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Study Design: A single-centre, retrospective cohort study., Objectives: To compare the clinical outcomes between nail-plate constructs and the plate-on-plate technique in the treatment of proximal femoral peri-implant fracture (PFPIF)., Methods: Thirty-seven patients with PFPIF treated at our hospital were included. All patients underwent at least 1-year follow-up. Imaging studies and medical records, including walking ability, complications, and functional outcomes 1 year after surgery, were thoroughly reviewed., Results: Twenty patients were treated with nail-plate constructs. Seventeen patients were treated with the plate-on-plate technique. The average surgical times in the plate-on-plate technique and nail-plate construct groups were 119.4 ± 23.4 min and 246.3 ± 48.0 min, respectively. The average blood losses in the plate-on-plate technique and nail-plate construct groups were 124.7 ± 41.6 mL and 434.3 ± 170.8 mL, respectively. The plate-on-plate technique group had a significantly shorter surgical time and less blood loss than the nail-plate construct group. No statistically significant differences were found in union time, ambulation status, 36-item Short Form Health Survey score, and complication rate between the two groups., Conclusion: The plate-on-plate technique can be considered an alternative option to reduce operation time and blood loss in the treatment of PFPIF, especially for older patients and those who are less capable of sustaining long-term operation and anaesthetic exposure., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Human metapneumovirus (HMPV) is a member of the genus Metapneumovirus in the family Pneumoviridae of the order Mononegavirales that can cause upper and lower respiratory tract disease. This retrospective study describes the epidemiology of hMPV based on community viral surveillance results from sentinel sites across Taiwan from 2013 to 2023. A total of 114 hMPV strains were isolated and analyzed to assess viral evolution through sequencing of their fusion protein genes. This study revealed that hMPV cases occur almost year-round in Taiwan, with a peak occurring during spring (March to May). Of the 114 infected patients, 68.4% were children under 4 years old. The geographical distribution of hMPV positivity was highest in Penghu County, followed by Changhua County and Hsinchu County. The clinical symptoms of hMPV infection are nonspecific, with fever (56.1%), cough (44.7%), rhinorrhea (21.1%), and sore throat (14.9%) being the most common. However, a few patients also developed severe central nervous system symptoms (1.8%) or dyspnea (0.9%). Phylogenetic analysis revealed genetic diversity among the 114 isolated hMPV strains, with the A2 lineage (57.9%) being the most frequently observed, followed by the B2 lineage (33.3%), in the Taiwanese community from 2013 to 2023. In conclusion, hMPV causes a serious acute respiratory disease in Taiwan that should not be neglected. Further epidemiological surveillance and investigations of the clinical characteristics of hMPV should be performed continually for prevention and control of this virus., (© 2024. The Author(s).)

The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), functions as a critical coregulator during RNA polymerase II (RNAPII) transcription. cMED recruits RNAPII and facilitates the assembly of the pre-initiation complex (PIC) at promoters. In contrast, CKM prevents RNAPII binding to cMED while simultaneously exerting positive or negative influence on gene transcription through its kinase function. Recent structural studies on cMED and CKM have revealed their intricate architectures and subunit interactions. Here, we explore these structures, providing a comprehensive insight into Mediator (cMED-CKM) architecture and its potential mechanism in regulating RNAPII transcription. Additionally, we discuss the remaining puzzles that require further investigation to fully understand how cMED coordinates with CKM to regulate transcription in various events., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vascular damage is one of the significant complications of diabetes mellitus (DM). Central to this damage is endothelial damage, especially under high-glucose conditions, which promotes inflammation via the NF-κB signaling pathway. Inflammatory processes in endothelial cells directly contribute to endothelial dysfunction, such as promoting inflammatory cytokine release and activation of adhesion molecules. Vitexin, a compound found in many medicinal plants, shows promise in countering oxidative stress in diabetic contexts and modulating blood glucose. However, its effect on high-glucose-induced endothelial cell activation has not yet been studied. This research explores vitexin's potential role in this process, focusing on its influence on the NF-κB pathway in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with 30 mM glucose (high glucose, HG) with or without vitexin treatment for 24 h. Western blotting assay was conducted for the NF-κB pathway and p-p38. Adhesion molecules (ICAM-1, VCAM-1, E-selectin, and MCP-1) were studied using flow cytometry, while pro-inflammatory cytokines were investigated using ELISA. Monocyte adhesion and vascular permeability tests were conducted to confirm the protective effect of vitexin under HG exposure. This study confirms vitexin's capacity to suppress p38 MAPK and NF-κB activation under HG conditions, reducing HG-elevated adhesion molecules and pro-inflammatory cytokine secretion. Additionally, vitexin mitigates HG-stimulated vascular permeability and monocyte adhesion. In conclusion, this study shows the therapeutic potential of vitexin against hyperglycemia-related vascular complications via p38 MAPK/NF-κB inhibition., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: With its minimally invasive approach, laparoscopic surgery has transformed the medical landscape. As the demand for these procedures escalates, there is a pressing need for adept surgeons trained in laparoscopic techniques. However, current training often falls short of catering to medical school education. This study evaluates the impact of a custom-designed laparoscopic training workshop on medical students' surgical skills and career aspirations., Methods: This prospective experimental study was conducted at the E-Da hospital in Kaohsiung City, Taiwan. Medical students from Taiwanese medical schools undergoing Clerk 5, Clerk 6, and Postgraduate Year 1 and 2 were invited to participate. Medical students (n = 44) underwent an endoscopic skill training workshop consisting of lectures, box training, and live tissue training. The trainees performed multiple tasks before and after training using our objective evaluation system. The primary outcome was assessed before and after training through a questionnaire assessing the influence of training on students' interest in surgery as a career. The secondary outcome measured improvement in skill acquisition, comparing the task completion time pre- and post-workshop. For the primary outcome, descriptive statistics were used to summarize the questionnaire responses, and paired t-tests were performed to determine significant changes in interest levels post-workshop. For the secondary outcome, paired t-tests were used to compare the time recorded pre- and post-training., Results: Post-training, participants exhibited significant proficiency gains, with task completion times reducing notably: 97 s (p = 0.0015) for Precision Beads Placement, 88.5 s (p < 0.0001) for Beads Transfer Exercise, 95 s (p < 0.0001) for Precision Balloon Cutting, and 137.8 s (p < 0.0001) for Intracorporeal Suture. The primary outcome showcased an increased mean score from 8.15 pre-workshop to 9.3 post-workshop, indicating a bolstered interest in surgery as a career. Additionally, post-training sentiment analysis underscored a predominant inclination toward surgery among 88% of participants., Conclusion: The custom-designed laparoscopic workshop significantly improved technical skills and positively influenced students' career aspirations toward surgery. Such hands-on training workshops can play a crucial role in medical education, bridging the gap between theoretical knowledge and practical skills and potentially shaping the future of budding medical professionals., (© 2024. The Author(s).)

