bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised Phase II study comparing alternating cycles of sunitinib and everolimus vs standard sequential administration in first‐line metastatic renal carcinoma (SUNRISES study)
Authors: Rodriguez‐Vida Alejo , Bamias Aristotelis , Esteban Emilio , Saez Maria Isabel , Lopez‐Brea Marta , Castellano Daniel , Caballero Cristina , Gonzalez‐Larriba Jose Luis , Calvo Emiliano , Macia Sonia , Ravaud Alain , Bellmunt Joaquim 
Published: July 2020

ObjectiveTo investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first‐line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti‐VEGFR therapy in mRCC.Patients and MethodsSUNRISES, a randomised open‐label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment‐naïve patients with clear‐cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression‐free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety.ResultsAccrual was low due to the advent of new‐generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1‐year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm.ConclusionsThe study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.
Complications after open and robot‐assisted radical prostatectomy and association with postoperative opioid use: an analysis of data from the PREVENTER trial
Authors: Huang Mitchell M. , Su Zhuo T. , Becker Russell E.N. , Pavlovich Christian P. , Partin Alan W. , Allaf Mohamad E. , Patel Hiten D. 
Published: July 2020

ObjectiveTo evaluate perioperative complications for open radical prostatectomy (ORP) and robot‐assisted RP (RARP) for patients enrolled in the PREvention of VENous ThromboEmbolism Following Radical Prostatectomy (PREVENTER; ClinicalTrials.gov Identifier: NCT03006562) trial, to determine predictors and impact on opioid consumption.Patients and MethodsA prospective cohort of 500 patients undergoing ORP and RARP was followed to determine rates of complications and opioid use. Complications were classified 30 days after RP using the Clavien–Dindo system. Patient characteristics and outcomes were compared using appropriate statistical tests. Logistic and linear regressions were performed to identify predictors of complications and evaluate the relationship between complications and postoperative opioid use.ResultsA total of 124 (24.8%) men underwent ORP and 376 (75.2%) RARP, with 418 (83.6%) receiving pelvic lymph node dissection (PLND). While 83 patients (16.6%) had complications, only 19 (3.8%) were major (Clavien–Dindo Grade ≥III), with no differences by surgical approach. PLND (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.25–8.71; P = 0.03) and Stage pT3b (OR 2.76, 95% CI 1.23–6.00;P = 0.01) were the only predictors of complications after controlling for potential confounders. Patients who had complications had greater inpatient (P = 0.02) and outpatient (P = 0.005) opioid use, which persisted after controlling for patient‐reported pain, attending surgeon variation, surgical approach, and undergoing PLND (inpatient β:77.2, 95% CI 17.9–136.5,P = 0.03; and outpatient β:21.9, 95% CI 4.7–39.1,P = 0.01).ConclusionIn an analysis of prospectively collected data, overall and major complications rates did not differ by surgical approach. Patients receiving PLND and with Stage pT3b disease had more complications. Complications were independently associated with higher inpatient and outpatient postoperative opioid use.
Effect of low‐energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer
Authors: Elkashef Ahmed , Barakat Nashwa , Khater Sherry M. , Awadalla Amira , Belal Fathallah , El‐Assmy Ahmed M. , Sheir Khaled Z. , Shokeir Ahmed A. 
Published: July 2020

ObjectivesTo study the efficacy of low‐energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa).Materials and MethodsA total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR‐210, hypoxia‐inducible factor (HIF)‐1α, tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity.ResultsThe EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53, miR‐210, HIF‐1α, TNF‐α and IL‐6. LESW increased urothelial concentration of EPI by 5.7‐fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI‐induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group.ConclusionsThe combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.
Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms
Authors: Alzate‐Correa Diego , Mei‐ling Liu Jillian , Jones Mikayla , Silva Talita M. , Alves Michele Joana , Burke Elizabeth , Zuñiga Jessica , Kaya Behiye , Zaza Giuliana , Aslan Mehmet Tahir , Blackburn Jessica , Shimada Marina Y. , Fernandes‐Junior Silvio A. , Baer Lisa A. , Stanford Kristin I. , Kempton Amber , Smith Sakima , Szujewski Caroline C. , Silbaugh Abby , Viemari Jean‐Charles , Takakura Ana C. , Garcia Alfredo J. , Moreira Thiago S. , Czeisler Catherine M. , Otero José J. 
Published: July 2020

AbstractCongenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal‐ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non‐cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non‐cell autonomous maldevelopment of key brainstem respiratory neurons.
Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms
Authors: Ma Yiyi , Klein Hans‐Ulrich , De Jager Philip L. 
Published: July 2020

AbstractThe past decade has seen the maturation of multiple different forms of high‐dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of “omic” data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or “omic” data is sufficient to capture the variance of AD or aging‐related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well‐characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.
Applying gene‐editing technology to elucidate the functional consequence of genetic and epigenetic variation in Alzheimer’s disease
Authors: Schrauben Michael , Dempster Emma , Lunnon Katie 
Published: July 2020

AbstractRecent studies have highlighted a potential role of genetic and epigenetic variation in the development of Alzheimer’s disease. Application of the CRISPR‐Cas genome‐editing platform has enabled investigation of the functional impact that Alzheimer’s disease‐associated gene mutations have on gene expression. Moreover, recent advances in the technology have led to the generation of CRISPR‐Cas–based tools that allow for high‐throughput interrogation of different risk variants to elucidate the interplay between genomic regulatory features, epigenetic modifications, and chromatin structure. In this review, we examine the various iterations of the CRISPR‐Cas system and their potential application for exploring the complex interactions and disruptions in gene regulatory circuits that contribute to Alzheimer’s disease.
Controls of pre‐existing structures on clinoform architecture and the associated progradational system elements
Authors: Clairmont Roberto , Kolawole Folarin , Omale Abah P. , Bedle Heather 
Published: July 2020

AbstractThere remains a limited understanding of the controls of pre‐existing structures on the architecture of deep‐water progradational sequences. In the Northern Taranaki Basin (NTB), New Zealand, Pliocene post‐extensional sedimentary sequences overlie Miocene back‐arc volcaniclastic units. We utilize seismic reflection datasets to investigate the relationships between the buried back‐arc mound‐shaped structures, and the spatio‐temporal changes in clinoform architecture and the associated progradational system elements within the overlying continental slope margin sequences. Our results reveal the following: (a) buried mound‐shaped structures in the northern domain of the study area, overlain by younging progression of shelf‐to‐basin prograding clinoforms; (b) folding of the deeper clinoforms that systematically decrease in magnitude with shallowing depth from the top of the seamounts; (c) overall, the N‐S‐trending continental slope margin evolves from a highly curvilinear/angular trend in the deeper clinoforms (Units 1 and 2) into a rectilinear geometry within the shallower post‐extensional intervals (Unit 3 and shallower); (d) Units 1 and 2 characterized by dominance of stacked offlap breaks and over‐steepened (7–10°) clinoform foreset slopes in the northern domain, and dominance of gently dipping foreset slopes (<6°) in the south; (e) Unit 3 shows very low (<5°) and intermediate (5–7°) foreset slopes across the entire survey; (f) in the northern domain, differential loading by prograding sequences about the buried seamounts and horst–graben structures induced a differential compaction of the deeper units, which influenced a temporal pinning of the prograding slope margin in pre‐Unit 2 times and (g) wide, closely spaced channel incision into over‐steepened slopes dominate the deeper prograding sequence in the northern domain, whereas narrower, straighter channels dominate the south. We show that the buried pre‐existing structures constitute rigid buttresses that modulated the syn‐depositional topography and post‐depositional architecture of the prograding sequences in the NTB. Our findings present a distinction in the controls on progradational sedimentation patterns between magmatic and non‐magmatic continental margins.
Relapse‐related molecular signature in early‐stage lung adenocarcinomas based on base excision repair, stimulator of interferon genes pathway and tumor‐infiltrating lymphocytes
Authors: Yang Bo , Rao Wen , Luo Hao , Zhang Liang , Wang Dong 
Published: July 2020

