Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish.

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.

Falsiroseomonas oryziterrae sp. nov., and Falsiroseomonas oryzae sp. nov., isolated from rice paddy soil.

Three Gram-stain-negative, aerobic, non-motile and coccobacilli-shaped bacterial strains, designated as NPKOSM-4T, NPKOSM-8 and MO-31T, were isolated from rice paddy soil. They had 96.5-100 % 16S rRNA gene sequence similarity to each other, and strains NPKOSM-4T and NPKOSM-8 showed 100 % 16S rRNA gene sequence similarity, confirming that they were the same species. Comparative analysis of 16S rRNA genes with closely related type strains showed that three isolates were most closely related to Falsiroseomonas terricola EM0302T (96.1-97.8 %), Falsiroseomonas wooponensis WW53T (95.51-96.3 %) and Falsiroseomonas bella CQN31T (96.0-96.5 %), respectively. The genomes of strains NPKOSM-4T and MO-31T consisted of 4 632 875 and 6 455 771 bps, respectively, with 72.0 and 72.1 mol% G+C content. The average nucleotide identity (ANI), average amino acid identity (AAI) and digital DNA-DNA hybridization (dDDH) values between strains NPKOSM-4T and MO-31T and type strains of Falsiroseomonas species were lower than the cut-offs (≥95 % for ANI, ≥95-96 % for AAI and ≥ 70 % for dDDH) required to define a bacterial species. The major fatty acids of strains NPKOSM-4T, NPKOSM-8 and MO-31T were C18 : 1 ω7c and C18 : 1 2-OH (<10 %) and the predominant quinone was Q-10. The polar lipids of strain NPKOSM-4T were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unidentified aminophospholipid and three unidentified aminolipids. The polar lipid profiles of strain MO-31T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unidentified aminolipid and three unidentified lipids. Based on their distinctive phenotypic, phylogenetic, and chemotaxonomic characteristics, strains NPKOSM-4T, NPKOSM-8 and MO-31T are considered to represent two novel species of the genus Falsiroseomonas, for which the names Falsiroseomonas oryziterrae sp. nov. [to accommodate strains NPKOSM-4T (= KACC 22135T=JCM 34745T), NPKOSM-8 (=KACC 22134=JCM 34746)] and Falsiroseomonas oryzae sp. nov. [to accommodate strain MO-31T (= KACC 22465T=JCM 35532T)] are proposed.

Erythrobacter oryzae sp. nov., isolated from rice paddy soil.

Two novel bacterial strains, designated as COR-2T and CR-8, were isolated from paddy soil. These isolates were aerobic, Gram-stain-negative, non-spore-forming, non-motile, rod-shaped, and formed orange-coloured colonies. Phylogenetic analysis based on 16S rRNA gene sequences showed that two strains formed a clear phylogenetic lineage with the genus Erythrobacter. Strains COR-2T and CR-8 showed 99.9 % 16S rRNA gene sequence similarity. Both strains had the highest 16S rRNA gene similarity of 99.1-99.7 % to Erythrobacter colymbi TPW-24T, Erythrobacter donghaensis SW-132T and Erythrobacter tepidarius DSM 10594T, respectively. The genome of strain COR-2T comprised 3 559 918 bp and the genomic DNA G + C content was 67.7 mol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain COR-2T and its closely related species of the genus Erythrobacter were 79.3-85.5% and 24.1-29.1 %, respectively. The major respiratory quinone was Q-10, while the major fatty acids were C18 : 1 ω7c and C17 : 1 ω6c. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, two unidentified phospholipids and eight unidentified lipids. Based on phylogenetic and phenotypic considerations, the two strains [COR-2T (type strain; = KACC 22941T=JCM 35529T) and CR-8 (= KACC 22945=JCM 35530)] are considered to represent novel species of the genus Erythrobacter, for which the name Erythrobacter oryzae sp. nov. is proposed.

Empirical Characterization of False Discovery Rates of Differentially Expressed Genes and Transcriptomic Benchmark Concentrations in Zebrafish Embryos.