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), regulates RNA Polymerase II (Pol II)-dependent transcription. cMED recruits Pol II and promotes pre-initiation complex (PIC) formation in a manner inhibited by the CKM, which is also implicated in post-initiation control of gene expression. Herein we report cryo-electron microscopy structures of the human complete Mediator and its CKM, which explains the basis for CKM inhibition of cMED-activated transcription. The CKM binds to cMED through an intrinsically disordered region (IDR) in MED13 and HEAT repeats in MED12. The CKM inhibits transcription by allocating its MED13 IDR to occlude binding of Pol II and MED26 to cMED and further obstructing cMED-PIC assembly through steric hindrance with TFIIH and the +1 nucleosome. Notably, MED12 binds to the cMED Hook, positioning CDK8 downstream of the transcription start site, which sheds new light on its stimulatory function in post-initiation events.

The early myocardial response of hypertension is an elevation of angiotensin-II (Ang-II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT-R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti-inflammatory and anti-oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang-II-induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang-II 1 μM for 24 h to induce cellular damage. We found that EA protected against Ang-II-increased cell surface area and pro-hypertrophic gene expression in H9c2. EA reduced Ang-II-caused AT-R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang-II-enhanced p38 and extracellular-signal-regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang-II stimulation also reversed NF-κB activity and iNOS expression. This study shows that EA protects against Ang-II-induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang-II-induced myocardial hypertrophy., (© 2024 Wiley Periodicals LLC.)

Background: Management of tibial pilon fracture in elderly patients with psychiatric illness remains challenging for orthopedic doctors because of patients' poor bone quality and inability for self-care. This study aimed to ascertain the viability and reliability of primary arthrodesis by using retrograde hindfoot nail for these difficult cases., Methods: We retrospectively reviewed eight elderly consecutive patients (age older than 65 years) with tibial pilon fractures and psychiatric illness from January of 2012 to December of 2019 in our institute. Primary tibiotalocalcaneal arthrodesis with retrograde hindfoot nail was used as a definitive procedure. The bone union time, wound complication rate, ankle alignment, necessity for narcotic agents, and ambulation status were evaluated., Results: The average length of follow-up was 22.25 months (range, 15-36 months). Additional bone grafting surgery was performed for one patient because of fusion-site nonunion 6 months postoperatively. Another patient required debridement and removal of posterior calcaneal screw because of implant prominence and local infection. Osseous union with angular deformity less than 10° was achieved in all patients finally. The average bone union time was 6.6 months (range, 4-12 months). In terms of walking ability, six patients were capable of outdoor ambulation (classes 2 and 3). Two patients required oral pain medication at the final visit., Conclusions: The current study involved only a small number of patients, and two of the eight cases encountered undesired complications (one local infection and one bone nonunion); however, we believe that our method may serve as a valuable alternative for the treatment of tibial pilon fractures in elderly patients with psychiatric illness, considering the specificity of this fragile population.

Human skeletal muscle contraction is triggered by activation of Na v 1.4 channels. Na v 1.4 channels can generate resurgent currents by channel reopening at hyperpolarized potentials through a gating transition dependent on the intracellular Na v β4 peptide in the physiological conditions. Tefluthrin (TEF) is a pyrethroid insecticide that can disrupt electrical signaling in nerves and skeletal muscle, resulting in seizures, muscle spasms, fasciculations, and mental confusion. TEF can also induce tail currents through other voltage-gated sodium channels in the absence of Na v β4 peptide, suggesting that muscle spasms may be caused by resurgent currents. Further, intracellular Na v β4 peptide and extracellular TEF may show competitive or synergistic effects; however, their binding sites are still unknown. To address these issues, electrophysiological recordings were performed on CHO-K1 cells expressing Na v 1.4 channels with intracellular Na v β4 peptide, extracellular TEF, or both. TEF and Na v β4 peptide induced a hyperpolarizing shift of activation and inactivation curves in the Na v 1.4 channel. TEF also substantially prolonged the inactivation time constants, while simultaneous application of Na v β4 peptide partially reversed this effect. Resurgent currents were enhanced by TEF and Na v β4 peptide at negative potentials, but TEF more potently enhances resurgent currents and dampens decay of resurgent currents. With longer depolarization, peak resurgent currents decay was fastest with the TEF alone. Molecular docking suggested that TEF and Na v β4 peptide binding site(s) are not in the narrowest part of the channel pore, but rather in the bundle-crossing regions and in the domain linkers, respectively. TEF can induce resurgent currents independently and synergistically with Na v β4 peptide, which may explain the muscle spasms observed in TEF intoxication., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest would prejudice the impartiality of this scientific work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Cyclin-dependent kinases (CDKs) play crucial roles in a range of essential cellular processes. While the classical two-step activation mechanism is generally applicable to cell cycle-related CDKs, both CDK7 and CDK8, involved in transcriptional regulation, adopt distinct mechanisms for kinase activation. In both cases, binding to their respective cyclin partners results in only partial activity, while their full activation requires the presence of an additional subunit. Recent structural studies of these two noncanonical kinases have provided unprecedented insights into their activation mechanisms, enabling us to understand how the third subunit coordinates the T-loop stabilization and enhances kinase activity. In this review, we summarize the structure and function of CDK7 and CDK8 within their respective functional complexes, while also describing their noncanonical activation mechanisms. These insights open new avenues for targeted drug discovery and potential therapeutic interventions in various diseases related to CDK7 and CDK8., 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 © 2023 Li, Tang and Tsai.)

