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Chih-Chang Yeh,1,2 Yu-Han Su,3 Yu-Jhe Lin,3 Pin-Jyun Chen,3 Chung-Sheng Shi,1 Cheng-Nan Chen,3,* Hsin-I Chang3,* 1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China; 2Orthopaedic Department, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan, Republic of China; 3Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan, Republic of China *These authors contributed equally to this work Abstract: Curcumin (Cur) and bisdemethoxycurcumin (BDMC), extracted from Curcuma longa, are poorly water-soluble polyphenol compounds that have shown anti-inflammatory potential for the treatment of osteoarthritis. To increase cellular uptake of Cur and BDMC in bone tissue, soybean phosphatidylcholines were used for liposome formulation. In this study, curcuminoid (Cur and BDMC)-loaded liposomes were characterized in terms of particle size, encapsulation efficiency, liposome stability, and cellular uptake. The results show that there is about 70% entrapment efficiency of Cur and BDMC in liposomes and that particle sizes are stable after liposome formation. Both types of liposome can inhibit macrophage inflammation and osteoclast differential activities. In comparison with free drugs (Cur and BDMC), curcuminoid-loaded liposomes were less cytotoxic and expressed high cellular uptake of the drugs. Of note is that Cur-loaded liposomes can prevent liposome-dependent inhibition of osteoblast differentiation and mineralization, but BDMC-loaded liposomes could not. With interleukin (IL)-1β stimulation, curcuminoid-loaded liposomes can successfully downregulate the expression of inflammatory markers on osteoblasts, and show a high osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio to prevent osteoclastogenesis. In the present study, we demonstrated that Cur and BDMC can be successfully encapsulated in liposomes and can reduce osteoclast activity and maintain osteoblast functions. Therefore, curcuminoid-loaded liposomes may slow osteoarthritis progression. Keywords: liposome, osteoarthritis, curcuminoid, OPG/RANKL ratio, bone turnover

Chung-Liang Lai,1,2 Shiuan-Yu Tseng,1,2 Chung-Nan Chen,3 Wan-Chun Liao,2 Chun-Hou Wang,4 Meng-Chih Lee,1,5,* Pi-Shan Hsu5,* 1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 2Department of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 3Department of Radiology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 4School of Physical Therapy, Chung Shan Medical University, Taichung, Taiwan; 5Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan*These authors contributed equally to this workBackground: The issue of osteoporosis-induced fractures has attracted the world's attention. Postmenopausal women are particularly at risk for this type of fracture. The nonmedicinal intervention for postmenopausal women is mainly exercise. Whole body vibration (WBV) is a simple and convenient exercise. There have been some studies investigating the effect of WBV on osteoporosis; however, the intervention models and results are different. This study mainly investigated the effect of high-frequency and high-magnitude WBV on the bone mineral density (BMD) of the lumbar spine in postmenopausal women.Methods: This study randomized 28 postmenopausal women into either the WBV group or the control group for a 6-month trial. The WBV group received an intervention of high-frequency (30 Hz) and high-magnitude (3.2 g) WBV in a natural full-standing posture for 5 minutes, three times per week, at a sports center. Dual-energy X-ray absorptiometry was used to measure the lumbar BMD of the two groups before and after the intervention.Results: Six months later, the BMD of the WBV group had significantly increased by 2.032% (P=0.047), while that of the control group had decreased by 0.046% (P=0.188). The comparison between the two groups showed that the BMD of the WBV group had increased significantly (P=0.016).Conclusion: This study found that 6 months of high-frequency and high-magnitude WBV yielded significant benefits to the BMD of the lumbar spine in postmenopausal women, and could therefore be provided as an alternative exercise.Keywords: whole body vibration, osteoporosis, postmenopausal women Corrigendum for this paper has been published

