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Lei Gao,1,2 Ruo-Wen Chen,2 John P Williams,3 Tong Li,4 Wei-Jiang Han,5 Qian-Nan Zhao,2 Yong Wang,2 Jian-Xiong An1,2 1Department of Anesthesiology, Weifang Medical University, Weifang City 261000, Shangdong, People’s Republic of China; 2Department of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, 100012, People’s Republic of China; 3Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; 4Department of Pain, Lanzhou Maternity and Child Healthcare Hospital, Lanzhou, 730030, People’s Republic of China; 5Department of Pain, Xishuangbanna Dai Nationality Autonomous Prefecture People’s Hospital, Xishuangbanna, 666100, People’s Republic of ChinaCorrespondence: Jian-Xiong AnDepartment of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beiyuan Road 3, Beijing 100012, People’s Republic of ChinaTel +86 138 0128 1750Fax +86 10 5952 0393Email anjianxiong@yeah.netBackground: Ozone injection around Gasserian ganglion (OIAGG) has been reported to be an effective treatment for trigeminal neuralgia (TN); however, there remain areas for improvement. To overcome one of these limitations, a multicenter examination of application would be extremely helpful.Objective: The goal of this report was to assess the efficacy of OIAGG for refractory TN across multiple centers and to explore factors predictive of successful treatment.Design: A multicenter, retrospective study.Setting: The study was conducted across 3 pain centers across China.Patients and Methods: A total of 103 subjects from 3 pain centers were enrolled in the study. An ozone-oxygen mixture gas at a concentration of 30 μg/mL was injected into the area around the Gasserian ganglion performed under C-arm X-ray guidance. Primary outcome measures included a pain assessment using a visual analog scale (VAS) and the Barrow Neurological Institute (BNI) pain intensity scale. Clinical assessment of patients for these outcome measures was performed at pretreatment, post-treatment, 6 months, 1 year and 2 years after the OIAGG.Results: Successful pain relief was defined as a score within BNI grades I–IIIa. The pain relief rates at post-treatment, 6 months, 1 year and 2 years after the procedure were 88.35%, 86.87%, 84.46% and 83.30%, respectively. The VAS at each observation time point was significantly different from the preoperative levels (P< 0.05). Logistic regression analysis showed that previous nerve damage had a significant effect on the treatment results. No significant complications or side effects were found during or after treatment.Conclusion: This multicenter research confirms our previous single center results that OIAGG is both effective and safe for patients with TN.Keywords: trigeminal neuralgia, trigeminal post-herpetic neuralgia, ozone therapy, Gasserian ganglion

Sha-Sha He,1,* Cheng-Tao Wang,1,* Zhen-Wei Peng,1,* Yu-Feng Ren,1 Li-Xia Lu,2 Rui-Wan Chen,1 Shao-Bo Liang,2,3 Yan Wang,1 Yong Chen11Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510080, People’s Republic of China; 3Department of Radiation Oncology, The First People’s Hospital of Foshan, Foshan, Guangdong 510080, People’s Republic of China*These authors contributed equally to this workObjective: To facilitate decision-making support for individual patients, development and external validation of a nomogram was undertaken to reveal prognostic factors and predict the value of concurrent chemoradiotherapy (CCRT) compared with radiotherapy (RT) for stage-II nasopharyngeal carcinoma (NPC) patients.Methods: Clinical data of 419 and 309 patients with American Joint Committee on Cancer (2017) stage-II NPC in two institutions in China were collected retrospectively. Overall survival (OS) and progression-free survival were compared using Kaplan–Meier estimates. Cox regression analysis was used to identify the prognostic factors for building the nomogram. Predictive accuracy and discriminative ability were measured using the Concordance Index.Results: Finally, there were 24 and 20 deaths in the development and validation group, respectively. Patients with stage T2N1, N1 stage, involvement of retropharyngeal and unilateral cervical lymph nodes, and who had RT alone had worse OS (P=0.019, 0.035, 0.003 and 0.010, respectively; log-rank test) than patients with stage T1N1 and T2N0, N0 stage, involvement of retropharyngeal or unilateral cervical lymph nodes, and CCRT, respectively. After multivariate analysis of the training set, age, neutrophil-to-lymphocyte ratio, therapy type, and pretreatment plasma concentration of Epstein–Barr virus DNA were independent prognostic factors of OS. A nomogram was established externally by involving all the factors stated above. The Concordance Index for the established nomogram to predict the OS of the training set was 0.793 (95% CI 0.689–0.897), and 0.803 (95% CI 0.696–0.910) in the validation set.Conclusion: These data suggest that the nomogram was validated externally, could predict long-term outcome accurately, and enable accurate stratification of risk groups for stage-II NPC. Our model facilitated individualized care of NPC patients.Keywords: chemotherapy, nasopharyngeal carcinoma, nomogram, prognosis, radiotherapy

Ruiwan Chen,1,* Chengtao Wang,1,* Yu Zhou,2,* Bixiu Wen1 1Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; 2Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China *These authors contributed equally to this work Introduction: To evaluate the prognostic value of circulating Epstein-Barr virus DNA for extranodal natural killer/T-Cell lymphoma, nasal type (ENKTL), we performed a meta-analysis of published studies that provided survival information with pre-/post-treatment circulating EBV DNA.Methods: Eligible studies that discussed prognostic significance of circulating EBV DNA in ENKTL were included. Random effects models were applied to obtain the estimated hazard ratios and 95% confidence intervals to evaluate prognostic significance (OS and DFS/PFS). Eleven studies covering a total of 562 subjects were included in this analysis.Results: The summary HRs and 95% CIs of pre-treatment EBV DNA for OS and PFS/DFS were 4.43 (95% CI 2.66–7.39, P

Jian-Xiong An,1,2 Hui Liu,1 Ruo-Wen Chen,1,2 Yong Wang,1 Wen-Xing Zhao,1 Derek Eastwood,3 John P Williams4 1Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University & Beijing Institute of Translational Medicine, Chinese Academy of Sciences, 2Department of Anesthesiology, Weifang Medical University, Beijing, People’s Republic of China; 3Department of Pain Services, Wirral University Teaching Hospital, Wirral, Merseyside, UK; 4Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Objective: The aim of this study was to evaluate the therapeutic effect of computed tomography (CT)-guided percutaneous ozone injection for refractory trigeminal neuralgia. Design: A retrospective evaluation was performed in the study. Setting: The study was conducted at a university hospital pain center. Patients and methods: A total of 29 patients with a clinical diagnosis of refractory trigeminal neuralgia were enrolled. All patients were treated with a percutaneous ozone injection and one patient was excluded. There were 21 patients with classical trigeminal neuralgia (group A) and seven patients with painful trigeminal neuropathy caused by post-herpetic neuralgia (group B). The percutaneous injection was an oxygen–ozone mixture at an ozone concentration of 30 mg/­mL into the Gasserian ganglion performed under CT guidance. The number of ­procedures performed varied from one to as many as 16. Outcomes were evaluated using visual analog scale (VAS) pain scores. Results: The combined VAS scores were 7.11 ± 1.23 pretreatment, 2.86 ± 1.69 posttreatment (P < 0.05) and 3.25 ± 2.01 after 6-month follow-up (P < 0.05). In group A, the VAS scores were 7.10 ± 1.04 pretreatment and 2.90 ± 1.84 posttreatment (P < 0.05). In group B, the VAS scores were 7.14 ± 1.77 pretreatment and 2.71 ± 1.25 posttreatment (P < 0.05). After 6-months follow-up, the VAS score was 3.38 ± 2.18 in group A and 2.86 ± 1.46 in group B, a decrease compared to pretreatment (P < 0.05). VAS of Group A and B showed no difference not only in pretreatment but also in postreatment and follow-up. Conclusion: Percutaneous ozone injection is a safe and effective treatment for patients with refractory trigeminal neuralgia. Keywords: trigeminal neuralgia, percutaneous ozone injection, Gasserian ganglion