AbstractApproximately 30% of patients with early‐stage non–small cell lung cancer (NSCLC) relapse within 5 years after surgery. Therefore, it is necessary to identify a robust and reliable prognostic signature for early‐stage NSCLC. Immunohistochemistry data from 147 patients with stage I lung adenocarcinoma (stage I‐LUAD) were analyzed for the protein expression of base excision repair (BER), stimulator of interferon genes (STING) and tumor‐infiltrating lymphocytes (TIL) to explore the relationship between protein expression and prognosis. A prediction model was further established by nomogram and externally verified using The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. XRCC1 and H2AX are negative prognostic markers for relapse‐free survival (RFS), while CD8, CD20 and STING are positive prognostic markers for RFS. Nomograms for RFS share common prognostic markers, including XRCC1, H2AX, STING, CD8 and CD20. The c‐index was 0.724 and 0.698 in the training cohort and the internal validation cohort, respectively. It was externally verified that the nomogram model had a good prediction for recurrence of stage I‐LUAD. Correlation analysis showed that APE1 and H2AX were negatively correlated with STING, while STING was positively correlated with TIL. BER, the STING pathway and TIL were associated with early recurrence and were correlated with the tissue expression of stage I‐LUAD. Our nomogram model was a good predictor for recurrence of stage I‐LUAD.
Cancer‐associated mutations in normal human endometrium: Surprise or expected?
Authors: Kyo Satoru , Sato Seiya , Nakayama Kentaro 
Published: July 2020

AbstractThe human endometrium is an essential component in human reproduction that has the unique characteristic of undergoing cyclic regeneration during each menstrual cycle. Vigorous regeneration after shedding may be sustained by stem/progenitor cells, for which molecular markers have not been fully identified. Although clonality analysis using X chromosome inactivation patterns has shown that normal human endometrial glands are composed of a monoclonal cell population, whether clonal expansion is derived from stem/progenitor cells remains unclear. Remarkable advances in next‐generation sequencing technology over the past decade have enabled somatic mutations to be detected in not only cancers, but also normal solid tissues. Unexpectedly frequent cancer‐associated mutations have been detected in a variety of normal tissues, and recent studies have clarified the mutational landscape of normal human endometrium. In epithelial glandular cells, representative cancer‐associated mutations are frequently observed in an age‐dependent manner, presumably leading to growth advantage. However, the extremely high mutation loads attributed to DNA mismatch repair deficiency and POLE mutations, as well as structural and copy number alterations, are specific to endometrial cancer, not to normal epithelial cells. The malignant conversion of normal epithelial cells requires these additional genetic hits, which are presumably accumulated during aging, and may therefore be a rare life event. These discoveries could be expected to shed light on the physiology and pathogenesis of the human endometrium and urge caution against the application of genetic screening for the early detection of endometrial cancer.
The recent challenges of highly contagious COVID‐19, causing respiratory infections: Symptoms, diagnosis, transmission, possible vaccines, animal models, and immunotherapy
Authors: Mohapatra Ranjan K. , Pintilie Lucia , Kandi Venkataramana , Sarangi Ashish K. , Das Debadutta , Sahu Raghaba , Perekhoda Lina 
Published: July 2020

AbstractCOVID‐19 is highly contagious pathogenic viral infection initiated from Wuhan seafood wholesale market of China on December 2019 and spread rapidly around the whole world due to onward transmission. This recent outbreak of novel coronavirus (CoV) was believed to be originated from bats and causing respiratory infections such as common cold, dry cough, fever, headache, dyspnea, pneumonia, and finally Severe Acute Respiratory Syndrome (SARS) in humans. For this widespread zoonotic virus, human‐to‐human transmission has resulted in nearly 83 lakh cases in 213 countries and territories with 4,50,686 deaths as on 19 June 2020. This review presents a report on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel virus and will provide ample references for the researchers toward the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.
Icaritin activates Nrf2/Keap1 signaling to protect neuronal cells from oxidative stress
Authors: Xu Yuyu , Lu Xiaoyan , Zhang Li , Wang Lijuan , Zhang Guimin , Yao Jingchun , Sun Chenghong 
Published: July 2020