Lai CL, Tseng SY, Chen CN, et al. Clin Interv Aging. 2013;8:1603–1609. On page 1603, the author affiliations have been listed incorrectly. The correct author list is as follows:Chung-Liang Lai1,2,6Shiuan-Yu Tseng1,2Chung-Nan Chen3Wan-Chun Liao2Chun-Hou Wang4Meng-Chih Lee1,5,*Pi-Shan Hsu5,*1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 2Department of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 3Department of Radiology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 4School of Physical Therapy, Chung Shan Medical University, Taichung, Taiwan; 5Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 6Central Taiwan University of Science and Technology, Taichung, TaiwanRead the original paper

Background: Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles.Methods and Results: HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment.Conclusions: Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test a fluid flow system for the investigation of the influence of shear stress on expression of plasminogen activator inhibitor 1 (PAI-1) in human osteoarthritic (OA) articular chondrocytes (from lesional and nonlesional sites) and human SW-1353 chondrocytes. METHODS: Human SW-1353 chondrocytes and OA and normal human articular chondrocytes were cultured on type II collagen-coated glass plates under static conditions or placed in a flow chamber to form a closed fluid-circulation system for exposure to different levels of shear stress (2-20 dyn/cm(2)). Real-time polymerase chain reaction was used to analyze PAI-1 gene expression, and protein kinase C (PKC) inhibitors and small interfering RNA were used to investigate the mechanism of shear stress-induced signal transduction in SW-1353 and OA (lesional and nonlesional) articular chondrocytes. RESULTS: There was a significant reduction in PAI-1 expression in OA chondrocytes obtained from lesional sites compared with those obtained from nonlesional sites. In SW-1353 chondrocytes subjected to 2 hours of shear flow, moderate shear stresses (5 and 10 dyn/cm(2)) generated significant PAI-1 expression, which was regulated through PKCalpha phosphorylation and Sp-1 activation. These levels of shear stress also increased PAI-1 expression in articular chondrocytes from nonlesional sites and from normal healthy cartilage through the activation of PKCalpha and Sp-1 signal transduction, but no effect of these levels of fluid shear stress was observed on OA chondrocytes from lesional sites. CONCLUSION: OA chondrocytes from lesional sites and those from nonlesional sites of human cartilage have differential responses to shear stress with regard to PAI-1 gene expression, and therefore diverse functional consequences can be observed. [ABSTRACT FROM AUTHOR]

ADP-ribosylation factor 6 (ARF6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wildtype, constitutively active, fast-cycling and dominant negative mutants of ARF6. The analysis revealed a novel link of ARF6 with hypoxia-inducible factor (HIF), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late outgrowth endothelial colony forming cells (ECFCs) and hypoxic mouse lungs in vivo . A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH ECFCs showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC, and oral CTC attenuated development of PH in chronically hypoxic mice. We identify epidermal growth factor receptor (EGFR) as a direct interactor of ARF6, and EGFR signalling as a crucial mechanism linking ARF6 and HIF activation. In conclusion, we are first to demonstrate a key role of ARF6 in the regulation of HIF-2α activation in vitro and in vivo and show that HIF-2α, a master-regulator of vascular remodelling in PAH, can be targeted by a clinically approved antibiotic chlortetracycline.

