, (3) discuss practical limitations of manually applied ECG interpretation approaches, and (4) highlight recently formulated methods designed to differentiate ventricular tachycardia and supraventricular wide complex tachycardia automatically.
Syllables in Sync Form a Link: Neural Phase-locking Reflects Word Knowledge during Language Learning
Authors: Batterink Laura 
Published: May 2020

Abstract
Language is composed of small building blocks, which combine to form larger meaningful structures. To understand language, we must process, track, and concatenate these building blocks into larger linguistic units as speech unfolds over time. An influential idea is that phase-locking of neural oscillations across different levels of linguistic structure provides a mechanism for this process. Building on this framework, the goal of the current study was to determine whether neural phase-locking occurs more robustly to novel linguistic items that are successfully learned and encoded into memory, compared to items that are not learned. Participants listened to a continuous speech stream composed of repeating nonsense words while their EEG was recorded and then performed a recognition test on the component words. Neural phase-locking to individual words during the learning period strongly predicted the strength of subsequent word knowledge, suggesting that neural phase-locking indexes the subjective perception of specific linguistic items during real-time language learning. These findings support neural oscillatory models of language, demonstrating that words that are successfully perceived as functional units are tracked by oscillatory activity at the matching word rate. In contrast, words that are not learned are processed merely as a sequence of unrelated syllables and thus not tracked by corresponding word-rate oscillations.
The Medial Temporal Lobe Is Critical for Spatial Relational Perception
Authors: Ruiz Nicholas A. , Meager Michael R. , Agarwal Sachin , Aly Mariam 
Published: May 2020

Abstract
The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations—representations of multidimensional features of experience and their unique relationship to one another—that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On “similar room” trials, they judged whether the rooms had the same spatial layout from a different perspective. On “similar art” trials, they judged whether the paintings could have been painted by the same artist. On “identical” trials, participants simply had to detect identical paintings or rooms. MTL lesion patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations and highlights its important contributions to rapid perceptual processes that benefit from attention.
Transoral Excision of Parapharyngeal Tumors
Authors: Lao Wilson P. , Han Peter S. , Lee Nathan H. , Gilde Jason E. , Inman Jared C. 
Published: May 2020

Objectives: The transoral approach for parapharyngeal space tumors has been criticized due to its restrictive exposure and increased rate of vascular and nerve injuries. However, for certain tumors—namely those that are prestyloid, benign, and well-encapsulated—the transoral approach reduces overall morbidity while providing direct access. Transoral surgeons can rely on this approach for select tumors seen clearly on intraoral examination in the bulging lateral pharynx. In this article and with a supplemental operative technique video, we demonstrate our transoral approach in these select patients. Methods: We reviewed our 26 cases using this approach and chose a representative case of a 50-year-old man who presented with a large, prestyloid, encapsulated parapharyngeal mass affecting his voice and swallowing. A transoral approach to the parapharyngeal tumor is illustrated. Results: A vertical curvilinear incision is completed from the hamulus to below the inferior extent of the tumor. Blunt dissection of the tumor capsule proceeds inferiorly. Controlled violation of the tumor capsule can aid in visualization. After tumor delivery, the wound is irrigated and closed. Conclusions: In our experience, the transoral approach is an effective method to access well-encapsulated, prestyloid parapharyngeal space tumors. Patient selection is important when considering a transoral approach.
Obesity as a Predictor of Prolonged Mechanical Ventilation
Authors: Shao Diana , Straub Jeffrey , Matrka Laura 
Published: May 2020

ObjectiveTo examine the effect of including obesity with parameters of the I‐TRACH scale in predicting the need for prolonged mechanical ventilation.Study DesignA retrospective cohort study.SettingTertiary care academic medical center.Subjects and MethodsConsecutive patients were identified retrospectively over a 45‐month period based on need for mechanical ventilation in the medical intensive care unit. Chart review was performed to collect demographic information as well as clinical data, including duration of mechanical ventilation, body mass index (BMI), and I‐TRACH parameters (heart rate >110, serum urea nitrogen >25, serum pH <7.25, serum creatinine >2, serum bicarbonate <20). Statistical analysis was performed to identify any predictors of prolonged mechanical ventilation, defined as ≥14 days and as ≥10 days.ResultsIn total, 455 patients were identified, with an average duration of mechanical ventilation of 10.4 days (range, 0‐248 days). On univariate and multivariate regression analysis, only BMI >30 reached statistical significance with respect to prolonged mechanical ventilation (P <. 05). The I‐TRACH parameters—either alone or in combination—were not significantly predictive.ConclusionThis study challenges previous findings regarding the I‐TRACH scale and the relation of its parameters to prolonged mechanical ventilation. Furthermore, BMI >30 alone was predictive of prolonged intubation. Inclusion of BMI in predictive models could assist current decision making in determining the likelihood of prolonged mechanical ventilation in medical intensive care unit patients going forward, and obesity should be considered a predictor of prolonged mechanical ventilation.
Effect of vertical cut on coronal coverage and rotation of tibial component in Oxford unicompartmental knee arthroplasty
Authors: Gao Guanghan , Li Zheng , Wang Yannong , Yang Guangzhong , Huang Jiang , An Shuai , Qiao Junjie , Cao Guanglei 
Published: May 2020