AbstractOur earlier study indicated that icaritin (ICT) protected mice from cerebral ischemic injury by inhibiting oxidative stress, and this study aimed to investigate its mechanism using a H2O2‐treated SH‐SY5Y cells model. Cell viability was assessed by cell counting kit 8 (CCK‐8). Oxidative stress parameters were detected by flow cytometry, and signaling pathways were analyzed by immunoblotting. We found that ICT alleviated apoptosis and intracellular and mitochondrial reactive oxygen species (ROS) levels, decreased the expressions of Bax and cleaved caspase‐3, and increased the expressions of Bcl‐2 compared to H2O2 group. ICT increased mitochondrial membrane potential (ΔΨm) and blocked the opening of mitochondrial membrane permeability transporter (MPT), and increased the activity of glutathione peroxidase (GSH‐px), catalase (CAT), and superoxide dismutase (SOD), meanwhile, decreased the activity of malondialdehyde (MDA) compared to H2O2 group. Further investigation revealed that ICT significantly up‐regulated the expressions of nuclear factor erythroid 2‐related factor 2 (Nrf2), heme oxygenase 1 (HO‐1) and NAD(P)H‐quinone oxidoreductase 1 (NQO‐1). The anti‐apoptosis and antioxidative effects of ICT were blocked bay ML385, a Nrf2/Keap1 signaling pathway inhibitor. These results indicate that ICT can play a neuroprotective role against oxidative stress injury by activating Nrf2/Keap1 signaling pathway.
Comprehensive flow cytometric reference intervals of leukocyte subsets from six study centers across Europe
Authors: Oras A , Quirant-Sanchez B , Popadic D , Thunberg S , Winqvist O , Heck S , Cwikowski M , Riemann D , Seliger B , Martinez Caceres E , Uibo R , Giese T 
Published: July 2020

Summary
A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/Treg/B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical–diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers.
Static computer‐aided, partially guided, and free‐handed implant placement: A systematic review and meta‐analysis of randomized controlled trials
Authors: Tattan Mustafa , Chambrone Leandro , González‐Martín Oscar , Avila‐Ortiz Gustavo 
Published: July 2020

AbstractObjectiveTo analyze the outcomes of static computer‐aided implant placement (sCAIP) compared to partially guided (PGIP) and free‐handed (FHIP) implant placement.Material and MethodsThis study was registered in PROSPERO (CRD42019131397). A comprehensive literature search was performed by two independent examiners. Only randomized controlled trials (RCTs) were selected. Treatment modalities included sCAIP, PGIP, and FHIP. Data pertaining to the outcomes of interest were extracted. Random‐effects meta‐analyses were feasible for a subset of outcomes.ResultsFrom an initial list of 2,870 records, fourteen articles for a total of ten RCTs were selected. Data from 7 of these studies allowed for the conduction of three meta‐analyses comparing accuracy of implant placement across modalities. Survival rate up to 12 months post‐loading was high (>98%) and comparable between treatments (low‐quality evidence). No tangible differences in terms of patient perception of intra‐ or postoperative discomfort were observed (low‐quality evidence). Quantitative analyses revealed significantly lower angular (MD = 4.41°, 95% CI 3.99–4.83, p < .00001), coronal (MD = 0.65 mm, 95% CI 0.50–0.79, p < .00001), and apical (MD = 1.13 mm, 95% CI 0.92–1.34, p < .00001) deviation values for sCAIP as compared to FHIP (8 studies, 383 patients, 878 implants, high‐quality evidence). A similar discrepancy, in favor of sCAIP, was observed for angular deviation only as compared to PGIP (MD = 2.11°, 95% CI 1.06–3.16, p < .00001).ConclusionssCAIP is associated with superior accuracy compared to PGIP and FHIP.