High-throughput transcriptomics (HTTr) is increasingly applied to zebrafish embryos to survey the toxicological effects of environmental chemicals. Before the adoption of this approach in regulatory testing, it is essential to characterize background noise in order to guide experimental designs. We thus empirically quantified the HTTr false discovery rate (FDR) across different embryo pool sizes, sample sizes, and concentration groups for toxicology studies. We exposed zebrafish embryos to 0.1% dimethyl sulfoxide (DMSO) for 5 days. Pools of 1, 5, 10, and 20 embryos were created (n = 24 samples for each pool size). Samples were sequenced on the TempO-Seq platform and then randomly assigned to mock treatment groups before differentially expressed gene (DEG), pathway, and benchmark concentration (BMC) analyses. Given that all samples were treated with DMSO, any significant DEGs, pathways, or BMCs are false positives. As expected, we found decreasing FDRs for DEG and pathway analyses with increasing pool and sample sizes. Similarly, FDRs for BMC analyses decreased with increasing pool size and concentration groups, with more stringent BMC premodel filtering reducing BMC FDRs. Our study provides foundational data for determining appropriate experiment designs for regulatory toxicity testing with HTTr in zebrafish embryos.

Menstrual and psychosocial characteristics associated with high-risk of premenstrual dysphoric disorder among university students: a cross-sectional study.

Up to 92 percent of Chinese women of reproductive age have pre-menstrual syndrome (PMS). The severe form of PMS (i.e. pre-menstrual dysphoric disorder [PMDD]) negatively affects women's everyday functioning and reproductive health. This study examined the relationships between menstrual, psychosocial characteristics and the risk of PMDD among young Chinese women. A cross-sectional online survey was conducted among Chinese university students in Hong Kong. Logistic regression was used to compute adjusted odds ratio (aOR) for the association of high-risk PMDD with menstrual and psychosocial characteristics. A total of 541 Chinese university students were recruited. Approximately 53 percent of female students were at high risk of developing PMDD. The high-risk PMDD group was significantly associated with a heavy volume of menstrual flow (aOR = 2.17, 95 percent CI 1.06-4.45), irregular menstrual cycle (1.72, 1.17-2.52), high dysmenorrhea (2.80, 1.95-4.04) and older ages of menarche (0.67, 0.45-0.98) in the menstrual characteristics. In the psychosocial characteristics, high-risk PMDD was significantly associated with symptoms of anxiety (2.19, 1.48-3.32) and depression (2.22, 1.48-3.32), high loneliness (1.94, 1.34-2.79) and low resilience (2.21, 1.52-3.23) levels. Additionally, resilience had a potential moderating effect on the associations between the high risk of PMDD and anxiety, depression and loneliness. The development and delivery of interventions that can enhance resilience and manage psychological distress would be beneficial for young Chinese women's reproductive health.

Validity assessment of oral health promotion activities targeting the older population for community care in South Korea: A Delphi study.

OBJECTIVE: The purpose of this study was to establish an oral health activity assessment tool for older people and evaluate its validity. BACKGROUND: To provide reasonable and efficient oral health promotion services with limited medical resources, a tool including categories and items of oral health promotion activities for older people should be prepared. MATERIALS AND METHODS: The tool initially consisted of 76 items on oral health promotion activities for older people classified into assessment-performance-evaluation stages. Topics for each stage included general and oral health, daily health, oral health status, behaviour, and awareness. In addition, two Delphi surveys were conducted on 10 experts who met the selection criteria, and the final items were derived based on the review opinions. RESULTS: As a result of the first and second Delphi surveys, the content validity for all items was ≥0.60 and the content validity index was ≥0.80. In the first survey, the degree of convergence in some items was 0-0.88. After modifying the contents according to expert opinions, the degree of convergence was improved from 0 to 0.50 in the second survey. The degree of agreement ranged from 0.75 to 1.00, indicating that experts agreed. Finally, a total of 65 items were derived. CONCLUSION: A 65-item tool was derived through two Delphi surveys for the assessment of oral health activities for older people. The use of the tool developed in this study would likely contribute to better prevention of oral diseases and the promotion of oral health among older people.