Although the height of the proliferating layer that was suppressed in the growth plate has been recognized as an adverse effect of cisplatin in pediatric cancer survivors, the detailed pathological mechanism has not been elucidated. Sirtuin-1 (SIRT1) has been reported as an essential modulator of cartilage homeostasis, but its role in cisplatin-induced damage of chondrocytes remains unclear. In this study, we examined how cisplatin affected the expression of SIRT1 and cell viability. Next, we showed downregulation of SIRT1 after cisplatin treatment resulted in suppression of Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), leading to inhibition of Nrf2 nuclear translocation and subsequently decreased Heme oxygenase-1(HO-1) and NAD(P)H Quinone Dehydrogenase 1(NQO-1) expression. Blockage of the SIRT1/ PGC-1α axis not only increased oxidative stress with lower antioxidant SOD and GSH, but also contributed to mitochondrial dysfunction evidenced by the collapse of membrane potential and repression of mitochondrial DNA copy number and ATP. We also found that Cisplatin up-regulated the p38 phosphorylation, pro-inflammatory events and matrix metalloproteinases (MMPs) in chondrocytes through the SIRT1-modulated antioxidant manner. Collectively, our findings suggest that preservation of SIRT1 in chondrocytes may be a potential target to ameliorate growth plate dysfunction for cisplatin-receiving pediatric cancer survivors., (© 2023 Wiley Periodicals LLC.)

Background: While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research., Method: We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data., Result: A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004)., Conclusion: The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan-Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy ( p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81-0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09-1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89-2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22-1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33-1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62-0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20-0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29-0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without ( p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal disorder of dogs wherein the esophagus is dilated and swallowing activity is reduced, causing regurgitation of ingesta. Affected individuals experience weight loss and malnourishment and are at risk for aspiration pneumonia, intussusception, and euthanasia. Great Danes have among the highest incidences of CIM across dog breeds, suggesting a genetic predisposition. We generated low-pass sequencing data for 83 Great Danes and used variant calls to impute missing whole genome single-nucleotide variants (SNVs) for each individual based on haplotypes phased from 624 high-coverage dog genomes, including 21 Great Danes. We validated the utility of our imputed data set for genome-wide association studies (GWASs) by mapping loci known to underlie coat phenotypes with simple and complex inheritance patterns. We conducted a GWAS for CIM with 2,010,300 SNVs, identifying a novel locus on canine chromosome 1 (P-val = 2.76 × 10 -10 ). Associated SNVs are intergenic or intronic and are found in two clusters across a 1.7-Mb region. Inspection of coding regions in high-coverage genomes from affected Great Danes did not reveal candidate causal variants, suggesting that regulatory variants underlie CIM. Further studies are necessary to assess the role of these non-coding variants., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to assess the effectiveness of swimming exercise in alleviating mechanical hypersensitivity and peripheral nerve degeneration associated with a pre-clinical model of painful diabetic neuropathy (PDN)., Methods: This study is a pre-clinical study conducted using the streptozocin (STZ)-induced PDN rat model. Rats were randomly allocated to three groups: a vehicle group of non-diabetic rats (Vehicle, n = 9), a group of rats with PDN (PDN, n = 8), and a group of rats with PDN that performed a swimming exercise program (PDN-SW, n = 10). The swimming exercise program included daily 30-minute swimming exercise, 5 days per week for 4 weeks. Von Frey testing was used to monitor hindpaw mechanical sensitivity over 4 weeks. Assessment of cutaneous peripheral nerve fiber integrity was performed after the 4-week study period via immunohistochemistry for protein gene product 9.5-positive (PGP9.5+) intra-epidermal nerve fiber density (IENFD) in hind-paw skin biopsies by a blinded investigator., Results: The results showed that swimming exercise mitigated but did not fully reverse mechanical hypersensitivity in rats with PDN. Immunohistochemical testing revealed that the rats in the PDN-SW group retained higher PGP9.5+ IENFD compared to the PDN group but did not reach normal levels of the Vehicle group., Conclusions: The results of this study indicate that swimming exercise can mitigate mechanical hypersensitivity and degeneration of peripheral nerve fibers in rats with experimental PDN., 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 © 2023 Elsevier B.V. All rights reserved.)

Atherosclerotic lesions play a critical role in leading cardiovascular diseases. Oxidized low-density lipoprotein (OxLDL) is a vital risk factor for atherosclerosis since it acts a crucial role in endothelial dysfunction and foam cell formation. Schisanhenol, a composition extracted from the fruit of Schisandra rubriflora, has been reported to have antioxidative effects on human LDL oxidation. This study investigates whether Schisanhenol protects against oxLDL-mediated endothelial damage by modulating the lectin-like oxLDL receptor-1 (LOX-1)-mediated inflammatory processes. Human umbilical vein endothelial cells (HUVECs) were pre-treated with 10 or 20 μM Schisanhenol for 2 h and then exposed to 150 μg/mL oxLDL. We revealed that Schisanhenol reduced oxLDL-enhanced LOX-1 expression. We also found that oxLDL down-regulated endothelial nitric oxide synthase (eNOS) as well as activated inducible NOS (iNOS), thereby enhancing the generation of nitric oxide (NO). Moreover, oxLDL elevated the expression levels of phosphorylated-p38MAPK, subsequently promoting NF-κB-modulated inflammatory responses. Pretreatment with Schisanhenol exerted significant cytoprotective function in all the above-mentioned detrimental events. Results from this present study reveal that Schisanhenol has a potential therapeutic effect on preventing oxLDL-induced endothelial injuries., (© 2023 Wiley Periodicals LLC.)

