bluuebunny/crossref_metadata_2025_split huggingface dataset:
High throughput solubility and redissolution screening for antibody purification via combinedPEGand zinc chloride precipitation
Authors: Gu Qin , Li Zhao , Coffman Jonathan L. , Przybycien Todd M. , Zydney Andrew L. 
Published: June 2020

AbstractAs upstream product titers increase, the downstream chromatographic capture step has become a significant “downstream bottleneck.” Precipitation becomes more attractive under these conditions as the supersaturation driving force increases with the ever‐increasing titer. In this study, two precipitating reagents with orthogonal mechanisms, polyethylene glycol (PEG) as a volume excluder and zinc chloride (ZnCl2) as a cross linker, were examined as precipitants for two monoclonal antibodies (mAbs), one stable and the other aggregation‐prone, in purified drug substance and harvested cell culture fluid forms. Manual batch solubility and redissolution experiments were performed as scouting experiments. A high throughput (HTP) liquid handling system was used to investigate the design space as fully as possible while reducing time, labor, and material requirements. Precipitation and redissolution were studied by systematically varying the concentrations of PEG and ZnCl2to identify combinations that resulted in high yield and good quality for the stable mAb; PEG concentrations in the range 7–7.5 wt/vol% together with 10 mM ZnCl2gave a yield of 97% and monomer contents of about 93%. While yield for the unstable mAb was high, quality was not acceptable. Performance at selected conditions was further corroborated for the stable mAb using a continuous tubular precipitation reactor at the laboratory scale. The HTP automation system was a powerful tool for locating desired (customized) conditions for antibodies of different physicochemical properties.
Genetic risk factors for lumbar disc disease
Authors: Doraisamy Ravichandran , Ramaswami Karthikeyan , Shanmugam Jeevithan , Subramanian Rashmi , Sivashankaran Balasubramanian 
Published: June 2020

AbstractAim and BackgroundLumbar disc degeneration (LDD) is thought to be multifactorial in origin. Very recently the focus has shifted to the involvement of a family of candidate genes in the pathogenesis of LDD. There is particular emphasis on the vitamin D receptor gene (VDR gene). The VDR polymorphisms FOK1, TAQ1, and APO1 have been variably associated with LDD.ObjectiveTo evaluate the association between the FOK1/Taq1 genes and LDD.Materials and MethodsOne hundred unrelated healthy (asymptomatic) individuals who presented for routine health checkup and 93 consecutive patients (43 males and 50 females) with no history of low back pain were enrolled in the study after informed consent was obtained. The MRI images of cases and controls were graded and peripheral blood samples were collected from all participants and sent for genetic analysis.ResultsIndividuals with the dominant genotype for Taq1 had a significantly higher association with LDD than those without it. There was no association between LDD and the Fok1 genotype.ConclusionGenetic predisposition is an important risk factor for LDD.
The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial
Authors: Zhao Qun , Lian Changhong , Huo Zhibin , Li Ming , Liu Yang , Fan Liqiao , Tan Bibo , Zhao Xuefeng , Zhang Zhidong , Wang Dong , Liu Yu , Guo Honghai , Yang Peigang , Tian Yuan , Li Yong 
Published: June 2020