Ruo-Wen Chen,1,2 Hui Liu,2 Jian-Xiong An,1,2 Xiao-Yan Qian,2 Yi-De Jiang,2 Doris K Cope,3 John P Williams,3 Rui Zhang,1 Li-Na Sun1 1Department of Anesthesiology, Weifang Medical University, Weifang City, Shandong, 2Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, China; 3Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Objective: The objective of this study was to investigate the effects of electro-acupuncture (EA) and pregabalin on cognition impairment induced by chronic trigeminal neuralgia (TN) in rats. Design: Controlled animal study. Setting: Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University. Subjects: Forty adult male Sprague Dawley rats. Methods: Rats were randomly divided into four groups. The TN model was induced by administration of cobra venom to the left infraorbital nerve. On postoperative day 14, either EA or pregabalin was administered, free behavioral activities were observed. Spatial learning and memory abilities were determined in the Morris water maze. The ultrastructural alterations of the Gasserian ganglion, medulla oblongata and hippocampus were examined by electron microscopy. The changes on long-term potentiation were investigated. Results: After treatment, the exploratory behavior increased and the grooming behavior decreased (P0.05). Vacuolar degeneration in the hippocampal neurons was mild in the EA group, while it was severe in the pregabalin group.Conclusion: EA and pregabalin could alleviate TN induced by cobra venom. EA could also inhibit the cognition deficit induced by TN, while pregabalin could not. Keywords: TN, cognition dysfunction, EA, pregabalin, LTP

Omar Moussa,1 Tahvi Frank,2 Ives A Valenzuela,1 Joah Aliancy,1 Dan Gong,3 Joaquin O De Rojas,4 Lora R Dagi Glass,1 Bryan J Winn,5 George A Cioffi,1 Royce WS Chen1 1Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, USA; 2Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; 3Department of Ophthalmology, Retina Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA; 4Center for Sight, Sarasota, FL, USA; 5Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USACorrespondence: Royce WS Chen, Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 W. 165th St, New York, NY, 10032, USA, Tel +1 212-305-9535, Email rc2631@cumc.columbia.eduPurpose: To evaluate efficacy of a novel risk stratification system in minimizing resident surgical complications and to evaluate whether the system could be used to safely introduce cataract surgery to earlier levels of training.Materials and Methods: This is a retrospective cross-sectional study on 530 non-consecutive cataract cases performed by residents at Columbia University. Risk scores, preoperative best corrected visual acuity (BCVA), intraoperative complications, postoperative day 1 (POD1), and month 1 (POM1) exam findings were tabulated. The relationship between risk scores and POD1 and POM1 BCVA was modeled using linear regression. The relationship between risk scores and complication rates was modeled using logistic regression. Logistic regression was used to model the rates of complications across different levels of training. Rates of complications were compared between diabetic versus non-diabetic patients using t-tests.Results: Risk scores did not have significant association with intraoperative complications. Risk scores were predictive of corneal edema (OR = 1.36, p = 0.0032) and having any POM1 complication (OR = 1.20, p = 0.034). Risk scores were predictive of POD1 (β = 0.13, p < 0.0001) and POM1 (β = 0.057, p = 0.00048) visual acuity. There was no significant association between level of training and rates of intraoperative (p = 0.9) or postoperative complications (p = 0.06). Rates of intraoperative complication trended higher among diabetic patients but was not statistically significant (p = 0.2).Conclusion: Higher risk scores were predictive of prolonged corneal edema but not risk of intraoperative complications. Our risk stratification system allowed us to safely introduce earlier phacoemulsification surgery.Keywords: cataract, cataract risk stratification, resident phacoemulsification surgery

Marlene D Wang, Cecile Truong, Zaid Mammo, Syed Amal Hussnain, Royce WS Chen Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, 10032, USACorrespondence: Royce WS ChenEdward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 W 165th St, New York, NY, 10032, USATel +1 212-342-4570Email Rc2631@cumc.columbia.eduBackground: Biomicroscopy, B-scan ultrasound imaging, and SD-OCT are all modalities used to characterize a posterior vitreous detachment (PVD). Our objective is to assess the precision of the diagnosis of PVD by SS-OCT.Methods: This prospective observational study examines ninety-five eyes of forty-nine patients with biomicroscopy, B-scan ultrasound, and SS-OCT for the presence or absence of a complete PVD. All SS-OCT images were reviewed by two retina specialists (RWSC, ZM). All three diagnostic methods were evaluated for agreement by Cohen’s kappa statistic.Results: The inter-rater reliability between retina specialists reading the SS-OCT images was 97.9% (κ = 0.957). Agreement on PVD status between SS-OCT and biomicroscopy was 85.3% (κ = 0.711). Agreement between SS-OCT and B-scan ultrasound was 83.2% (κ = 0.667). Agreement between B-scan ultrasound and biomicroscopy was 87.4% (κ = 0.743).Conclusion: For the diagnosis of complete PVD, SS-OCT allows for high accuracy and agreement between graders.Keywords: optical coherence tomography, swept source, posterior vitreous detachment

Myocardial fibrosis (MF) is involved in hypertension, myocardial infarction and heart failure. It has been reported that circular RNA (circRNA) is a key regulatory factor of MF progression. In this study, we revealed that circ&#95;0002295 and CXCR2 were elevated, and miR-1287 was reduced in MF patients. Knockdown of circ&#95;0002295 effectively suppressed the proliferation, migration and MF progression. Circ&#95;0002295 was the molecular sponge of miR-12878, and miR-1287 inhibitor reversed the biological functions of circ&#95;0002295 on the myocardial fibrosis. CXCR2 was a target gene of miR-1287, and CXCR2 silencing relieved the impacts of miR-1287 inhibitor on cardiac myofibroblasts. Circ&#95;0002295 promoted MF progression by regulating the miR-1287/CXCR2 axis, providing a possible circRNA-targeted therapy for MF., (© 2023 John Wiley & Sons Australia, Ltd.)

Study Objectives: Opioid-related adverse events (OAEs), including opioid use disorders, overdose, and death, are serious public health concerns. OAEs are often associated with disrupted sleep, but the long-term relationship between poor sleep and subsequent OAE risk remains unknown. This study investigates whether sleep behavior traits are associated with incident OAEs in a large population cohort., Methods: 444 039 participants (mean age ± SD 57 ± 8 years) from the UK Biobank reported their sleep behavior traits (sleep duration, daytime sleepiness, insomnia-like complaints, napping, and chronotype) between 2006 and 2010. The frequency/severity of these traits determined a poor sleep behavior impacts score (0-9). Incident OAEs were obtained from hospitalization records during 12-year median follow-up. Cox proportional hazards models examined the association between sleep and OAEs., Results: Short and long sleep duration, frequent daytime sleepiness, insomnia symptoms, and napping, but not chronotype, were associated with increased OAE risk in fully adjusted models. Compared to the minimal poor sleep behavior impacts group (scores of 0-1), the moderate (4-5) and significant (6-9) groups had hazard ratios of 1.47 (95% confidence interval [1.27, 1.71]), p < 0.001, and 2.19 ([1.82, 2.64], p < 0.001), respectively. The latter risk magnitude is greater than the risk associated with preexisting psychiatric illness or sedative-hypnotic medication use. In participants with moderate/significant poor sleep impacts (vs. minimal), subgroup analysis revealed that age <65 years was associated with a higher OAE risk than in those ≥65 years., Conclusions: Certain sleep behavior traits and overall poor sleep impacts are associated with an increased risk for opioid-related adverse events., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities., (© 2023. The Author(s).)