Introduction: Treating a terrible triad injury of the elbow remains a challenge for orthopedic surgeons, especially in elderly patients due to the poor quality of the surrounding soft tissue and bony structures. In the present study, we propose a treatment protocol using an internal joint stabilizer through a single posterior approach and analyze the clinical results., Materials and Methods: We retrospectively reviewed 15 elderly patients with terrible triad injuries of the elbow who underwent our treatment protocol from January 2015 to December 2020. The surgery involved a posterior approach, identification of the ulnar nerve, bone and ligament reconstruction, and the application of the internal joint stabilizer. A rehabilitation program was initiated immediately after the operation. Surgery-related complications, elbow range of motion (ROM), and functional outcomes were evaluated., Results: The mean follow-up period was 21.7 months (range, 16-36 months). ROM at the final follow-up was 130° in extension to flexion and 164° in pronation to supination. The mean Mayo Elbow Performance Score was 94 at the final follow-up. Major complications included breaking of the internal joint stabilizer in 2 patients, transient numbness over the ulnar nerve territory in one, and local infection due to irritation of the internal joint stabilizer in one., Conclusions: Although the current study involved only a small number of patients and the protocol comprised two stages of operation, we believe that such a technique may be a valuable alternative for the treatment of these difficult cases., Level of Clinical Evidence: 4., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Most eukaryotic promoter regions are divergently transcribed. As the RNA polymerase II pre-initiation complex (PIC) is intrinsically asymmetric and responsible for transcription in a single direction, it is unknown how divergent transcription arises. Here, the Saccharomyces cerevisiae Mediator complexed with a PIC (Med-PIC) was assembled on a divergent promoter and analyzed by cryoelectron microscopy. The structure reveals two distinct Med-PICs forming a dimer through the Mediator tail module, induced by a homodimeric activator protein localized near the dimerization interface. The tail dimer is associated with ∼80-bp upstream DNA, such that two flanking core promoter regions are positioned and oriented in a suitable form for PIC assembly in opposite directions. Also, cryoelectron tomography visualized the progress of the PIC assembly on the two core promoter regions, providing direct evidence for the role of the Med-PIC dimer in divergent transcription., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Hypertrophic cardiomyopathy accompanies numerous cardiovascular diseases, and the intervention of cardiac hypertrophy is an important issue to prevent detrimental consequences. Mangiferin (MGN) is a glucosylxanthone found in Mangifera indica , which exhibits anti-oxidant and anti-inflammatory properties. Various studies have demonstrated the cardioprotective potential of MGN, but the mechanisms behind its beneficial effects have not been fully revealed. Here, angiotensin-II (Ang-II) was used to induce cardiac hypertrophy, and we examined cell size, expression of hypertrophy markers (e.g., ANP, BNP, and [Formula: see text]-MHC), and oxidative stress (e.g., the ratio of NADPH/NADP[Formula: see text], the expression of p22phox and p67phox, and ROS and SOD production) of cardiomyocytes. Moreover, we assessed the activation of mitogen-activated protein kinase (MAPK) signaling (e.g., p38 and ERK) and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, an annexin V/PI assay was employed to evaluate whether MGN administration can attenuate Ang-II-elicited apoptosis. Lastly, the expression of Ang-II type 1 receptor (AT1) was measured to confirm its involvement in MGN-mediated protection. Our results showed that treatment with MGN attenuated the Ang-II-induced cell size, expression of hypertrophy markers, and oxidative stress in cardiomyocytes. MGN also abrogated the activation of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, MGN prevented apoptosis and downregulated the elevation of AT1 in cardiomyocytes that had been exposed to Ang-II. Altogether, these results demonstrated the potential of using MGN to ameliorate the Ang-II-associated cardiac hypertrophy, which may be due to its anti-oxidant and anti-inflammatory effects through suppression of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis.

Atherosclerotic cardiovascular diseases, commonly known as the formation of fibrofatty lesions in the artery wall, are the leading causes of death globally. Oxidized low-density lipoprotein (oxLDL) is one of the major components of atherosclerotic plaques. It is evident that dietary supplementation containing sources of antioxidants can prevent atherogenic diseases. Schisanhenol (SAL), a dibenzocyclooctene lignin, has been shown to attenuate oxLDL-induced apoptosis and the generation of reactive oxygen species (ROS) in endothelial cells. However, the underlying molecular mechanisms are still largely unknown. In this study, human umbilical vein endothelial cells (HUVECs) were pre-treated with SAL and oxLDL. Our results showed that adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was enhanced in cells pre-treated with SAL in time-dependent and dose-dependent manners. Subsequently, oxLDL-induced AMPK dephosphorylation and protein kinase C (PKC) phosphorylation were significantly reversed in the presence of SAL. In addition, SAL treatment led to an inhibiting effect on the oxLDL-induced membrane assembly of NADPH oxidase subunits, and a similar effect was observed in ROS generation. This effect was further confirmed using knockdown AMPK with small interfering RNA (siRNA) and pharmaceutical reagents, such as the AMPK activator (AICAR), PKC inhibitor (Gö 6983), and ROS inhibitor (DPI). Furthermore, the oxLDL-induced intracellular calcium rise and the potential collapse of the mitochondrial membrane reduced the Bcl-2/Bax ratio, and released cytochrome c from the mitochondria, leading to the subsequent activation of caspase-3 in HUVECs, which were also markedly suppressed by SAL pretreatment. The results mentioned above may provide additional insights into the possible molecular mechanisms underlying the cardiovascular protective effects of SAL.

Background: This study aimed to evaluate the outcome of using an External Joint Stabilizer - Elbow (EJS-E) for persistent elbow instability based on biomechanical experiments and analysis of clinical results., Methods: An EJS-E was used in 17 elbow instability patients. The median follow-up was 26 months (range, 12-42 months). We evaluated the flexion-extension and pronation-supination movement arcs, visual analog scale (VAS) score, Mayo Elbow Performance Score (MEPS), Broberg and Morrey classification system, and occurrence of complications in these patients. Moreover, construct stiffness and maximum strength tests were performed to evaluate the strength of the fixation techniques., Results: The final median range of the extension-to-flexion and pronation-to-supination arc of the elbow was 135° (range, 110°-150°) and 165° (range, 125°-180°), respectively. The VAS pain scores were > 3 in two patients. The median MEPS was 90 (range, 80-100 points). Five patients showed signs of grade I post-traumatic osteoarthritis according to the Broberg and Morrey radiographic classification system, while grade II changes were observed in three patients. Complications included axis pin loosening with pin-tract infection in two patients, transient ulnar nerve symptoms in two patients, heterotopic ossification in two patients, and suture anchors infection in one patient. Based on the biomechanical testing results, the EJS-E exhibited higher stiffness and resisting force in varus loading. It was 0.5 (N/mm) stiffer and 1.8 (N·m) stronger than the internal joint stabilizer (IJS) by difference of medians (p < 0.05)., Conclusions: Biomechanical and clinical outcomes show that EJS-E via the posterior approach can restore mobility and stability in all patients, thus serving as a valuable alternative option for the treatment of persistent instability of the elbow., (© 2022. The Author(s).)

Background: Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery., Methods: This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5-10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL)., Results: We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care., Conclusion: The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.KEY MESSAGESThe fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.