Battery-Free, Wireless, Cuff-Type, Multimodal Physical Sensor for Continuous Temperature and Strain Monitoring of Nerve.

Peripheral nerve injuries cause various disabilities related to loss of motor and sensory functions. The treatment of these injuries typically requires surgical operations for improving functional recovery of the nerve. However, capabilities for continuous nerve monitoring remain a challenge. Herein, a battery-free, wireless, cuff-type, implantable, multimodal physical sensing platform for continuous in vivo monitoring of temperature and strain from the injured nerve is introduced. The thin, soft temperature, and strain sensors wrapped around the nerve exhibit good sensitivity, excellent stability, high linearity, and minimum hysteresis in relevant ranges. In particular, the strain sensor integrated with circuits for temperature compensation provides reliable, accurate strain monitoring with negligible temperature dependence. The system enables power harvesting and data communication to wireless, multiple implanted devices wrapped around the nerve. Experimental evaluations, verified by numerical simulations, with animal tests, demonstrate the feasibility and stability of the sensor system, which has great potential for continuous in vivo nerve monitoring from an early stage to complete regeneration.

Oryzibacter oryziterrae gen. nov., sp. nov., isolated from rice paddy soil.

A novel Gram-stain-negative, aerobic, motile and pleomorphic rod-shaped bacterial strain, designated COJ-58T, was isolated from rice paddy soil. Strain COJ-58T grew optimally at 20-30 °C, at pH 5.0-8.0 and with 0-1.0 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain COJ-58T forms a distinct lineage within the family Pleomorphomonadaceae, with highest similarity to Pleomorphomonas carboxyditropha SVCO-16T (95.9 %), Pleomorphomonas koreensis Y9T (95.8 %), Pleomorphomonas oryzae F-7T (95.7 %) and Pleomorphomonas diazotrophica R5-392T (95.6 %), respectively. The average nucleotide identity, digital DNA-DNA hybridization, average amino acid identity and percentage of conserved proteins values between the genomes of strain COJ-58T and its closely related taxa are ≤77.2 %, ≤21.6 %, ≤68.3 % and ≤61.3 %, respectively. The genome size of strain COJ-58T is 4.9 Mb and the genomic DNA G + C content is 63.7 mol%. The major fatty acids are C18 : 1 ω7c, C16 : 0 and summed feature 2 (C14 : 0 3-OH and/or iso-C16 : 1 I). The differential phenotypic and genotypic characteristics of strain COJ-58T indicate that it represents a novel genus and species, for which the name Oryzibacter oryziterrae gen. nov., sp. nov. is proposed, with strain COJ-58T (=KACC 22108T=JCM 34744T) as the type strain.

Preclinical safety assessment of the suction-assisted intradermal injection of the SARS-CoV-2 DNA vaccine candidate pGO-1002 in white rabbit.

pGO-1002, a non-viral DNA vaccine that expresses both spike and ORF3a antigens of SARS-CoV-2, is undergoing phase 1 and phase 2a clinical trials in Korea and the US. A preclinical repeated-dose toxicity study in New Zealand white rabbits in compliance with Good Laboratory Practice (GLP) was conducted to assess the potential toxicity, local tolerance, and immunogenicity of the vaccine and GeneDerm suction device. The dose rate was 1.2 mg/head pGO-1002, and this was administered intradermally to a group of animals (eight animals/sex/group) three times at 2-week intervals, followed by a 4-week recovery period. After each administration, suction was applied to the injection site using the GeneDerm device. Mortality, clinical signs, body weight, food consumption, skin irritation, ophthalmology, body temperature, urinalysis, and clinical pathology were also monitored. Gross observations and histopathological evaluation were performed. Overall, pGO-1002 administration-related changes were confined to minor damage or changes at the injection site, increased spleen weight and minimal increased cellularity in white pulp. All changes of injection site were considered local inflammatory changes or pharmacological actions due to the vaccine with the changes in spleen considered consistent with vaccine-induced immune activation. All findings showed reversibility during the 4-week recovery period. Animals vaccinated with pGO-1002, administered by intradermal injection and followed by application of suction with GeneDerm, developed humoral and cellular responses against the SARS-CoV-2 antigens consistent with prior studies in rats. Collectively, it was concluded that the pGO-1002 vaccine was safe and effective under these experimental conditions and these data supported future human study of the vaccine, now known as GLS-5310, for clinical trial use.