This study simulated the effects of diving activities on the physiology, enzymatic, and transcriptional responses of Acropora microphthalma. Touching had less impact on Fv/Fm, but a few zooxanthellae were decreased and minor MDA was elevated. Caspase 3 was activated to remove damaged cells, and SOD was increased to alleviate oxidative damage. Under double or triple diving stress, we observed mass loss of zooxanthellae and Fv/Fm, a significant increase in MDA, and SOD, CAT was activated in response to oxidative stress. Transcriptome analyses showed that corals activated immune signaling pathways, anti-oxidation pathways, lysosomal, phagosomal, and cellular autophagy pathways to manage oxidation stress. Moreover, it up-regulated carbohydrate metabolisms, as well as lipopolysaccharide metabolism, glycosphingolipid biosynthesis, photorespiration, amino acid metabolism, and fatty acid beta-oxidation, but down-regulated fatty acid biosynthesis to answer energy insufficiency. This research supported that even in a short time, improper diving activities could have a serious impact on coral health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To validate and use the Chinese Version of the M. D. Anderson Symptom Inventory (MDASI-C) to assess the symptom burden of breast cancer patients in China., Methods: A total of 342 breast cancer patients in China participated in this study. Their symptoms were investigated with the MDASI-C from November 2020 to February 2021, and the reliability and validity of this tool were evaluated, respectively. Cluster analysis and correlation analysis were also performed., Results: The Cronbach's alpha coefficient values of the symptom and interference items were 0.827 and 0.880, respectively. Construct validity revealed a four-factor structure. The Kaiser-Meyer-Olkin value was 0.760. The Karnofsky Performance Status, treatment phase, and cancer stage of the patients were grouped, and the differences of scores within the groups were significant. In addition, the employment status, education level, and age of the patients were significantly correlated with the symptoms. The correlation analysis of the education level of the patients showed that most of the symptoms and interference items were reduced as the education level was increased. The top three symptoms were disturbed sleep (3.10±2.52), difficulty remembering (2.54±2.30), and fatigue (2.24±2.13). The clinical and biochemical indicators such as body mass index and neutral granulocyte lymphocyte ratio had effects on many symptoms. As the patients' BMI increased, the patients' pain, disturbed sleep, and difficulty remembering were aggravated, and numbness was alleviated., Conclusion: The MDASI-C is a reliable and effective assessment tool to evaluate patients with breast cancer in China. The symptoms are related to many clinical and biochemical indicators., (© 2022. Huazhong University of Science and Technology.)

Background: The Hippo pathway is an essential signaling cascade that regulates cell and organ growth. However, there is no consensus about (i) the expression levels of the Hippo signaling core components yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in lung cancer, especially in small cell lung cancer (SCLC), or (ii) their association with the prognosis of patients with SCLC., Methods: We screened relevant articles and identified eligible studies in the PubMed, EMBASE, COCHRANE, and WanFang databases. A combined analysis was performed to investigate (i) the expression levels of the major effectors, YAP and TAZ, in lung cancer and its subsets and (ii) their prognostic role in lung cancer, especially in SCLC., Results: In total, 6 studies related to TAZ and 13 studies concerning YAP were enrolled in this meta-analysis. We found that high TAZ expression was significantly associated with poor overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in the overall population [ P h < 0.001, crude hazard ratio (HR) = 1.629, 95% CI = 1.199-2.214 for TAZ expression; P h = 0.029, adjusted HR = 2.127, 95% CI = 1.307-3.460 for TAZ], the Caucasian population ( P h = 0.043, crude HR = 1.233, 95% CI = 1.030-1.477 for TAZ expression), and the Asian population ( P h = 0.551, adjusted HR = 2.676, 95% CI = 1.798-3.982 for TAZ). Moreover, there was a significant negative association between YAP expression and an unsatisfactory survival of patients with lung cancer ( P h = 0.327, crude HR = 1.652, 95% CI = 1.211-2.253 for YAP expression) and patients with NSCLC [disease-free survival (DFS): Ph = 0.693, crude HR = 2.562, 95% CI = 1.876-3.499 for YAP expression; Ph = 0.920, crude HR = 2.617, 95% CI = 1.690-4.052 for YAP -mRNA; OS: Ph = 0.878, crude HR = 1.777, 95% CI = 1.233-2.562 for YAP expression], especially in the Asian population (DFS: P h = 0.414, crude HR = 2.515, 95% CI = 1.755-3.063; OS: P h = 0.712, crude HR = 1.772, 95% CI = 1.214-2.587). However, no association was observed in the multivariate combined analysis. High YAP expression was significantly associated with short OS of patients with SCLC in our combined multivariate analysis in the Asian population ( P h = 0.289, crude HR = 4.482, 95% CI = 2.182-9.209), but not with crude data ( P h = 0.033, crude HR = 1.654, 95% CI = 0.434-6.300)., Conclusion: The Hippo pathway is involved in carcinogenesis and progression of NSCLC and SCLC, and high expression levels of YAP and TAZ are independent and novel prognostic factors for lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Xie, Chen, You, Ye, Chen, Chen and Xu.)

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A novel thermophilic bacterium, designated SCSIO 07484 T , was isolated from marine sediment sampled in the South China Sea. Growth occurred at 30-60 °C, pH 6.0-8.0 and in the presence of 0-3 % (w/v) NaCl. Cells of strain SCSIO 07484 T were rod-shaped and flagellum-forming. No soluble pigment was observed. The phylogenetic analysis of the 16S rRNA gene sequences indicated that SCSIO 07484 T belonged to the family Paenibacillaceae and clustered with members of the genus Brevibacillus in the phylogenetic trees with less than 96.2 % similarities. The cell wall contained meso -diaminopimelic acid. Whole-cell hydrolysates contained arabinose, glucose and ribose. The predominant menaquinone was MK-7. Major fatty acids were iso-C 16 : 0 , iso-C 15 : 0 , C 16 : 0 and iso-C 14 : 0 . Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylmonomethylethanolamine were its diagnostic polar lipids. The whole genome size of strain SCSIO 07484 T was 4 079 826 bp with a DNA G+C content of 56.2 mol%, including one circular chromosome of 3 978392 bp and one plasmid of 101434 bp. Based on the polyphasic analysis of strain SCSIO 07484 T , it is considered to represent a novel species of the genus Brevibacillus , for which the name Brevibacillus marinus sp. nov. is proposed with the type strain SCSIO 07484 T (=DSM 106769 T =CGMCC 1.15814 T ).