AbstractObjectivesExploring the efficacy and safety of perioperative chemotherapy on patients with AGC at different clinical and pathological stages.MethodsA phase III randomized, multicenter, trial comparing adjuvant (arm A) or perioperative S‐1 plus oxaliplatin (SOX, arm B), and perioperative capecitabine plus oxaliplatin (XELOX, arm C) was initiated in T3/4, node + gastric cancer patients (unclear). Each patient received an 8‐cycle chemotherapy (3 weeks for one cycle). Group arms B and C received two cycles preoperatively, and six cycles postoperatively. Primary endpoints were R0 resection rate and DFS, and secondary endpoints included OS, ORR, DCR, and safety. This study was registered on Clinicaltrials.gov. NCT01516944.ResultsA total of 749 patients were randomly assigned into groups A, B, and C. Group A received 1460 circles chemotherapy and group B received 1177 circles while group C received 1200 circles. R0 resection rates in the three groups were 81.7%, 88.7%, and 83.1%, respectively. The difference between groups A and B was considered to be statistically significant (P = .018), and no significant difference between groups B and C (P = .051). Hazard ratio were compared between groups B and C and DFS showed 0.72 (0.67‐0.77 with 95% CI), Pnon‐inferiority < .0001, Plog‐rank = .064). The CI top limit actually lower than the estimated value of 1.38, which indicated noninferiority of SOX to XELOX.ConclusionsCompared with PAC, perioperative chemotherapy showed a significant improvement in R0 resection rates and prognosis in AGC patients with higher safety rates. This study was powered to show superiority of perioperative over adjuvant SOX, and noninferiority of SOX to XELOX. Volume measurement, repeated laparoscopic exploration combined with exfoliative cytology can be used as a supplementary method in the clinical staging and efficacy evaluation of AGC.
The effectiveness of chemotherapy for patients with pT3N0M0 renal pelvic urothelial carcinomas: An inverse probability of treatment weighting comparison using Surveillance, Epidemiology, and End Results data
Authors: Liu Zefu , Huang Jialing , Li Xiangdong , Huang Chaowen , Ye Yunlin , Zhang Jinxin , Liu Zhouwei 
Published: June 2020

AbstractIntroductionUnlike the established evidence to use chemotherapy for urothelial carcinoma of the bladder, presently there are insufficient data to inform a recommendation on upper urinary tract urothelial carcinoma treatment. The prognosis for patients with stage T4 and positive lymph nodes is poor; however, primary tumors in the renal pelvis are associated with favorable prognoses compared to those located in the ureter. Our study aimed at investigating the effectiveness of chemotherapy in patients with pT3N0M0 renal pelvic urothelial carcinomas (RPUC) who have relative favorable prognosis.MethodsPatients with pT3N0M0 tumors who underwent radical nephroureterectomy combined with bladder cuff excision between 2005 and 2014 and registered in the Surveillance, Epidemiology, and End Results database were eligible for inclusion (n = 939). Baseline characteristics between the chemotherapy and observation groups were controlled for with inverse probability of treatment weighting (IPTW)‐adjusted analysis.ResultsAfter the IPTW‐adjusted analysis, the 5‐year IPTW‐adjusted rates of overall survival (OS) for the chemotherapy and observation groups were 53.1% and 44.9%, respectively. The IPTW‐adjusted Kaplan‐Meier curves suggested that chemotherapy was associated with increased OS compared with observation (P = .028). In the IPTW‐adjusted Cox proportional hazards regression model, chemotherapy was associated with favorable survival benefits compared with observation (hazard ratio [HR] 0.71, 95% CI 0.52‐0.92, P = .031), and this was maintained after bootstrapping (HR 0.72, 95% CI 0.49‐0.93). Chemotherapy had a protective effect on OS benefits, which were found in a majority of the results of the subgroup analysis and were consistent with the main results (all P‐interactions > 0.05).ConclusionChemotherapy may provide significant OS benefits for patients with pT3N0M0 RPUC. The results of our study could strengthen the evidence for using adjuvant chemotherapy in this rare group of patients.
Development and Validation of a Paediatric Abusive Head Trauma Awareness Questionnaire for Healthcare Professionals: A Two‐Stage Questionnaire Development Study
Authors: Chen Yi‐Wen , Feng Jui‐Ying 
Published: June 2020

This two‐stage study aimed to develop and validate a paediatric abusive head trauma (AHT) awareness questionnaire for healthcare professionals. In stage one, an item pool was created for the AHT awareness questionnaire. Four experts assessed the content validity. Test–retest reliability and internal consistency were examined using a pilot study of 24 healthcare professionals. In stage two, 302 healthcare professionals from a medical centre in southern Taiwan were recruited to establish the questionnaire's psychometric properties. The final version of the questionnaire comprised 81 items, including demographics, attitudes towards childrearing and four sub‐concepts on AHT awareness (infant crying, soothing skills, clinical manifestations and consequences of AHT, and risk factors of AHT). The content validity of the questionnaire was satisfactory with a score of 0.91 to 1.0 for the scale content validity index. The test–retest reliability was 0.51–0.71. Cronbach's alphas for the final sample were 0.52–0.93 for the four subscales. Exploratory factor analysis extracted two factors as risk factors of AHT with a total explained variance of 55.9 per cent. This questionnaire is useful in understanding AHT awareness with identified aspects among healthcare professionals and other professionals working in child protection fields. Items and subscales of the AHT awareness questionnaire could act as a reference guide for future training programmes.‘This two‐stage study aimed to develop and validate a paediatric abusive head trauma (AHT) awareness questionnaire for healthcare professionals’Key Practitioner Messages