Objective This study was performed to investigate the influence of a standard Oxford vertical cut on the coronal coverage and rotation of the tibial component and determine whether a relationship exists between coverage and rotation. Methods We retrospectively analyzed 71 patients with anteromedial osteoarthritis of the knee treated by Oxford unicompartmental knee arthroplasty in one center from October 2016 to October 2017. The distance of coronal coverage was measured on a postoperative anteroposterior view of the tibial component. Two different reference lines between the lateral wall of the tibial component were defined as rotation angle α and β, respectively, on a computed tomography scan. Results The mean distance was 0.3 ± 1.1 mm. The mean angle α and β were 5.7° ± 4.6° and 8.4° ± 4.6°, respectively. There were no significant differences in the distance according to the tibial component rotation or in the α and β angles according to the coronal coverage. No significant correlation was found between the α and β angles and the distance. Conclusion A standard tibial vertical cut caused various changes in coronal coverage and rotation of the tibial component. The rotation of the tibial component did not affect coverage within a certain range.
Clinical features and prognostic factors in patients with bone metastases from non-small cell lung cancer
Authors: Wu Xiao-Tian , Zhou Jian-Wei , Pan Long-Ci , Ge Ting 
Published: May 2020

Objective To investigate the clinical features and evaluate the prognostic factors in patients with bone metastases from non-small cell lung cancer (NSCLC). Methods We retrospectively investigated 356 patients with NSCLC with bone metastases from January 2012 to December 2017. The overall survival (OS) and 1-year survival rate were calculated by Kaplan–Meier analysis and compared by univariate analysis using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. Results A total of 694 sites of bone metastases were determined among the 356 patients. The most common site of bone metastases was the ribs. The median OS was 12.5 months and the 1-year survival was 50.8% in the overall population. Univariate analysis revealed that histological type, number of bone metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), bisphosphonate therapy, and serum calcium, lactate dehydrogenase, and alkaline phosphatase were significantly correlated with prognosis. Multivariate analysis identified multiple bone metastases, ECOG PS ≥2, lactate dehydrogenase ≥225 U/L, and alkaline phosphatase ≥140 U/L as independent negative prognostic factors. Conclusion Multiple bone metastases, high ECOG PS, and high serum alkaline phosphatase and lactate dehydrogenase are independent negative prognostic factors for bone metastases from NSCLC.
Single-dwell treatment with a low-sodium solution in hypertensive peritoneal dialysis patients
Authors: Davies Simon , Haraldsson Börje , Vrtovsnik François , Schwenger Vedat , Fan Stanley , Klein Alexandre , Atiye Saynab , Gauly Adelheid 
Published: May 2020

Background: Patients on peritoneal dialysis (PD) may suffer from sodium (Na) and fluid overload, hypertension and increased cardiovascular risk. Low-Na dialysis solution, by increasing the diffusive removal of Na, might improve blood pressure (BP) management. Methods: A glucose-compensated, low-Na PD solution (112 mmol/L Na and 2% glucose) was compared to a standard-Na solution (133 mmol/L Na and 1.5% glucose) in a prospective, randomised, single-blind study in hypertensive patients on PD. One daily exchange of the standard dialysis regimen was substituted by either of the study solutions for 6 months. The primary outcome (response) was defined as either a decrease of 24-h systolic BP (SBP) by ≥6 mmHg or a fall in BP requiring a medical intervention (e.g. a reduction of antihypertensive medication) at 8 weeks. Results: One hundred twenty-three patients were assessed for efficacy. Response criteria were achieved in 34.5% and 29.1% of patients using low- and standard-Na solutions, respectively ( p = 0.51). Small reductions in 24 h, office, and self-measured BP were observed, more marked with low-Na than with standard-Na solution, but only the between-group difference for self-measured SBP and diastolic BP was significant ( p = 0.002 and p = 0.003). Total body water decreased in the low-Na group and increased in the control group, but between-group differences were not significant. Hypotension and dizziness occurred in 27.0% and in 11.1% of patients in the low-Na group and in 16.9% and 4.6% in the control group, respectively. Conclusions: Superiority of low-Na PD solution over standard-Na solution for control of BP could not be shown. The once daily use of a low-Na PD solution was associated with more hypotensive episodes, suggesting the need to reassess the overall concept of how Na-reduced solutions might be incorporated within the treatment schedule.
The Role of Suppressing Inflammation in the Treatment of Atherosclerotic Cardiovascular Disease
Authors: Roman Yuani M. , Hernandez Adrian V. , White C. Michael 
Published: May 2020

Objective: To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD). Data Sources: An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [( C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine)]. Additional references were identified from the citations. Study Selection and Data Extraction: English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included. Data Synthesis: Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4. Relevance to Patient Care and Clinical Practice: Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option. Conclusions: Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.