Background: Doxorubicin is a first-line chemotherapy agent on human myelogenous leukemia clinical treatment, but the development of chemoresistance has largely limited curative effect. In this study, we aimed to evaluate the biological function and molecular mechanisms of CrkL to Doxorubicin resistance., Methods: Quantitative reverse transcription-PCR (qRT-PCR) assay was performed to examine the expression of CrkL in K562 and K562/ADR cells. The expression of CrkL was silenced through RNA interference technology. MTT assay and flow cytometry were performed to detect the proliferation inhibition and apoptosis rate after CrkL siRNA transfection. The protein expression changes of PI3K/AKT/MRP1 pathway induced by CrkL siRNA were observed by Western Blot assay. Xenograft tumor model was carried out to observe tumor growth in vivo., Results: We observed that silencing of CrkL could effectively increase apoptosis rate induced by doxorubicin and dramatically reversed doxorubicin resistance in K562/ADR cells. Further studies revealed knockdown CrkL expression suppressed PI3K/Akt/MRP1 signaling, which indicated CrkL siRNA reversed doxorubicin effect through regulating PI3K/Akt/MRP1 pathway. In addition, overexpression of MRP1 could evidently reduce apoptosis rate and reversed the inhibitory effects of doxorubicin resistance caused by CrkL siRNA on K562/ADR cells. Finally, in vivo experiments revealed that CrkL silencing acted a tumor-suppressing role in myelogenous leukemia via regulating PI3K/Akt/MRP1 signaling., Conclusion: Together, we indicated that CrkL is up-regulated in myelogenous leukemia cells and silencing of CrkL could reverse Doxorubicin resistance effectively. These results show a potential novel strategy for intervention chemoresistance in myelogenous leukemia during chemotherapy., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Two novel marine actinobacteria, designated as SCSIO 60955 T and SCSIO 61214 T , were isolated from deep-sea sediment samples collected from the South China Sea. The cells of these organisms stained Gram-negative and were rod shaped. These strains were aerobic, and catalase- and oxidase-positive. Optimal growth occurred at 28 °C and pH 7 over 14 days of cultivation. Both strains possessed phospholipids and phosphoglycolipids. The main menaquinone was MK-7. The major fatty acid was C 16:0 . The peptidoglycan structure was type A1γ' (meso-Dpm). Analysis of genome sequences revealed that the genome size of SCSIO 60955 T was 3.37 Mbp with G + C content of 76.1%, while the genome size of SCSIO 61214 T was 3.67 Mbp with a G + C content of 74.8%. The ANI and 16S rRNA gene analysis results showed that the pairwise similarities between the two strains were 73.4% and 97.7% and that with other recognized Thermoleophilia species were less than 69.1% and 87.8%, respectively. Phylogenetic analysis of the 16S rRNA gene sequences showed that strains SCSIO 60955 T and SCSIO 61214 T were separately clustered together and formed a well-separated phylogenetic branch distinct from their most related neighbor Gaiella occulta. Based on the data presented here, these two strains are proposed to represent two novel species of a novel genus, for which the name Miltoncostaea marina gen. nov., sp. nov., with the type strain SCSIO 60955 T (=DSM 110281 T =CGMCC 1.18757 T ), and Miltoncostaea oceani sp. nov., with the type strain SCSIO 61214 T (=KCTC 49527 T =CGMCC 1.18758 T ) are proposed. We also propose that these organisms represent a novel family named Miltoncostaeaceae fam. nov. of a novel order Miltoncostaeales ord. nov., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Purpose: To identify the role of gender and other factors in influencing ophthalmologists' compensation., Design: Cross-sectional study., Participants: U.S. practicing ophthalmologists., Methods: Between January and March 2020, an anonymous survey was sent to U.S. residency program directors and practicing ophthalmologists who recently completed residency training. Respondents who completed residency ≤ 10 years ago and responded to questions about gender, fellowship training, state of practice, and salary were included. Propensity score match (PSM) analysis was performed with age, academic residency, top residency, fellowship, state median wage, practice type, ethnicity, and number of workdays. Multivariate linear regression (MLR) analysis controlled for additional factors along with the aforementioned variables., Main Outcome Measures: Base starting salary with bonus (SWB) received in the first year of clinical position was the main outcome measure. A multiplier of 1.2 (20%) was added to the base salary to account for bonus., Results: Of 684 respondents, 384 (56% were female, 44% were male) from 68 programs were included. Female ophthalmologists received a mean initial SWB that was $33 139.80 less than that of their male colleagues (12.5%, P = 0.00). The PSM analysis showed an SWB difference of -$27 273.89 (10.3% gap, P = 0.0015). Additionally, SWB differences were calculated with the number of workdays substituted by operating room (OR) days (-$27 793.67 [10.5% gap, P = 0.0013]) and clinic days (-$23 597.57 [8.90% gap, P = 0.0064]) in separate PSM analyses. The SWB differences between genders were significant using MLR analyses, which also controlled for work, clinic, and OR days separately (-$22 261.49, $-18 604.65, and $-16 191.26, respectively; P = 0.017, P = 0.015, P = 0.002, respectively). Gender independently predicted income in all 3 analyses (P < 0.05). Although an association between gender and the attempt to negotiate was not detected, a greater portion of men subjectively reported success in negotiation (P = 0.03)., Conclusions: Female ophthalmologists earn significantly less than their male colleagues in the first year of clinical practice. Salary differences persist after controlling for demographic, educational, and practice type variables with MLR and PSM analyses. These income differences may lead to a substantial loss of accumulated earnings over an individual's career., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Actinobacteria are ubiquitous in marine ecosystems, and they are regarded as an important, underexplored, potential pharmaceutical resource. The orders Gaiellales and Rubrobacterales are deep taxonomic lineages of the phylum Actinobacteria, both are represented by a single genus and contain only a few species. Although they have been detected frequently by high-throughput sequencing, their functions and characteristics in marine habitats remain unknown due to the lack of indigenous phenotypes. Here, we investigated the status of the orders in South China Sea (SCS) sediments using culture-independent and culture-dependent methods. Gaiellales is the second-most abundant order of Actinobacteria and was widely distributed in SCS sediments at water depths of 42-4,280 m, and four novel marine representatives in this group were successfully cultured. Rubrobacterales was present at low abundance in energy-limited marine habitats. An isolation strategy for Rubrobacterales from marine samples was proposed, and a total of 138 mesophilic Rubrobacterales strains were isolated under conditions of light and culture time combined with high-salinity or low-nutrient media. Marine representatives recovered in this study formed branches with a complex evolutionary history in the phylogenetic tree. Overall, the data indicate that both Gaiellales and Rubrobacterales can adapt to and survive in extreme deep-sea environments. This study lays the groundwork for further analysis of the distribution and diversity of the orders Gaiellales and Rubrobacterales in the ocean and provides a specific culture strategy for each group. The results open a window for further research on the ecological roles of the two orders in marine ecosystems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, He, Cui, Li, Shi, Long and Tian.)

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies., Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR)., Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing., Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL., (©2021 American Association for Cancer Research.)

Two novel Gram-stain-positive bacteria, designated as SCSIO 52909 T and SCSIO 52915 T , were isolated from a deep-sea sediment sample collected at about 3448 m water depth of the South China Sea. Phenotypic, chemotaxonomic and genomic characteristics were investigated. These strains were aerobic and tested positive for catalase activity, oxidase activity and nitrate reduction. Optimal growth occurred at 28 °C, pH 7 and 3% salinity over 14 days cultivation. Its peptidoglycan structure was type A3α (l-Lys-l-Ala) and the only menaquinone was MK-8. Both strains possessed diphosphatidylglycerol, phosphatidylglycerol, an unidentified phosphoglycolipid, an unidentified glycolipid and an unidentified phospholipid. Their major fatty acids differed, but both contained iso-branched components of C 16 : 0 12-methyl. Genome sequencing revealed two large genomes of 4.58 Mbp with G+C content of 67.0 mol% in SCSIO 52909 T and of 4.42 Mbp with G+C content of 69.1 % in SCSIO 52915 T . The two novel strains encoded genes for metabolism that are absent in most other Rubrobacter species, and possessed many more gene copy numbers of alkaline phosphatase and thioredoxin reductase. Results of gANI and 16S rRNA gene analyses suggested that the two strains represent two new species, with 74.9, 95.0 % pairwise similarity between each other, and less than 74.3 and 93.5 % to other recognized Rubrobacter species, respectively. In the phylogenetic analysis, strains SCSIO 52909 T and SCSIO 52915 T were separately clustered together and formed a well-separated phylogenetic branch distinct from the other known species in the genus Rubrobacter . Based on the data presented here, these two strains should be recognized as two new species in the genus Rubrobacter , for which the names Rubrobacter tropicus sp. nov., with the type strain SCSIO 52909 T (=KCTC 49412 T =CGMCC 1.13853 T ), and Rubrobacter marinus sp. nov., with the type strain SCSIO 52915 T (=KCTC 49411 T =CGMCC 1.13852 T ), are proposed.