Multiplex SNP Genotyping Using SWITCH: Sequence-Specific Nanoparticle with Interpretative Toehold-Mediated Sequence Decoding in Hydrogel.

Single nucleotide polymorphisms (SNPs) that can alter phenotypes of individuals play a pivotal role in disease development and, more importantly, responses to therapy. However, SNP genotyping has been challenging due to the similarity of SNP alleles and their low concentration in biological samples. Sequence-specific nanoparticle with interpretative toehold-mediated sequence decoding in hydrogel (SWITCH) for multiplex SNP genotyping is presented. The encoding with gold nanoparticle probes transduces each SNP target to ≈1000 invaders with prominently different sequences between wild and mutant types, featuring polymerase chain reaction (PCR)-free amplification. Subsequently, the toehold-mediated DNA replacement in hydrogel microparticles decodes the invaders via SNP-specific fluorescence signals. The 4-plex detection of the warfarin-associated SNP targets spiked in commercially validated human serum (S1-100ML, Merck) is successfully demonstrated with excellent specificity. This work is the first technology development presenting PCR-free, multiplex SNP genotyping with a single reporting fluorophore, to the best of knowledge.

Roseomonas rosulenta sp. nov., isolated from rice paddy soil.

Three bacterial isolates, Gram-stain-negative, non-motile, coccobacilli-shaped bacteria, strains OP-27T, OP-5 and OP-30, were isolated from rice paddy soil. Phylogenetic analyses based on 16S rRNA gene sequences revealed that three isolates belonged to the genus Roseomonas, showing the highest sequence similarities to Roseomonas sediminicola FW-3T (98.1%) and Roseomonas lacus TH-G33T (98.0%). The genome size of strain OP-27T was 5.2 Mb in a single contig with DNA G+C content of 71.2%. The genome included 5164 predicted protein-coding genes, as well as 48 tRNA, 4 rRNA and 4 mRNA genes. The average nucleotide identity value between strain OP-27T and type strains of related species of the genus Roseomonas were 81.1-83.1%, and the digital DNA-DNA hybridization values of strain OP-27T and the related strains were 24.6-26.8%, respectively. The DNA-DNA hybridization values between strains OP-27T, OP-5 and OP-30 were 84-100% and its closest relative, Roseomonas sediminicola KACC 16616T was 21.1%. The major fatty acids were C18:1 ω7c, C18:1 2-OH and C16:0 and predominant quinone was Q-10. Based on its distinctive phenotypic, phylogenetic, and chemotaxonomic characteristics, the three strains are considered to represent novel species of the genus Roseomonas, for which the name Roseomonas rosulenta sp. nov. is proposed. The type strain is OP-27T (=KACC 21501T= NBRC 114497T).

Roseomonas rubea sp. nov., isolated from rice paddy soil.

Three pale-red-pigmented, Gram-stain-negative, coccobacilli-shaped, motile and strictly aerobic bacteria, strains MO17T, MO41 and NPKOSM1, were isolated from rice paddy soil. Colonies were circular with entire edges, convex and pale red. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strains MO17T, MO41 and NPKOSM1 belonged to the genus Roseomonas and were closely related to Roseomonas sediminicola FW-3T (98.2 %), Roseomonas oryzicola YC6724T (98.0 %), Roseomonas soli 5N26T (98.0 %), Roseomonas eburnea BUT-5T (97.8 %), Roseomonas alkaliterrae YIM 78007T (97.7 %), Roseomonas lacus TH-G33T (97.6 %) and Roseomonas terrae DS-48T (96.8 %). The DNA-DNA hybridization values between strains MO17T, MO41 and NPKOSM1 were 84-92 %, and the values between the three strains and their close phylogenetic relatives were also below 70 %. The major cellular fatty acids were C18 : 1 ω7c, C16 : 0 and summed feature 3 (C16 : 1 ω7c and/or iso-C15 : 0 2OH). The predominant respiratory quinone was identified as Q-10. The polar lipids detected were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unidentified aminophospholipid and two unknown phospholipids. Based on their distinctive phenotypic, phylogenetic and chemotaxonomic characteristics, the three strains are considered to represent novel species of the genus Roseomonas for which the name Roseomonas rubea sp. nov. is proposed. The type strain is MO17T (=KACC 19933T=NBRC 114495T).