Background: Vertebral compression fractures (VCFs) often occur in patients with osteoporosis. These fractures can also lead to postural changes. Several studies have shown that patients with vertebral compression fractures have a restrictive pattern in their pulmonary function. Percutaneous vertebroplasty (PVP) is the standard treatment for vertebral compression fractures, with the benefits of pain relief and enhancement of vertebral stability for partially collapsed vertebral bodies. However, the effects of PVP on short-term recovery of respiratory performance have not been investigated. Therefore, this study aimed to investigate the changes in pulmonary function, respiratory muscle strength, maximal voluntary ventilation (MVV), and chest mobility in patients with vertebral compression fractures after PVP. Methods: This research was approved by the clinic committee of the E-DA Hospital Institutional Review Board (EMRP07109N) and registered in the Thai Clinical Trials Registry (TCTR20211029005). We recruited 32 VCF patients. Four-time points were measured: before and after PVP and 1 and 3 weeks after PVP. We measured pulmonary function and maximum voluntary ventilation (MVV) by using spirometry. Respiratory muscle strength was assessed by using a respiratory pressure meter. The chest expansion test was used to evaluate chest mobility. A visual analogue scale (VAS) was used to assess resting and aggravated back pain. Results: Chest expansion and back pain improved at each time point after PVP. MVV showed significant progress at both 1 and 3 weeks after discharge. Forced expiratory volume in 1 second (FEV1) and maximal inspiratory muscle strength significantly improved 1 week after discharge. Conclusion: Taking all the data together, PVP not only can resolve severe back pain but can also provide excellent improvements in MVV and chest mobility in patients with vertebral compression fractures.

Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis (LSS). In hypertrophic ligamentum flavum (LF) cells, oxidative stress activates intracellular signaling and induces the expression of inflammatory and fibrotic markers. This study explored whether healthy and hypertrophic LF cells respond differently to oxidative stress, via examining the levels of phosphorylated p38 (p-p38), inducible nitric oxide synthase (iNOS), and α -smooth muscle actin ( α -SMA). Furthermore, the efficacy of N-acetylcysteine (NAC), an antioxidant, in reversing the fibrogenic and proinflammatory effects of oxidative stress in hypertrophic LF cells was investigated by assessing the expression levels of p-p38, p-p65, iNOS, TGF- β , α -SMA, vimentin, and collagen I under H 2 O 2 treatment with or without NAC. Under oxidative stress, p-p38 increased significantly in both hypertrophic and healthy LF cells, and iNOS was elevated in only the hypertrophic LF cells. This revealed that oxidative stress negatively affected both hypertrophic and healthy LF cells, with the hypertrophic LF cells exhibiting more active inflammation than did the healthy cells. After H 2 O 2 treatment, p-p38, p-p65, iNOS, TGF- β , vimentin, and collagen I increased significantly, and NAC administration reversed the effects of oxidative stress. These results can form the basis of a novel therapeutic treatment for LFH using antioxidants., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yu-Chia Hsu et al.)

Objective: This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN)., Methods: This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator., Results: The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves., Conclusion: This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use., Impact: These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.

Introduction: Internal fixation is the treatment of choice for subtrochanteric fractures in most conditions. However, it may be an unsuitable procedure for patients with poor health status, osteomyelitis, and surrounding soft tissue compromise. This study aimed to ascertain the viability and reliability of using external locking plate fixation for these difficult cases., Methods: Eleven patients with femoral subtrochanteric fractures who received external locking plate fixation in our institute from January 2014 to December 2019 were enrolled in our study. The bone union time, wound complication, alignment, and necessity for narcotic agents were evaluated., Results: The average length of follow-up was 17.5 months (range, 14-26 months). The mean time for bone union was 17.7 weeks (range, 15-21 weeks). The indications included poor health condition, soft tissue compromise, and post-operative osteomyelitis. Pin tract infection was noted in two patients who were treated successfully with oral antibiotics administration and removal of the involved screws. Osseous union with varus deformity <10° was achieved in all patients except one. Three patients required an orally administered pain killer at the final visit. The average Harris Hip Score at one year post-operatively was 66.6 (range, 49-80)., Conclusions: Although the current study only involved 11 patients, we believe that our method may serve as a valuable alternative for the treatment of a femoral subtrochanteric fracture in selected cases., Level of Evidence: Level IV, retrospective case series., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Despite increasing availability and more successful interventional approaches to restore coronary reperfusion, myocardial ischemia-reperfusion injury is a substantial cause of morbidity and mortality worldwide. During myocardial ischemia, the myocardium becomes profoundly hypoxic, thus causing stabilization of hypoxia-inducible transcription factors (HIF). Stabilization of HIF leads to a transcriptional program that promotes adaptation to hypoxia and cellular survival. Transcriptional consequences of HIF stabilization include increases in extracellular production and signaling effects of adenosine. Extracellular adenosine functions as a signaling molecule via the activation of adenosine receptors. Several studies implicated adenosine signaling in cardioprotection, particularly through the activation of the Adora2a and Adora2b receptors. Adenosine receptor activation can lead to metabolic adaptation to enhance ischemia tolerance or dampen myocardial reperfusion injury via signaling events on immune cells. Many studies highlight that clinical strategies to target the hypoxia-adenosine link could be considered for clinical trials. This could be achieved by using pharmacologic HIF activators or by directly enhancing extracellular adenosine production or signaling as a therapy for patients with acute myocardial infarction, or undergoing cardiac surgery.

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a–regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy., Competing Interests: The authors have declared that no competing interests exist.

Osteoarthritis (OA) is a common degenerative joint disease. The pathological changes of chondrocytes involve oxidative stress, the pro-inflammatory response, and pro-apoptotic events. Galectin-3 (Gal-3) is a 35 kDa protein with a special chimeric structure. Gal-3 participates in the progression of many diseases, such as cancer metastasis and heart failure. A previous study demonstrated that Gal-3 expression in human cartilage with OA is increased. However, the role of Gal-3 in chondrocyte dysfunction in joints is still unclear. In this study, we applied Gal-3 (5-20 μg/ml) to TC28a2 human chondrocyte cells for 24 h to induce chondrocyte dysfunction. We found that Gal-3 upregulated TLR-4 and MyD88 expression and NADPH oxidase, thereby increasing intracellular ROS in the chondrocytes. Gal-3 increased phosphorylated MEK1/2 and ERK levels, and promoted NF-κB activity. This activation of NF-κB was reduced by silencing TLR-4 and NOX-2. In addition, Gal-3 caused apoptosis of chondrocytes through the mitochondrial-dependent pathway via the TLR-4/NADPH oxidase/MAPK axis. Our study proves the pathogenic role of Gal-3 in Gal-3-induced chondrocyte dysfunction and injuries., (© 2021 Wiley Periodicals LLC.)