Pivotal trials of beta-blockers (BB) and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in acute myocardial infarction (AMI) were largely conducted prior to the widespread adoption of early revascularization. A total of 15,073 patients with AMI who underwent inhospital coronary revascularization from January 2007 to December 2013 were analyzed. At 12 months, BB was significantly associated with a lower incidence of major adverse cardiovascular events (MACE, adjusted HR 0.80, 95% CI 0.70-0.93) and all-cause mortality (adjusted HR 0.69, 95% CI 0.55-0.88), while ACEI/ARB was significantly associated with lower all-cause mortality (adjusted HR 0.80, 95% CI 0.66-0.98) and heart failure (HF) hospitalization (adjusted HR 0.80, 95% CI 0.68-0.95). Combined BB and ACEI/ARB use was associated with the lowest incidence of MACE (adjusted HR 0.70, 95% CI 0.57-0.86), all-cause mortality (adjusted HR 0.55, 95% CI 0.40-0.77) and HF hospitalization (adjusted HR 0.64, 95% CI 0.48-0.86). This were consistent for left ventricular ejection fraction < 50% or ≥ 50%. In conclusion, in AMI managed with revascularization, both BB and ACEI/ARB were associated with a lower incidence of 12-month all-cause mortality. Combined BB and ACEI/ARB was associated with the lowest incidence of all-cause mortality and HF hospitalization.

BACKGROUNDFrom March 2, 2020, to April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize the COVID-19 impact on NYC resident physicians.METHODSIRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors April 3-12, 2020, encompassing events from March 2, 2020, to April 12, 2020.RESULTSFrom an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2306 residents. In 45.1% of programs, at least 1 resident with confirmed COVID-19 was reported. One hundred one resident physicians were confirmed COVID-19-positive, with an additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. Two COVID-19-positive residents were hospitalized, with 1 in intensive care. Among specialties with more than 100 residents represented, negative binomial regression indicated that infection risk differed by specialty (P = 0.039). In 80% of programs, quarantining a resident was reported. Ninety of 91 programs reported reuse or extended mask use, and 43 programs reported that personal protective equipment (PPE) was suboptimal. Sixty-five programs (74.7%) redeployed residents elsewhere to support COVID-19 efforts.CONCLUSIONMany resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty.FUNDINGNational Eye Institute Core Grant P30EY019007; Research to Prevent Blindness Unrestricted Grant; Parker Family Chair; University of Pennsylvania.

Aims: In patients with bicuspid aortic valve (BAV) and preserved left ventricular (LV) ejection fraction (EF), the frequency of impaired LV global longitudinal strain (GLS) and its prognostic implications are unknown. The present study evaluated the proportion and prognostic value of impaired LV GLS in patients with BAV and preserved LVEF., Methods and Results: Five hundred and thirteen patients (68% men; mean age 44 ± 18 years) with BAV and preserved LVEF (>50%) were divided into five groups according to the type of BAV dysfunction: (i) normal function BAV, (ii) mild aortic stenosis (AS) or aortic regurgitation (AR), (iii) ≥moderate isolated AS, (iv) ≥moderate isolated AR, and (v) ≥moderate mixed AS and AR. LV systolic dysfunction based on 2D speckle-tracking echocardiography was defined as a cut-off value of LVGLS (-13.6%). The primary outcome was aortic valve intervention or all-cause mortality. The proportion of patients with LVGLS ≤-13.6% was the highest in the normal BAV group (97%) and the lowest in the group with moderate and severe mixed AS and AR (79%). During a median follow-up of 10 years, 210 (41%) patients underwent aortic valve replacement and 17 (3%) died. Patients with preserved LV systolic function (LVGLS ≤ -13.6%) had significantly better event-free survival compared to those with impaired LV systolic function (LVGLS > -13.6%). LVGLS was independently associated with increased risk of events (mainly aortic valve replacement): hazard ratio 1.09; P < 0.001., Conclusion: Impaired LVGLS in BAV with preserved LVEF is not infrequent and was independently associated with increased risk of events (mainly aortic valve replacement events)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

A novel marine actinobacterium, strain SCSIO 58843 T , was isolated from the sediment sample collected from the South China Sea. Strain SCSIO 58843 T was Gram-stain-positive, aerobic and rod shaped. The whole-cell hydrolysis of amino acids contained dd-DAP, alanine, glutamic acid, glycine and aspartic acid. The main menaquinone was MK-9(H 8 ). The major fatty acids were C 17 : 1   ω 8c and C 17 : 0 . The major phospholipids were diphosphatidylglycerol (DPG), phosphatidylinositol (PI), phospatidylcholine (PC) and phosphatidylinositolmannoside (PIM). The G+C content of the genomic DNA was 72.5 %. Phylogenetic analysis of the 16S rRNA gene sequences showed that strain SCSIO 58843 T formed a new lineage in the family Iamiaceae and had the highest similarity of 93.8 % with Iamia majanohamensis DSM 19957 T . Strain SCSIO 58843 T can be distinguished from these known genera in the family Iamiaceae by polyphasic data analyses, and represents a novel genus and novel species, for which Actinomarinicola tropica gen. nov., sp. nov is proposed with the type strain SCSIO 58843 T (=KCTC 49408 T =CGMCC 1.17503 T ).

A novel Gram-stain-negative bacterium, designated as SCSIO 06110 T , was isolated from a deep-sea sediment of the West Pacific Ocean. Cells were 0.5-0.8 µm in width and 3.0-4.0 µm in length, spore-forming, rod-shaped with peritrichous flagella. Positive for catalase and urease, negative for oxidase and nitrate reduction. Growth occurred at 15-37 °C, pH 6-9 and 1-5 % (w/v) NaCl, with optimum growth at 28 °C, pH 7 and 3 % (w/v) NaCl. MK-7 was the only menaquinone. The strain possessed diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and two unidentified phospholipids. Iso-C 16 : 0 , iso-C 15 : 0 and iso-C 14 : 0 were the major fatty acids. The novel isolate clustered with genera in the family Paenibacillaceae , but formed a separated branch with the closest relative Chengkuizengella sediminis J15A17 T (91.1 % sequence similarity) when compared in a phylogenetic analysis of 16S rRNA gene sequences. The DNA G+C content of strain SCSIO 06110 T was 38.5 mol%. Based on the polyphasic data presented, a new genus, Longirhabdus gen. nov., is proposed in the family Paenibacillaceae with the type species Longirhabdus pacifica sp. nov. and the type strain SCSIO 06110 T (=DSM 105158 T =CGMCC 1.16550 T ).