Multisystem Inflammatory Syndrome in an Adult Following COVID-19 mRNA Vaccination: Successful Treatment With Medium-Dose Steroids and Colchicine.

Multisystem inflammatory syndrome in children and adults (MIS-C/A) was rarely reported as a complication of coronavirus disease 2019 (COVID-19) and potential adverse events following COVID-19 vaccination. Recently, the case definition of MIS-C/A was developed by the Brighton Collaboration Network. However, only a limited number of adult patients with MIS-A following immunization have been reported, and there is still little evidence for adequate treatment. A 57-year-old man presented with fever, headache, vomiting, and hypotension 24 days after receiving the second COVID-19 vaccination with the Pfizer-BioNTech vaccine. According to the Brighton Collaboration Case Definition, the patient met a definitive case of MIS-A after vaccination (level 1 of diagnostic certainty). After administration of medium-dose prednisolone (20 mg/d) with colchicine (1.2 mg/d), all symptoms and signs improved rapidly. The dose of prednisolone was gradually tapered from the third week, and the patient confirmed a full recovery without medication after 8 weeks. This is the first report showing that low-dose steroids in combination with colchicine may be an effective treatment option for MIS-A after vaccination.

Volumetric Splenomegaly in Patients With Polycythemia Vera.

BACKGROUND: Non-palpable splenomegaly in patients with polycythemia vera (PV) has seldom been addressed. In this retrospective study, we evaluated non-palpable, volumetric splenomegaly defined based on age- and body surface area (BSA)-matched criteria in patients with PV diagnosed according to the 2016 World Health Organization diagnostic criteria. METHODS: Patients with PV who underwent abdominal computed tomography (CT) and who had palpable splenomegaly at diagnosis from January 1991 to December 2020 at Chungnam National University Hospital were enrolled. The spleen volume of each patient was determined by volumetric analysis of abdominal CT and adjusted for the patient's age and BSA. Then the degree of splenomegaly was classified as no splenomegaly, borderline volumetric splenomegaly, overt volumetric splenomegaly, or palpable splenomegaly. RESULTS: Of the 87 PV patients enrolled, 15 (17.2%) had no splenomegaly, whereas 17 (19.5%), 45 (51.7%), and 10 (11.5%) had borderline volumetric, overt volumetric, and palpable splenomegaly, respectively. The degree of splenomegaly did not affect the cumulative incidence of thrombotic vascular events (10-year incidence: 7.7%, 0%, 22.3%, and 50.7%, respectively, P = 0.414). By contrast, splenomegaly tended to adversely affect myelofibrotic transformation (10-year cumulative incidence: 0%, 0%, 7.1%, and 30.3%, respectively, P = 0.062). Moreover, the cumulative incidence of myelofibrotic transformation was significantly higher in patients with overt volumetric or palpable splenomegaly than those with no or borderline volumetric splenomegaly (10-year incidence: 0% vs. 10.3%, respectively; 15-year incidence: 0% vs. 26.3%, respectively, P = 0.020). Overall survival (OS) differed among patients with different degrees of splenomegaly (15-year OS: 100%, 78.6%, 71.7%, and 51.9%, respectively, P = 0.021). CONCLUSION: The degree of splenomegaly, including volumetric splenomegaly, based on age- and BSA-matched reference spleen volumes at diagnosis reflects disease progression in PV patients. Therefore, volumetric splenomegaly should be evaluated at the time of diagnosis and taken into consideration when predicting the prognosis of patients with PV.

Effects of a multimodal approach to food art therapy on people with mild cognitive impairment and mild dementia.