We developed and validated a questionnaire to assess healthcare professionals' awareness of paediatric AHT.
This is the first instrument developed to measure healthcare professionals' awareness of paediatric AHT with acceptable psychometric properties for use in Taiwan.
The questionnaire can be used to understand healthcare professionals' awareness of paediatric AHT.
This questionnaire may also be used to explore other professionals' awareness of paediatric AHT and to design related education programmes.
A Hydroxyquinoline‐Based Unnatural Amino Acid for the Design of Novel Artificial Metalloenzymes
Authors: Drienovská Ivana , Scheele Remkes A. , Gutiérrez de Souza Cora , Roelfes Gerard 
Published: June 2020

AbstractWe have examined the potential of the noncanonical amino acid (8‐hydroxyquinolin‐3‐yl)alanine (HQAla) for the design of artificial metalloenzymes. HQAla, a versatile chelator of late transition metals, was introduced into the lactococcal multidrug‐resistance regulator (LmrR) by stop codon suppression methodology. LmrR_HQAla was shown to complex efficiently with three different metal ions, CuII, ZnII and RhIII to form unique artificial metalloenzymes. The catalytic potential of the CuII‐bound LmrR_HQAla enzyme was shown through its ability to catalyse asymmetric Friedel‐Craft alkylation and water addition, whereas the ZnII‐coupled enzyme was shown to mimic natural Zn hydrolase activity.
Association between surgical risk and 30‐day stroke after transcatheter versus surgical aortic valve replacement: a systematic review and meta‐analysis
Authors: Matsuda Yuji , Nai Fovino Luca , Giacoppo Daniele , Scotti Andrea , Massussi Mauro , Ueshima Daisuke , Sasano Tetsuo , Fabris Tommaso , Tarantini Giuseppe 
Published: June 2020

AbstractBackgroundStroke is a feared complication of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR).ObjectivesWith this meta‐analysis we aimed to evaluate the incidence of 30‐day stroke with TAVR and SAVR focusing on its possible correlation with surgical risk.MethodsMajor electronic databases were searched for studies published between January 2002 and October 2019 reporting the rates of 30‐day stroke after TAVR and SAVR. Data were pooled using fixed‐ and random‐effects models. The primary outcome of the study was stroke rate within 30‐day from TAVR or SAVR. Results were stratified according to surgical risk score (high, intermediate and low).ResultsA total of 23 studies were identified (TAVR: 14,589 patients; SAVR: 11,681 patients). Regardless of the model used, in the overall population TAVR was associated with a significant reduction in the risk of stroke compared with SAVR (fixed effect: OR 0.78, 95% CI 0.66–0.92, p = .003; random‐effects: OR 0.80, 95% CI 0.64–1.00, p = .045). Rates of 30‐day stroke after TAVR and SAVR were not significantly different in the high‐ (OR 1.01, 95% CI 0.44–1.98, p = .105) and intermediate‐risk groups (OR 0.92, 95% CI 0.63–1.36, p = .319), while low‐risk patients had a lower rate of 30‐day stroke after TAVR than SAVR (OR 0.65, 95% CI 0.50–0.83, p < .001). Meta‐regression showed a significant association between surgical risk score and 30‐day stroke rate (p = .007).ConclusionsTAVR is associated with a lower risk of 30‐day stroke compared with SAVR, mainly as a result of the significant advantage observed in patients at low surgical risk.
Robotic telestenting performance in transcontinental and regional pre‐clinical models
Authors: Madder Ryan D. , VanOosterhout Stacie , Parker Jessica , Sconzert Kalyna , Li Yao , Kottenstette Nicholas , Madsen Abigail , Sungur John‐Michael , Bergman Per 
Published: June 2020