Importance: Although almost equal numbers of male and female medical students enter into ophthalmology residency programs, whether they have similar surgical experiences during training is unclear., Objective: To determine differences for cataract surgery and total procedural volume between male and female residents during ophthalmology residency., Design, Setting, Participants: This retrospective, longitudinal analysis of resident case logs from 24 US ophthalmology residency programs spanned July 2005 to June 2017. A total of 1271 residents were included. Data were analyzed from August 12, 2017, through April 4, 2018., Main Outcomes and Measures: Variables analyzed included mean volumes of cataract surgery and total procedures, resident gender, and maternity or paternity leave status., Results: Among the 1271 residents included in the analysis (815 men [64.1%]), being female was associated with performing fewer cataract operations and total procedures. Male residents performed a mean (SD) of 176.7 (66.2) cataract operations, and female residents performed a mean (SD) of 161.7 (56.2) (mean difference, -15.0 [95% CI, -22.2 to -7.8]; P < .001); men performed a mean (SD) of 509.4 (208.6) total procedures and women performed a mean (SD) of 451.3 (158.8) (mean difference, -58.1 [95% CI, -80.2 to -36.0]; P < .001). Eighty-five of 815 male residents (10.4%) and 71 of 456 female residents (15.6%) took parental leave. Male residents who took paternity leave performed a mean of 27.5 (95% CI, 13.3 to 41.6; P < .001) more cataract operations compared with men who did not take leave, but female residents who took maternity leave performed similar numbers of operations as women who did not take leave (mean difference, -2.0 [95% CI, -18.0 to 14.0]; P = .81). From 2005 to 2017, each additional year was associated with a 5.5 (95% CI, 4.4 to 6.7; P < .001) increase in cataract volume and 24.4 (95% CI, 20.9 to 27.8; P < .001) increase in total procedural volume. This increase was not different between genders for cataract procedure volume (β = -1.6 [95% CI, -3.7 to 0.4]; P = .11) but was different for total procedural volume such that the increase in total procedural volume over time for men was greater than that for women (β = -8.0 [95% CI, -14.0 to -2.1]; P = .008)., Conclusions and Relevance: Female residents performed 7.8 to 22.2 fewer cataract operations and 36.0 to 80.2 fewer total procedures compared with their male counterparts from 2005 to 2017, a finding that warrants further exploration to ensure that residents have equivalent surgical training experiences during residency regardless of gender. However, this study included a limited number of programs (24 of 119 [20.2%]). Future research including all ophthalmology residency programs may minimize the selection bias issues present in this study.

The trigeminal nucleus caudalis (TNc) receives extensive afferent innervation from peripheral sensory neurons of the trigeminal ganglion (TG), and is the first central relay in the circuitry underpinning orofacial pain. Despite the initial characterization of the neurons in the superficial laminae, many questions remain. Here we report on electrophysiological properties of 535 superficial lamina I/II TNc neurons. Based on their firing pattern, we assigned these cells to five main groups, including (1) tonic, (2) phasic, (3) delayed, (4) H-current, and (5) tonic-phasic neurons, groups that exhibit distinct intrinsic properties and share some similarity with groups identified in the spinal dorsal horn. Driving predominantly nociceptive TG primary afferents using optogenetic stimulation in TRPV1/ChR2 animals, we found that tonic and H-current cells are most likely to receive pure monosynaptic input, whereas delayed neurons are more likely to exhibit inputs that appear polysynaptic. Finally, for the first time in TNc neurons, we used unsupervised clustering analysis methods and found that the kinetics of the action potentials and other intrinsic properties of these groups differ significantly from one another. Unsupervised spectral clustering based solely on a single voltage response to rheobase current was sufficient to group cells with shared properties independent of action potential discharge pattern, indicating that this approach can be effectively applied to identify functional neuronal subclasses. Together, our data illustrate that cells in the TNc with distinct patterns of TRPV1/ChR2 afferent innervation are physiologically diverse, but can be understood as a few major groups of cells having shared functional properties., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

A novel bacterium, designated SCSIO 07575 T , was isolated from a deep-sea hydrothermal sediment sample collected from the western Pacific Ocean. Growth at 65 °C was observed, but not at 70   °C or below 37 °C. The optimum conditions for growth were at 55-65 °C, pH 7.0 and in the presence of 2 % (w/v) NaCl. Strain SCSIO 07575 T showed filamentous growth. Unstable formation of white aerial mycelia was observed, which disappeared after several times' subculture. Abundant substrate mycelia were observed with grape-like spores. No soluble pigment was observed. Phylogenetic analysis of 16S rRNA gene sequences showed that SCSIO 07575 T belonged to the family Thermoactinomycetaceae and formed a distinct clade in the phylogenetic tree. The cell-wall peptidoglycan contained meso-diaminopimelic acid. Whole-cell hydrolysates contained ribose, xylose, glucose and galactose. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified aminophospholipid and two unidentified phospholipids. The predominant menaquinone was MK-7. Major fatty acids were iso-C15 : 0, iso-C17 : 0 and iso-C16 : 0. Based on the whole genome sequence analysis, the genome size was 2 751 094 bp with a DNA G+C value of 57.2 mol%, including one circular chromosome and one plasmid. On the basis of polyphasic data, strain SCSIO 07575 T represented a novel species of a new genus within the family Thermoactinomycetaceae, for which the name Staphylospora gen. nov. is proposed with the type species Staphylospora marina sp. nov. and the type strain SCSIO 07575 T (=DSM 106793 T =CGMCC 1.15879 T ).

Objectives: To validate and use the Chinese Version of the M. D. Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI-C) to assess the symptom burden of Chinese-speaking patients with gastrointestinal cancer., Methods: In total, 527 patients with postoperative or advanced digestive tract tumors were enrolled in the trial, who had definitive diagnoses and different treatments in our cancer center. MDASI-GI-C was administered to these patients between February and December 2017. The item-scale correlations and internal consistency were evaluated. Construct validity was established by factor analysis. Hierarchical cluster analysis was performed., Results: Cronbach's alpha of the symptom severity and interference subscales was 0.842 and 0.859, respectively. Construct validity revealed a four-factor structure. Known-group validity was established by comparing the MDASI-GI-C scores between patients having different Karnofsky Performance Status scores (≤70 or >70), which were observed to have significant differences. The overall mean subscale scores for the core and interference subscales were 1.63 ± 2.02 and 2.17 ± 2.34, respectively. Fatigue, disturbed sleep, and lack of appetite had the highest scores for most serious symptoms. No significant differences in age, working status, and educational level were found., Conclusions: MDASI-GI-C is a reliable and valid tool for assessing cancer-related symptoms in Chinese-speaking patients with digestive tract tumors, facilitates the understanding of the common symptoms of patients with digestive tract tumors, and enables timely management of these symptoms. Cognitive debriefing demonstrated that the patients found MDASI-GI-C to be an easy-to-use and understandable instrument., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Accumulating evidence suggests that pseudogenes play potential roles in the regulation of their cognate wild-type genes, oncogenes, and tumor suppressor genes. ANXA2P2 (annexin A2 pseudogene 2) is one of three pseudogenes of annexin A2 that have recently been shown to be aberrantly transcribed in hepatocellular carcinoma (HCC) cells. However, its clinical meaning and biological function in HCC have remained unclear. Therefore, the present study was aimed at exploring the prognostic value of a high expression of ANXA2P2 in HCC tissue and at identifying whether it can affect the efficacy of targeted drugs (sorafenib, regorafenib, and lenvatinib)., Methods: We obtained ANXA2P2 mRNA expression levels from The Cancer Genome Atlas (TCGA) RNA sequence database. The expression levels of ANXA2P2 in 49 pairs of intratumoral and peritumoral liver tissues were examined by RT-PCR. Wound healing and transwell assays were performed to confirm the tumor-promoting properties of ANXA2P2 in HCC cells. CCK8 assay was conducted to identify whether ANXA2P2 can affect the growth of HCC cells when administered with targeted drugs (sorafenib, regorafenib, and lenvatinib)., Results: The expression of ANXA2P2 in HCC tissues was significantly higher than that in adjacent cancerous tissues from TCGA database and validation group. Additionally, patients with high ANXA2P2 expression in HCC tissue had a shorter overall survival, whereas no statistically significant correlation was found between ANXA2P2 expression and disease-free survival ( p = 0.08) as well as other clinical parameters, such as age, gender, histological grade, T classification, stage, albumin level, alpha-fetoprotein, and vascular invasion ( p = 0.7323, 0.8807, 0.5762, 0.8515, 0.7113, 0.242, 1.0000, and 0.7685, respectively). Furthermore, in vitro experiments showed that knockdown of ANXA2P2 inhibited migration and invasion of HCC cells but did not have an influence on the HCC cell proliferation when treated with targeted drugs (sorafenib, regorafenib, and lenvatinib)., Conclusion: Our study confirmed elevated ANXA2P2 expression levels in HCC tissue compared with adjacent noncancerous tissue and a worse prognosis of patients with high ANXA2P2 levels in the HCC tissue. The newly found properties of promoting migration and invasion of ANXA2P2 in HCC help to explain this phenomenon. ANXA2P2 could be a novel and suitable predicative biomarker for the risk assessment of recurrence or metastasis of HCC patients but may not be effective to predict the efficacy of targeted drugs.