BACKGROUND: Food art therapy (FAT) has multiple modalities in which cognition, emotion, and social changes are stimulated. The purpose of this study was to design a multimodal approach to a food art therapy (MM-FAT) program and identify its effects on cognitive ability, daily living functioning, depression, self-esteem, self-efficacy, self-expression, and social functioning in individuals with mild cognitive impairment (MCI) and mild dementia by employing a mixed methods research design. METHODS: The participants included 39 patients from a public dementia care centre in Seoul, Korea. The intervention group, which comprised 20 participants, received 12 MM-FAT sessions 3 times a week for 4 weeks, and the control group, which included 19 participants, received usual care. The MM-FAT program was evaluated based on its effectiveness on cognitive, daily living, emotional, and social functioning outcome measures at three time points using repeated measures analysis of variance. Semi-structured interviews (n = 9) were conducted to evaluate the overall experience of the MM-FAT program and its outcomes. RESULTS: The findings reveal that MM-FAT has a positive effect on the cognitive, emotional, and social functioning of individuals with MCI and mild dementia. However, there were no enhancements in individuals' daily living functioning, and the lasting effects of the intervention could not be assessed. Cognition and depression increased significantly at the end of the MM-FAT program. Self-expression and self-efficacy were significantly higher in the MM-FAT group than in the control group. The semi-structured interviews revealed improvements in participants' behaviour, communication, and interaction. CONCLUSION: This mixed methods study focused on individuals with MCI or mild dementia contributes to an understanding of the effectiveness of a FAT program employing a multimodal approach. Despite the COVID-19 pandemic, the study was able to enrich the effects of MM-FAT on cognitive, emotional, and social functioning through qualitative findings.

Preliminary outcomes of arthroscopic biceps rerouting for the treatment of large to massive rotator cuff tears.

BACKGROUND: We aimed to evaluate the short-term outcomes of arthroscopic biceps rerouting (ABR) for the treatment of large to massive rotator cuff tears (LMRCTs). METHODS: A prospective evaluation of patients treated with ABR for the repair of LMRCTs was performed, with a minimum follow-up period of 18 months. Range of motion and functional outcomes (visual analog scale pain score, American Shoulder and Elbow Surgeons score, and Korean Shoulder Scale score) were assessed preoperatively and at final follow-up. Radiographs were used to evaluate the acromiohumeral interval (AHI). Magnetic resonance imaging was performed at 2 and 12 months postoperatively to examine the integrity of the repaired rotator cuff tendons. RESULTS: Eighty patients who met the study criteria underwent ABR from March 2017 to January 2019 in our hospital. Of these patients, 61 could be evaluated ≥18 months after surgery. The average age of the enrolled patients was 64.5 years. The visual analog scale pain score decreased from 3.7 preoperatively to 1.6 at final follow-up (P = .019), the American Shoulder and Elbow Surgeons score improved from 60.0 to 85.2 (P < .001), and the Korean Shoulder Scale score improved from 64.3 to 85.3 (P = .001). Assessment of range of motion showed significant improvement in forward flexion (from 138° to 146°, P < .001), external rotation at 90° of abduction (from 80° to 85°, P = .037), and internal rotation (from spinal level 9 to spinal level 10, P = .015) from preoperatively to last follow-up. The AHI was 7.1 mm at baseline and improved significantly to 9.7 mm at 3 months postoperatively (P < .001). The mean AHI at last follow-up was only 9 mm, but this was still significantly better than the mean preoperative AHI (P < .001). Of the patients, 16 (26%) exhibited a retear of the repaired rotator cuff on magnetic resonance imaging at 12 months postoperatively. Male sex was the only significant risk factor for retear (P = .037). CONCLUSION: ABR improved the functional and radiologic outcomes of patients with LMRCTs. The ABR technique can be a useful treatment option for LMRCTs.

Perioperative Systemic Treatment for Muscle-Invasive Bladder Cancer: Current Evidence and Future Perspectives.

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.

Loss of Von Hippel-Lindau (VHL) Tumor Suppressor Gene Function: VHL-HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC).