Background: Previous studies have reported that chemotherapy results in substantial long-term risk of heart failure. Exercise ameliorates exercise responses and exercise tolerance in patients receiving chemotherapy. The cardioprotective effect of real-time exercise in breast cancer is still unclear., Objectives: The aim of the present study was to determine the effect of real-time moderate-to-high-intensity exercise training in women with breast cancer undergoing chemotherapy and to follow up on parameters of cardiac function and exercise capacity at different times. We hypothesized that early moderate-to-high-intensity exercise training has beneficial effects on cardiac function in women with breast cancer undergoing chemotherapy., Methods: This was a randomized controlled study that included 32 women randomly allocated into the control or exercise group. Exercise began with the first cycle of chemotherapy, and the training program was maintained during chemotherapy with 2 to 3 sessions per week for 3 months. Patients were instructed to perform moderate-to-high-intensity training with aerobic and resistance training. Outcome measurements were echocardiography and cardiopulmonary exercise test. The primary outcome was the change in left ventricle ejection fraction (LVEF). The secondary outcome was peak oxygen consumption (peak VO 2 )., Results: The control group showed lower cardiac systolic function than the exercise group [mean (SD) LVEF 62% (2) and 70% (5), P<0.05], reduced cardiac diastolic function, and cardiac hypertrophy at 3, 6 and 12 months after chemotherapy. At 6 months after chemotherapy, the exercise group exhibited relatively higher exercise capacity than controls [mean (SD) VO 2 12.1 (2.2) and 13.6 (2.2) mL/kg/min, P<0.05]. The main effect size of the study based on echocardiography outcomes was 0.25 (95% confidence interval 0.23 to 0.27), a medium effect size., Conclusions: Moderate-to-high-intensity exercise training in breast cancer patients undergoing chemotherapy may prevent impaired cardiac function., Clinical Trial Registration: https://www., Clinicaltrials: in.th (Identifier TCTR20190330002)., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Diabetes mellitus is a well-known metabolic disorder with numerous complications, such as macrovascular diseases (e.g., coronary heart disease, diabetic cardiomyopathy, stroke, and peripheral vascular disease), microvascular diseases (e.g., diabetic nephropathy, retinopathy, and diabetic cataract), and neuropathy. Multiple contributing factors are implicated in these complications, and the accumulation of oxidative stress is one of the critical ones. Several lines of evidence have suggested that oxidative stress may induce epigenetic modifications that eventually contribute to diabetic vascular complications. As one kind of epigenetic regulator involved in various disorders, non-coding RNAs have received great attention over the past few years. Non-coding RNAs can be roughly divided into short (such as microRNAs; ~21-25 nucleotides) or long non-coding RNAs (lncRNAs; >200 nucleotides). In this review, we briefly discussed the research regarding the roles of various lncRNAs, such as MALAT1, MEG3, GAS5, SNHG16, CASC2, HOTAIR, in the development of diabetic vascular complications in response to the stimulation of oxidative stress.

Cisplatin is massively used to treat solid tumors. However, several severe adverse effects, such as cardiotoxicity, are obstacles to its clinical application. Cardiotoxicity may lead to congestive heart failure and even sudden cardiac death in patients receiving cisplatin. Therefore, finding a novel therapeutic strategy for the prevention of cisplatin-induced cardiotoxicity is urgent. Quercetin is a flavonol compound that can be found in dietary fruits and vegetables. The antioxidant function and anti-inflammatory capacity of quercetin have been reported. However, whether quercetin could protect against cisplatin-caused apoptosis and cellular damage in cardiomyocytes is still unclear. H9c2 cardiomyocytes were treated with cisplatin (40 μM) for 24 h to induce cellular damage with or without quercetin pretreatment. We found that quercetin activates Nrf2 and HO-1 expression, thereby mitigating cisplatin-caused cytotoxicity in H9c2 cells. Quercetin also increases SOD levels, maintains mitochondrial function, and reduces oxidative stress under cisplatin stimulation. Quercetin attenuates cisplatin-induced apoptosis and inflammation in H9c2 cardiomyocytes; however, these cytoprotective effects were diminished by silencing Nrf2 and HO-1. In conclusion, this study reports that quercetin has the potential to antagonize cisplatin-caused cardiotoxicity by reducing ROS-mediated mitochondrial damage and inflammation via the Nrf2/HO-1 and p38MAPK/NF-[Formula: see text]Bp65/IL-8 signaling pathway. This study provided the theoretical basis and experimental proof for the clinical application of quercetin as a new effective strategy to relieve chemotherapy-induced cardiotoxicity.

The upregulation of tumor necrosis factor-alpha (TNF-α) is a common event in arthritis, and the subsequent signaling cascade that leads to tissue damage has become the research focus. To explore a potential therapeutic strategy to prevent cartilage degradation, we tested the effect of ginsenoside Rg3, a bioactive component of Panax ginseng , on TNF-α-stimulated chondrocytes.TC28a2 Human Chondrocytes were treated with TNF-α to induce damage of chondrocytes. SIRT1 and PGC-1a expression levels were investigated by Western blotting assay. Mitochondrial SIRT3 and acetylated Cyclophilin D (CypD) were investigated using mitochondrial isolation. The mitochondrial mass number and mitochondrial DNA copy were studied for mitochondrial biogenesis. MitoSOX and JC-1 were used for the investigation of mitochondrial ROS and membrane potential. Apoptotic markers, pro-inflammatory events were also tested to prove the protective effects of Rg3. We showed Rg3 reversed the TNF-α-inhibited SIRT1 expression. Moreover, the activation of the SIRT1/PGC-1α/SIRT3 pathway by Rg3 suppressed the TNF-α-induced acetylation of CypD, resulting in less mitochondrial dysfunction and accumulation of reactive oxygen species (ROS). Additionally, we demonstrated that the reduction of ROS ameliorated the TNF-α-elicited apoptosis. Furthermore, the Rg3-reverted SIRT1/PGC-1α/SIRT3 activation mediated the repression of p38 MAPK, which downregulated the NF-κB translocation in the TNF-α-treated cells. Our results revealed that administration of Rg3 diminished the production of interleukin 8 (IL-8) and matrix metallopeptidase 9 (MMP-9) in chondrocytes via SIRT1/PGC-1α/SIRT3/p38 MAPK/NF-κB signaling in response to TNF-α stimulation. Taken together, we showed that Rg3 may serve as an adjunct therapy for patients with arthritis.