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11 + MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL., (© 2019 by The American Society of Hematology.)

A novel basophilic bacterial strain, designated as SCSIO 08040 T , was recovered from a deep-sea sediment sample collected from the Indian Ocean. The strain was Gram-stain-negative, vibrioid or spiral, light pink, 0.6-1.0 µm wide and 1.0-2.5 µm long. Growth occurred at 20-45 °C, pH 7-11 and <5 % (w/v) NaCl, with optimum growth at 28-37 °C, pH 7 and 0-3 % (w/v) NaCl. Catalase-, oxidase and urease-positive, nitrate reduction-negative. Analysis of 16S rRNA gene sequencing revealed that strain SCSIO 08040 T had the highest similarity of 95.3 % to Rhodocista pekingensis 3-p T . Phylogenetic analysis based on nearly complete 16S rRNA gene sequences showed that the novel isolate formed a distinct phylogenetic lineage in the family Rhodospirillaceae. The whole-cell hydrolysate contained meso-diaminopimelic acid, galactose, mannose and xylose. The total cellular fatty acid profile was dominated by C18:1ω7c and C19:0cycloω8c. Q-10 was the predominant ubiquinone. The major phospholipids were diphosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine. The DNA G+C content of strain SCSIO 08040 T was 66.82 mol%. Based on these polyphasic data, a new genus, Indioceanicola gen. nov., is proposed in the family Rhodospirillaceae with the type species Indioceanicola profundi sp. nov. and the type strain SCSIO 08040 T (=DSM 105146 T =CGMCC 1.15812 T ).

A novel mesophilic marine actinobacterial strain, designated as SCSIO 08198 T , was isolated from a deep-sea sediment sample collected from the Indian Ocean. The strain was Gram-stain-positive, rod-shaped and salmon pink in colour. Good growth occurred on marine agar with 1-5 % (w/v) NaCl and incubation at 28 °C for more than a fortnight. Sensitive to short ultraviolet radiation. Analysis of 16S rRNA gene sequences revealed that strain SCSIO 08198 T had the highest similarity of 97.2 % to Rubrobacter radiotolerans DSM 5868 T , and loosely related (<94.2 %) to all other species in the genus Rubrobacter. Phylogenetic analysis based on nearly complete 16S rRNA gene sequences revealed that the novel isolate shared a lineage with members of the genus Rubrobacter. The total cellular fatty acid profile was dominated by C16 : 0 12-methyl. MK-8 was the main menaquinone. The peptidoglycan type was A3α (l-Lys-l-Ala). The major phospholipids were diphosphatidylglycerol, phosphatidylglycerol and unidentified phospholipids. Based on the whole genome sequence analysis, the genome size is 3 078 689 bp with DNA G+C value of 63.8 mol%, including one circular chromosome and two plasmids. Based on these polyphasic data, a new species, Rubrobacterindicoceani sp. nov., is proposed, with the type strain SCSIO 08198 T (=DSM 105148 T =CGMCC 1.16398 T ).

Purpose: Nausea and vomiting are common, undesirable symptoms during cesarean section. We conducted this study to assess the antiemetic properties of propofol for the prevention and immediate treatment of post-delivery nausea and vomiting during cesarean section under combined spinal-epidural anesthesia., Methods: Eighty women undergoing elective cesarean delivery under combined spinal-epidural anesthesia were randomized to receive either propofol at a plasma concentration of 1000 ng/mL or normal saline immediately after clamping of the umbilical cord. The incidence of post-delivery nausea and vomiting, patients requiring rescue antiemetic, bispectral index, sedation score, and the incidence of hypotension were assessed intraoperatively. Satisfaction and neonatal behavioral neurological assessments were evaluated postoperatively., Results: The incidence of nausea was significantly lower in the propofol group compared to the placebo group (25% versus 60%, P < 0.001). The incidence of retching and vomiting showed no significant difference between the two groups. Propofol 20 mg as a rescue antiemetic was significantly effective in both the groups. Satisfaction level of patients and obstetricians in the propofol group was higher than in the placebo group. There was no statistical difference in the incidence of hypotension between the two groups both pre- and post-delivery. There was no difference in postoperative neonatal behavioral neurological assessment between groups., Conclusion: Propofol at a plasma concentration of 1000 ng/mL significantly reduced the incidence of post-delivery nausea compared to placebo, but had no effect on reducing retching or vomiting episodes during cesarean section.

Purpose: Knowledge on the utility of prophylactic 360° laser retinopexy before pars plana vitrectomy in the absence of peripheral retinal pathology is limited. This study compares the occurrence of rhegmatogenous events in the setting of small-gauge pars plana vitrectomy with and without prophylactic preoperative laser., Methods: Our multicenter, retrospective case-control analysis reviewed patients who underwent epiretinal membrane removal or macular hole repair through 23- or 25-gauge pars plana vitrectomy: 205 controls who did not receive prophylactic laser and 176 cases who received preoperative prophylactic laser retinopexy anterior to the equator. Main outcome measures were the rate and characteristics of postoperative retinal tears and detachments. Patients with previous pars plana vitrectomy or significant retinal disease were excluded., Results: Of those patients with prophylactic laser and those without, there was no significant difference in the number of retinal breaks (1.7% vs. 0.49%, respectively; P = 0.339) or retinal detachments (0% vs. 0.49%, respectively; P = 1.00). Of the lasered group, there was one sclerotomy-related retinal break and two non-sclerotomy-related retinal breaks. Of the nonlasered group, there was one non-sclerotomy-related retinal break and one sclerotomy-related retinal detachment., Conclusion: Preoperative prophylactic peripheral laser retinopexy does not seem to offer an added benefit in the prevention of intraoperative and postoperative rhegmatogenous events.