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel-Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL-HIF-VEGF/VEGFR pathway, which involves the von Hippel-Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL-HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL-HIF pathway.

IFNL3-adjuvanted HCV DNA vaccine reduces regulatory T cell frequency and increases virus-specific T cell responses.

BACKGROUND & AIMS: Although direct-acting antiviral (DAA) treatment results in a sustained virologic response (SVR) in most patients with chronic HCV infection, they are at risk of re-infection. Moreover, the immune system is not completely normalized even after SVR (e.g. increased regulatory T [Treg] cell frequency). We developed a DNA vaccine, GLS-6150, to prevent re-infection of patients with DAA-induced SVR and evaluated its safety and immunogenicity in individuals with chronic HCV infection. METHODS: GLS-6150 consists of plasmids encoding HCV non-structural proteins (NS3-NS5A) and adjuvant IFNL3. The vaccine was administered 4 times at 4-weekly intervals to 3 groups (1, 3, or 6 mg/vaccination; n = 6 per group), followed by a 6 mg boost at 24 weeks (n = 14). Peripheral blood T cell responses were evaluated by interferon (IFN)-γ enzyme-linked immunospot assays, intracellular cytokine staining, and major histocompatibility complex class-I (MHC-I) dextramer staining. Treg cell frequency was assessed by flow cytometry. RESULTS: Severe adverse events or vaccine discontinuation were not reported. The IFN-γ spot-forming cells specific to NS3-NS5A were increased by GLS-6150. Both CD4+ and CD8+ T cells produced multiple cytokines. However, the frequency and phenotype of HCV-specific MHC-I dextramer+CD8+ T cells were not changed. Interestingly, the frequency of Treg cells, particularly activated Treg cells, was decreased by GLS-6150, as expected from previous reports that IFNL3 adjuvants decrease Treg cell frequency. Ex vivo IFN-λ3 treatment reduced Treg frequency in pre-vaccination peripheral blood mononuclear cells. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-γ-producing T cell responses in the study participants. CONCLUSIONS: We demonstrate that GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effects. A phase I clinical trial of GLS-6150 is currently underway in patients with DAA-induced SVR. CLINICAL TRIAL NUMBER: NCT02027116. LAY SUMMARY: Although direct-acting antivirals (DAAs) are successfully used for the treatment of chronic hepatitis C virus (HCV) infection, a prophylactic HCV vaccine needs to be developed, especially for patients who achieve a sustained virologic response. In the current study, we show that a DNA vaccine (GLS-6150) was safe and increased HCV-specific T cell responses. A clinical trial is underway to test this vaccine in patients with a sustained virologic response following DAA therapy.

Elioraea rosea sp. nov., a plant promoting bacterium isolated from floodwater of a paddy field.

A Gram-stain-negative bacterium, designated strain PF-30T, was isolated from floodwater of a paddy field in South Korea. Strain PF-30T was found to be a strictly aerobic, motile and pink-pigmented rods which can grow at 25-40 °C (optimum, 28 °C), at pH 5.0-9.0 (optimum pH 7.0) and at salinities of 0.5-3.0 % NaCl (optimum 0.5 % NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain PF-30T belongs to the genus Elioraea, showing highest sequence similarity to Elioraea tepidiphila TU-7T (97.1%) and less than 91.3 % similarity with other members of the family Acetobacteraceae. The average nucleotide identity (ANI) and DNA-DNA relatedness between the strain PF-30T and E. tepidiphila TU-7T yielded an ANI value of 75.1 % and DNA-DNA relatedness of 11.7±0.7 %, respectively. The major fatty acids were identified as C18 : 0 and C18 : 1 ω7c. The predominant respiratory quinone was identified as Q-10. The DNA G+C content was determined to be 69.9 mol%. The strain PF-30T was observed to produce plant-growth-promoting materials such as indole-3-acetic acid (IAA), siderophore and phytase. On the basis of the results from phylogenetic, chemotaxonomic and phenotypic data, we concluded that strain PF-30T represents a novel species of the genus Elioraea, for which the name Elioraea rosea sp. nov. is proposed. The type strain is PF-30T (=KACC 19985T=NBRC 113984T).