AbstractObjectivesThis study was conducted to evaluate the association of geographic distance with robotic telestenting performance by comparing performance measures in transcontinental and regional pre‐clinical models of telestenting.BackgroundRobotic telestenting, in which percutaneous coronary intervention (PCI) is performed on a remotely located patient, might improve PCI access, but has not been attempted over vast distances likely required to reach many underserved regions.MethodsTelestenting performance was compared in regional (Boston to New York [206 miles]) and transcontinental (Boston to San Francisco [3,085 miles]) ex vivo models of telestenting, wherein a physician in Boston attempted robotic PCI on endovascular simulators in New York and San Francisco, respectively. PCI was attempted over both wired and fifth generation (5G)‐wireless networks. Outcome measures included procedural success, procedural time, and perceived latency.ResultsProcedural success was achieved in 20 consecutive target lesions in the regional model and in 16 consecutive target lesions in the transcontinental model. The transcontinental model had a greater latency than the regional model over both wired (121.5 ± 2.4 ms vs. 67.8 ± 0.9 ms; p < .001) and 5G‐wireless networks (162.5 ± 1.1 ms vs. 86.6 ± 0.6 ms; p < .001), but perceived latencies were graded “imperceptible” in all cases in both models. Transcontinental and regional models did not have significantly different procedural times over wired (4.1 ± 1.9 min vs. 9.0 ± 7.1 min; p = .051) or 5G‐wireless (3.0 ± 0.6 vs. 6.3 ± 1.2; p = .36) networks.ConclusionsTranscontinental robotic manipulation of coronary devices is now possible and was not associated with adverse performance compared to robotic telestenting conducted regionally.
Distributed Control Strategy with Smith's Predictor in a Pilot‐Scale Diabatic Distillation Unit
Authors: Zierhut Elton Joao , Battisti Rodrigo , Machado Ricardo Antonio Francisco , Marangoni Cintia 
Published: June 2020

AbstractIntrinsic characteristics of distillation such as dead time and high nonlinearities do not allow the complete elimination of transient times when any external disturbance or set‐point change occurs. Thus, aiming at the use of easy‐tuning systems, a distributed‐action control in trays of a diabatic distillation unit with Smith's predictor was implemented in the Simulink environment to further reduce transient times and out‐of‐specification product. The distributed‐action strategy with Smith's predictor led to a reduction of 33.3 min (33 %) in the transient time of the top temperature control loop and 66 % in out‐of‐specification product, when compared with the conventional strategy, and thus is shown to be an efficient approach to increasing the productivity of distillation plants.
Atmospheric Oxygen Mediated Radical Hydrothiolation of Alkenes
Authors: McCourt Ruairí O. , Scanlan Eoin M. 
Published: June 2020

AbstractA mild, metal‐free, atmospheric oxygen‐mediated radical hydrothiolation of alkenes (and alkyne) is reported. A variety of sulfur containing motifs including alkanethiols, thiophenols and thioacids undergo an atmospheric oxygen‐mediated radical hydrothiolation reaction with a plethora of alkenes in good yield with excellent functional group compatibility, typically with short reaction times to furnish a range of functionalized products. Biomolecules proved tolerant to the conditions and the procedure is robust and easily executable requiring no specialized equipment. Concise mechanistic studies confirm the process proceeds through radical intermediates in a thiol‐ene reaction manifold. The methodology offers an efficient “green” approach for thiol‐ene mediated “click” ligation and a milder alternative to thermally initiated hydrothiolation processes.
Doxycycline as an initial treatment of bullous pemphigoid in Japanese patients
Authors: Kimura Kiyoto , Kawai Kazuhiro 
Published: June 2020