Introduction: Despite recent prognostic improvements, mantle cell lymphoma (MCL) remains incurable. Bruton tyrosine kinase (BTK) is a key receptor in B-cell tumorigenesis, and the benefits of the first BTK inhibitor, ibrutinib, are becoming clear in MCL. However, off-target activities, which contribute to ibrutinib-related adverse events, suggest potential for further improvement of this drug class. Areas covered: The authors systematically interrogated ClinicalTrials.gov for trials containing keywords for BTK and MCL. Published literature for new and emerging BTK inhibitors being investigated in MCL was then identified (PubMed and Embase), summarized, and placed in the context of treatment guidelines. Expert commentary: Reduced off-target effects of new and emerging covalent, irreversible BTK inhibitors under investigation in patients with MCL offer the potential of improved safety compared with ibrutinib. Efficacy may also be favorable based on trial data for acalabrutinib, which has just been approved in the USA as second-line therapy for MCL. The role of BTK inhibitors in treating MCL will evolve substantially over the coming years as results from a number of trials become available, particularly in relation to potential upfront use and possible synergy with other targeted therapies such as B-cell lymphoma 2, phosphoinositide 3-kinase and checkpoint inhibitors.

Background: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied., Methods: We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m 2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m 2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS)., Results: With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease., Conclusion: Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen., Trial Registration: ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

Neuroendocrine tumors (NETs) of the gastrointestinal tract often spread to the liver, while primary hepatic NETs (PHNETs), first described by Edmondson in 1958, are very rare. The majority of existing reports regarding PHNETs have small sample sizes, and the clinicopathological characteristics and prognostic factors are still unclear. The aim of the present study was to analyze the clinicopathological features and explore the prognostic factors of PHNETs. From March 2012 to March 2017, 28 cases of PHNETs were retrospectively evaluated to analyze the clinicopathological features and explore the prognostic factors of PHNETs. The 28 PHNETs patients were males (n=15) and females (n=13) aged between 32 and 76 years (mean=53 years). Among them, 16 patients had clinical symptoms. The remaining 12 patients had no obvious clinical symptoms, only hepatoncus was observed during physical examination. Single-factor analysis showed that carbohydrate antigen 125 (CA125), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hemoglobin (HB), Ki-67 positive index (PI), surgical treatment and pathological grading were correlated to PHNET prognosis (P<0.05); multifactor analysis revealed that Ki-67 PI was associated with the prognosis (P<0.05). Thus, the prognosis of PHNETs may be effectively predicted using the indexes of CA125, ALT, AST, HB, Ki-67 PI, pathological grading and surgical treatment. Pathological classification of grade 3, high expression of Ki-67 PI, abnormal elevation of CA125, abnormalities of ALT and AST, anemia and lack of radical operation indicated a poor prognosis. High expression of Ki-67 PI was an independent prognostic factor for PHNETs.

This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30 + peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789., (© 2018 by The American Society of Hematology.)

Previous studies have revealed that the peritumoral environment has a profound influence on tumor initiation and progression. Zinc-binding protein-89 (ZBP-89) has been observed to be involved with tumor development, recurrence, and metastasis. High intratumoral expression of ZBP-89 has been associated with improved prognosis in several tumor types. However, the prognostic values of peritumoral expression of ZBP-89 remain to be elucidated in patients with hepatocellular carcinoma (HCC) following curative resection. In the present study, peritumoral ZBP-89 expression was examined using immunohistochemistry in 102 HCC patients who had received curative hepatectomy. Expression of ZBP-89 protein was positive in 66.3% of the peritumoral samples from 102 HCC patients. HCC patients with high peritumoral ZBP-89 expression exhibited significantly shorter disease-free survival (DFS) times (P=0.012) than those patients with low peritumoral ZBP-89 expression. Additionally, high ZBP-89 expression in peritumoral HCC tissue was positively associated with the presence of liver cirrhosis. Univariate and multivariate Cox proportional hazard regression analyses demonstrated that albumin levels ≤35 g/l, multiple tumors, tumor sizes ≥5 cm, and macroscopic vascular invasion may serve as independent prognostic factors for overall survival (OS) [hazard ratio (HR)=2.031; P=0.014] in patients with HCC. The multivariate Cox regression model identified that high ZBP-89 expression, multiple tumors and macroscopic vascular invasion were independent prognostic factors for shorter DFS durations. High expression of ZBP-89 in peritumoral HCC tissues was associated with a shorter DFS in HCC patients following curative hepatectomy. Additionally, high ZBP-89 expression in peritumoral HCC tissue was positively associated with the presence of liver cirrhosis in HCC patients, indicating that cirrhosis accompanied by high ZBP-89 expression may be a contributing factor to the poor prognosis of patients with HCC. Therefore, peritumoral ZBP-89 expression may be a good prognostic marker to predict DFS time in HCC patients following curative hepatectomy and may provide novel insights into the molecular mechanisms of HCC initiation.

The roots of Codonopsis cordifolioidea (classified as campanulaceae cordifolioidea), locally known as Tsoong, have been used as a tonic food. The major components isolated from Tsoong have been demonstrated to present anti‑human immunodeficiency virus‑1 activities and cytotoxicity against various tumor cell lines. However, the possible effects of the novel compound isolated from Tsoong, cordifoliketones A, on pancreatic ductal adenocarcinoma (PDAC) cells, are still unknown. In the present study, cordifoliketones A extractions were prepared from Tsoong, and the possible effects on PDAC cell growth, apoptosis, migration and invasion in vitro and in vivo were exlored. The cytotoxicity assay, apoptosis assay, western blotting, migration and invasion assay, and a PDAC cell (AsPC‑1, BxPC‑3 and PANC‑1) xenograft mice model were employed. The results demonstrated that treatment with cordifoliketones A: i) inhibited proliferation and promoted apoptosis of PDAC cells; ii) significantly induced apoptosis and altered expression of apoptosis‑associated proteins in a dose‑dependent manner; iii) suppressed migration and invasion of PDAC cells in a dose‑dependent manner; and iv) restrained the growth of PDAC neoplasm in nude mice. Furthermore, cordifoliketones A demonstrated non‑cytotoxic activity in a panel of normal human cells, including hTERT‑HPNE, 293, hepatocyte HL‑7702 and HL‑1 cells. Therefore, these data indicated that cordifoliketones A may be a potential candidate compound for the prevention of PDAC cell proliferation and metastasis, presumably by induction apoptosis and inhibiting viability, invasion and migration of PDAC cells.

Heme oxygenase-1 (HO-1) plays a key role in anti-oxidation, anti-apoptosis, and anti-proliferation in various types of cancers. However, the relationship between HO-1 expression and gastric cancer development remains largely unknown. In this study, the protein expression of HO-1 in human gastric cancer was measured by immunohistochemistry on paraffin sections of 89 paired gastric carcinoma tissues and adjacent non-cancer tissues. The correlation of HO-1 expression with 5-year overall survival rate was estimated. The effects of decreased HO-1 expression by two strands of small interfered RNAs (siRNAs) on cell apoptosis, proliferation, and invasion of gastric cancer cell lines were examined by flow cytometry, the MTT assay, and the cell migration assay, respectively. High expression of HO-1 was detected in 11.2% (10/89) of gastric carcinoma tissues, compared with 1.1% (1/89) in matched adjacent normal tissues, and correlated with a decreased survival rate in gastric cancer patients. There were no significant correlations between HO-1 expression and clinical characteristics. Downregulation of HO-1 expression using two strands of siRNAs promoted apoptosis and inhibited the proliferation and invasion of two gastric cancer cell lines, SGC7901 and MKN-28 cells. This study demonstrated that HO-1 plays a vital role in the development of gastric cancer and may serve as a therapeutic target of this type of cancer.