Background: Doxorubicin (Dox) is a widely used anthracycline drug to treat cancer, yet numerous adverse effects influencing different organs may offset the treatment outcome, which in turn affects the patient's quality of life. Low-level lasers (LLLs) have resulted in several novel indications in addition to traditional orthopedic conditions, such as increased fatigue resistance and muscle strength. However, the mechanisms by which LLL irradiation exerts beneficial effects on muscle atrophy are still largely unknown., Results: The present study aimed to test our hypothesis that LLL irradiation protects skeletal muscles against Dox-induced muscle wasting by using both animal and C2C12 myoblast cell models. We established SD rats treated with 4 consecutive Dox injections (12 mg/kg cumulative dose) and C2C12 myoblast cells incubated with 2 μM Dox to explore the protective effects of LLL irradiation. We found that LLL irradiation markedly alleviated Dox-induced muscle wasting in rats. Additionally, LLL irradiation inhibited Dox-induced mitochondrial dysfunction, apoptosis, and oxidative stress via the activation of AMPK and upregulation of SIRT1 with its downstream signaling PGC-1α. These aforementioned beneficial effects of LLL irradiation were reversed by knockdown AMPK, SIRT1, and PGC-1α in C2C12 cells transfected with siRNA and were negated by cotreatment with mitochondrial antioxidant and P38MAPK inhibitor. Therefore, AMPK/SIRT1/PGC-1α pathway activation may represent a new mechanism by which LLL irradiation exerts protection against Dox myotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis., Conclusion: Our findings may provide a novel adjuvant intervention that can potentially benefit cancer patients from Dox-induced muscle wasting., (© 2021. The Author(s).)

Objective: To identify, in myometrial stem/progenitor cells, the presumptive cell of origin for uterine fibroids, substrates of Mediator-associated cyclin dependent kinase 8/19 (CDK8/19), which is known to be disrupted by uterine fibroid driver mutations in Mediator complex subunit 12 (MED12)., Design: Experimental study., Setting: Academic research laboratory., Patient(s): Women undergoing hysterectomy for uterine fibroids., Intervention(s): Stable isotopic labeling of amino acids in cell culture (SILAC) coupled with chemical inhibition of CDK8/19 and downstream quantitative phosphoproteomics and transcriptomic analyses in myometrial stem/progenitor cells., Main Outcome Measure(s): High-confidence Mediator kinase substrates identified by SILAC-based quantitative phosphoproteomics were determined using an empirical Bayes analysis and validated orthogonally by in vitro kinase assay featuring reconstituted Mediator kinase modules comprising wild-type or G44D mutant MED12 corresponding to the most frequent uterine fibroid driver mutation in MED12. Mediator kinase-regulated transcripts identified by RNA sequencing were linked to Mediator kinase substrates by computational analyses., Result(s): A total of 296 unique phosphosites in 166 proteins were significantly decreased (≥ twofold) upon CDK8/19 inhibition, including 118 phosphosites in 71 nuclear proteins representing high-confidence Mediator kinase substrates linked to RNA polymerase II transcription, RNA processing and transport, chromatin modification, cytoskeletal architecture, and DNA replication and repair. Orthogonal validation confirmed a subset of these proteins, including Cut Like Homeobox 1 (CUX1) and Forkhead Box K1 (FOXK1), to be direct targets of MED12-dependent CDK8 phosphorylation in a manner abrogated by the most common uterine fibroid driver mutation (G44D) in MED12, implicating these substrates in disease pathogenesis. Transcriptome-wide profiling of Mediator kinase-inhibited myometrial stem/progenitor cells revealed alterations in cell cycle and myogenic gene expression programs to which Mediator kinase substrates could be linked directly. Among these, CUX1 is an established transcriptional regulator of the cell cycle whose corresponding gene on chromosome 7q is the locus for a recurrent breakpoint in uterine fibroids, linking MED12 and Mediator kinase with CUX1 for the first time in uterine fibroid pathogenesis. FOXK1, a transcriptional regulator of myogenic stem cell fate, was found to be coordinately enriched along with kinase, but not core, Mediator subunits in myometrial stem/progenitor cells compared with differentiated uterine smooth muscle cells., Conclusion(s): These studies identify a new catalog of pathologically and biologically relevant Mediator kinase substrates implicated in the pathogenesis of MED12 mutation-positive uterine fibroids, and further uncover a biochemical basis to link Mediator kinase activity with CUX1 and FOXK1 in the regulation of myometrial stem/progenitor cell fate., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

(1) Background: To investigate the prognostic value of cancer-inflammation prognostic index (CIPI) in patients with metastatic colorectal cancer (mCRC) on regorafenib treatment; (2) Methods: Patients with mCRC who were given regorafenib as later-line treatment at Kaohsiung and Linkou Chang-Gung Memorial Hospital between November 2014 and January 2021 were consecutively enrolled. All relevant clinicopathologic, laboratory data and survival status were recorded. Independent prognostic factors were determined by the multivariate Cox regression method; (3) Results: In total, 106 patients in the training cohort and 250 in the validation cohort were enrolled. The median OS for patients with CIPI ≥ 300 and < 300 in the training cohort was 3.8 and 9.0 months, respectively (hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.82-4.23; p < 0.0001). Time to regorafenib, liver metastasis and CIPI were independent factors by multivariate Cox regression analyses. A new scoring model demonstrated a good discriminatory ability to risk stratification of a patient's survival; (4) Conclusions: We identified CIPI as a novel serum marker highly associated with overall survival in patients with mCRC receiving regorafenib treatment. Further confirmatory studies are warranted.