AbstractObjectivesTetracycline antibiotics have been used in bullous pemphigoid (BP) for their anti‐inflammatory effects. In Japan, tetracycline and minocycline, but not doxycycline, have been generally used in BP, although doxycycline has a better side‐effect profile than other tetracycline antibiotics. To determine the effectiveness and safety of doxycycline in Japanese BP patients, we performed a retrospective cohort study.MethodsWe analyzed 27 Japanese BP patients in whom doxycycline was used as a first‐line treatment at Kido Hospital between April 1, 2014, and August 31, 2019. We estimated time to prednisolone treatment as a primary measure of effectiveness of doxycycline, because second‐line prednisolone treatment was initiated when each physician judged that disease activity could not be controlled with doxycycline alone.ResultsDuring the median follow‐up of 63 weeks, second‐line prednisolone treatment was initiated in 22 of 27 patients. Median time to prednisolone treatment was 7 weeks. Severe disease based on the Bullous Pemphigoid Disease Area Index (BPDAI) and eosinophilia were the risk factors for prednisolone treatment. At 6 weeks, 14 of 27 patients were under doxycycline treatment without prednisolone, and significant decreases of BPDAI scores were achieved. In 9 of these 14 patients, prednisolone treatment was started after 6 weeks, but the recurrent or mild remaining lesions could be controlled with relatively low‐dose prednisolone in combination with doxycycline. No severe adverse events related to doxycycline occurred.ConclusionsDoxycycline has short‐term effectiveness, potential corticosteroid‐sparing effect, and long‐term safety in Japanese BP patients with mild to moderate disease and no eosinophilia.
Rationally Designed Polypharmacology: α‐Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl‐1 and HDM2
Authors: Conlon Ivie L. , Drennen Brandon , Lanning Maryanna E. , Hughes Samuel , Rothhaas Rebecca , Wilder Paul T. , MacKerell Alexander D. , Fletcher Steven 
Published: June 2020

AbstractProtein–protein interactions (PPIs), many of which are dominated by α‐helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl‐2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl‐2 pro‐life proteins, such as Mcl‐1, and pro‐death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor‐suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl‐1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl‐1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl‐1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α‐helical domains of their partner proteins.
Biomarker‐driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum‐based chemotherapy
Authors: Park Sehhoon , Shim Joonho , Mortimer Peter G. S. , Smith Simon A. , Godin Robert E. , Hollingsworth Simon J. , Kim Hee‐Jung , Jung Hyun Ae , Sun Jong‐Mu , Park Woong‐Yang , Ahn Jin Seok , Ahn Myung‐Ju , Lee Se‐Hoon , Park Keunchil 
Published: June 2020

BackgroundA high percentage of small cell lung cancer (SCLC) cases harbor cell cycle–related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker‐driven, multiarm umbrella study.MethodsThe SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co‐alterations were allocated to adavosertib (SUKSES protocol C [SUKSES‐C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES‐D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non–biomarker‐selected arm: adavosertib (SUKSES‐N1; 21 patients) or AZD2811NP (SUKSES‐N3; 15 patients).ResultsPatients in the SUKSES‐C and SUKSES‐N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES‐C and 6 patients in SUKSES‐N1. The median progression‐free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES‐C and 1.2 months (95% CI, 1.1‐1.4 months) for SUKSES‐N1. Patients in the SUKSES‐D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES‐N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9‐1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES‐C and SUKSES‐N1 arms and 50.0% in the SUKSES‐D arm. Target‐related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule.ConclusionsTo the best of the authors' knowledge, the current study is the first biomarker‐driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.
A Joint Action in Times of Pandemic: The German BioImaging Recommendations for Operating Imaging Core Facilities During the SARS‐Cov‐2 Emergency
Authors: Dietzel Steffen , Ferrando‐May Elisa , Fried Hans , Kukat Christian , Naumann Angela , Nitschke Roland , Pasierbek Pawel , Peychl Jan , Rasse Tobias Manuel , Schroth‐Diez Britta , Stöckl Martin Thomas , Terjung Stefan , Thuenauer Roland , Tulok Silke , Weidtkamp‐Peters Stefanie ,   German BioImaging‐Society for Microscopy and Image Analysis
Published: June 2020

AbstractOperating shared resource laboratories (SRLs) in times of pandemic is a challenge for research institutions. In a multiuser, high‐turnover working space, the transmission of infectious agents is difficult to control. To address this challenge, imaging core facility managers being members of German BioImaging discussed how shared microscopes could be operated with minimal risk of spreading SARS‐CoV‐2 between users and staff. Here, we describe the resulting guidelines and explain their rationale, with a focus on separating users in space and time, protective face masks, and keeping surfaces virus‐free. These recommendations may prove useful for other types of SRLs. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals LLC. on behalf of International Society for Advancement of Cytometry.