Objective: To determine whether ultrasound (US)-detected synovitis affects the therapeutic efficacy of hyaluronic acid (HA) injection for treating knee OA., Methods: Patients with symptomatic knee OA were recruited. All the patients received HA injection two times at 2-week intervals. Clinical assessments were performed using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC) at baseline and 1 and 6 months after treatment. Imaging evaluation was based on complete knee US examination and the Kellgren-Lawrence grading. Suprapatellar synovial fluid (SF) depth, synovial hypertrophy (SH) and vascularity were measured through US., Results: In total, 137 patients who fulfilled the inclusion criteria were included in the analysis. All patients demonstrated improvement in VAS and WOMAC scores at 1 and 6 months after treatment (P < 0.001). Moreover, regression model-based analysis revealed significant associations of SF depth with the VAS and WOMAC scores in all patients. Each centimetre increase in the effusion diameter was associated with a decrease in the 1-month post-treatment VAS improvement percentage (15.26; 95% CI: 0.05, 29.5; P = 0.042) and 6-month post-treatment WOMAC improvement (37.43; 95% CI: 37.68, 50.69; P < 0.01). However, SH and vascularity were not significantly associated with VAS or WOMAC scores., Conclusion: Ultrasound detected suprapatellar effusion predicts reduced efficacy of HA injection in knee OA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Doxorubicin (Dox) is an effective anthracycline anticancer drug. However, recent studies have revealed that Dox resistance is a highly critical issue, and a significant reason for treatment failure. Baicalin is a flavonoid component in the roots of Scutellaria baicalensis Georgi; however, whether baicalin can increase chemosensitivity in breast cancers is still unclear. In this study, we found that cellular apoptosis occurs when excessive intracellular ROS is generated, triggered by the dual intervention of baicalin and doxorubicin, which increases intracellular calcium [Ca 2+ ] i concentrations. Increased [Ca 2+ ] i concentrations decrease the mitochondrial membrane potential (△Ψ m ), thereby causing cellular apoptosis. Pretreatment with NAC (ROS inhibitor) or BATBA (Ca 2+ chelator) reduces baicalin-induced chemosensitivity. The findings of this study demonstrate that the effect of baicalin on Dox treatment could enhance cytotoxicity toward breast cancer cells via the ROS/[Ca 2+ ] i -mediated intrinsic apoptosis pathway-thus potentially lessening the required dosage of doxorubicin, and further exploring associated mechanisms in combined treatments for breast cancer clinical interventions in the future.

Objective: To compare Pneumocystis jirovecii pneumonia (PJP) risk between patients with autoimmune rheumatic diseases (ARD) and the general population METHODS: We identified patients with ARD recorded in the National Health Insurance Research Database of Taiwan from 2002 to 2015 and randomly selected a comparison cohort from the general population matched for age and sex. We analyzed PJP risk stratified by sex, age, comorbidities, and medications using Cox proportional hazard model., Results: We enrolled 103,117 patients with ARD. PJP risk significantly increased in patients with any ARD and with each individual ARD like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SjS), polymyositis and dermatomyositis (PM/DM), systemic sclerosis (SSc), and systemic vasculitis. Patients with PM/DM showed prominent risk with incidence rate of 12.47/100,000 patient year (95% confidence interval (CI), 32.16-86.70). In a time-dependent Cox proportional hazard model with comorbidities and medications as covariates, PM/DM, SSc, SLE, and SjS significantly increased adjusted hazard ratios (aHR) of 5.40, 5.12, 4.09, and 3.64, respectively (95% CI of 2.82-10.35, 2.16-12.13, 2.41-6.95, and 2.06-6.42, respectively). AHR after adjusting for male sex, cancer, human immunodeficiency virus infection (HIV), and interstitial lung disease also significantly increased. Use of daily oral steroid dose of >10 mg conferred the highest risk followed by mycophenolate. Use of injected steroids, cyclophosphamide, biological agents, methotrexate, and cyclosporine conferred a significantly higher risk., Conclusion: Underlying ARD significantly predisposes patients to PJP, with PM/DM posing the highest threat. In addition to underlying disease, comorbidities and concomitant immunosuppressants are major risks. The strongest risk is recent daily steroid dose of >10 mg. Mycophenolate seems to be a more prominent risk factor than cyclophosphamide. Key Points • Autoimmune rheumatic diseases (ARD) significantly increased the overall risk of PJP, and so did each individual ARD. • Use of steroids, mycophenolate, cyclophosphamide, biological agents, methotrexate, and cyclosporine all significantly increased risk of PJP. • Male, elderly, malignancy, HIV, and interstitial lung disease are also related to increased risk of PJP. • Underlying ARD, comorbidities, and use of immunosuppressant should all be considered in determining the overall risk of PJP., (© 2021. International League of Associations for Rheumatology (ILAR).)

The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair -knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc- HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice., (Copyright © 2021, American Association for the Advancement of Science.)

The molecular basis underlying the interaction between retrotransposable elements (RTEs) and the human genome remains poorly understood. Here, we profiled N 6 -methyladenosine (m 6 A) deposition on nascent RNAs in human cells by developing a new method MINT-Seq, which revealed that many classes of RTE RNAs, particularly intronic LINE-1s (L1s), are strongly methylated. These m 6 A-marked intronic L1s (MILs) are evolutionarily young, sense-oriented to hosting genes, and are bound by a dozen RNA binding proteins (RBPs) that are putative novel readers of m 6 A-modified RNAs, including a nuclear matrix protein SAFB. Notably, m 6 A positively controls the expression of both autonomous L1s and co-transcribed L1 relics, promoting L1 retrotransposition. We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se, where they act as transcriptional "roadblocks" to impede the hosting gene expression, revealing a novel host-weakening strategy by the L1s. In counteraction, the host uses the SAFB reader complex to bind m 6 A-L1s to reduce their levels, and to safeguard hosting gene transcription. Remarkably, our analysis identified thousands of MILs in multiple human fetal tissues, enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders. We propose that this m 6 A-orchestrated L1-host interaction plays widespread roles in gene regulation, genome integrity, human development and diseases., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: This study presents an intelligent table tennis e-training system based on a neural network (NN) model that recognizes data from sensors built into an armband device, with the component values (performances scores) estimated through principal component analysis (PCA)., Methods: Six expert male table tennis players on the National Youth Team (mean age 17.8 ± 1.2 years) and seven novice male players (mean age 20.5 ± 1.5 years) with less than 1 year of experience were recruited into the study. Three-axis peak forearm angular velocity, acceleration, and eight-channel integrated electromyographic data were used to classify both player level and stroke phase. Data were preprocessed through PCA extraction from forehand loop signals. The model was trained using 160 datasets from five experts and five novices and validated using 48 new datasets from one expert and two novices., Results: The overall model's recognition accuracy was 89.84%, and its prediction accuracies for testing and new data were 93.75% and 85.42%, respectively. Principal components corresponding to the skills "explosive force of the forearm" and "wrist muscle control" were extracted, and their factor scores were standardized (0-100) to score the skills of the players. Assessment results indicated that expert scores generally fell between 60 and 100, whereas novice scores were less than 70., Conclusion: The developed system can provide useful information to quantify expert-novice differences in fore-hand loop skills.