DDX3 is a DEAD-box RNA helicase that plays multiple roles in RNA metabolism, including translation. We previously reported that DDX3 is required for translation of PACT, a binding partner of Dicer, suggesting a role for DDX3 in microRNA (miRNA) biogenesis and RNA interference (RNAi). Emerging evidence suggests that DDX3 plays a vital role in tumorigenesis and cancer progression, however, its underlying mechanism is still not fully understood. Here, we showed that the control of PACT by DDX3 is conserved in human cells and Caenorhabditis elegans. Using a miRNA microarray, we found that DDX3 regulates the expression of a small subset of cancer-related miRNAs. These oncogenic miRNAs were down-regulated by knockdown of DDX3 or PACT and up-regulated by overexpression of DDX3 or PACT in HEK293T cells. Similar results were obtained in human cancer HCT116 and HeLa cells. Dual luciferase reporter assay showed that DDX3 and PACT are required for short hairpin RNA (shRNA)-induced RNAi. We also performed co-immunoprecipitation to confirm the interaction between DDX3 and AGO2, a significant component of the RNA-induced silencing complex, supporting a role for DDX3 in the RNAi pathway. We further examined the effects of DDX3 and PACT on cell proliferation, and stable overexpression of DDX3 in HEK293 cells results in loss of contact inhibition of cell growth. Hence, we propose that DDX3 may participate in cancer development by regulating the RNAi pathway., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: There is a lack of uniformity across hospitals in applying inpatient versus observation status for short-stay (<48 h) pediatric hospitalizations, with negative financial implications associated with observation. Children with medical complexity (CMC) represent a growing population and incur high costs of care. The financial implications of inpatient and observation status for CMC have not been studied., Objectives: To compare costs and reimbursement for short-stay hospitalizations for CMC by inpatient and observation status, overall and stratified by payor., Methods: We performed a cohort study of short-stay hospitalizations for CMC from 2016 to 2021 at 10 children's hospitals reporting reimbursement in the Pediatric Health Information System and Revenue Management Program. The primary outcome was the cost coverage ratio (CCR), defined as an encounter's reimbursement divided by the estimated cost., Results: There were 89,282 encounters included. The median costs per encounter were similar across observation ($5206, IQR $3604-$7484) and inpatient ($6547, IQR $4725-$9349) encounters. For government payors, the median CCR was 0.6 (IQR 0.2-0.9) for observation encounters and 1.2 (IQR 0.8-1.9) for inpatient. For nongovernment payors, the median CCR was 1.6 (IQR 1.3-1.9) for observation and 1.6 (IQR 1.4-2) for inpatient. Government reimbursement was associated with increased risk for financial loss (OR 13.91, 95% CI 7.23, 26.77) and with a median net loss of $985,952 (IQR $389,871-$1,700,041) per hospital annually for observation encounters., Conclusions: Government-paid observation encounters for CMC are associated with significant financial loss at children's hospitals. This reimbursement model may pose a threat to children's hospitals' ability to care for CMC., (© 2024 The Author(s). Journal of Hospital Medicine published by Wiley Periodicals LLC on behalf of Society of Hospital Medicine.)

Pathological diagnosis plays a pivotal role in risk classification and personalized treatment planning for patients with oropharyngeal cancers. However, challenges arise in cases involving trismus and tumors with submucosal spread, hindering traditional endoscopic biopsies and open incisional biopsies. In this study, we examined the clinical and pathological data of patients with trismus who underwent transoral ultrasound-guided core biopsy (USCB) for their oropharyngeal tumors, comparing this method with existing diagnostic approaches. Seventeen patients presenting with oropharyngeal tumors and trismus underwent transoral USCB for diagnosis. Of these, 14 patients were diagnosed with squamous cell carcinoma, while the remaining 3 were diagnosed with lymphoma. The procedure resulted in minimal wound size and effective bleeding control through compression, without encountering any complications. In conclusion, transoral USCB emerges as a precise diagnostic tool for patients with oropharyngeal tumors and trismus, offering a valuable adjunct to conventional open and endoscopic biopsies., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Regorafenib, an oral multikinase inhibitor, is approved for the treatment of various metastatic/advanced cancers. Although clinical trials have reported the efficacy of regorafenib in multiple cancer types, its immunomodulatory activity in head and neck squamous cell carcinoma (HNSCC) remains unclear., Main Methods: This study investigated the effects of regorafenib on tumorigenesis by using two mouse models of HNSCC. The distribution of immune cells in tumor tissues was assessed through flow cytometry, RNA sequencing, and multiplex immunofluorescence staining., Key Findings: Regorafenib exhibited significant antitumor activity in our HNSCC mouse models. Tumor-infiltrating lymphocyte isolation and RNA sequencing revealed that regorafenib can activate immune functions. Moreover, regorafenib-treated tumor-conditioned medium regulated macrophage proliferation ex vivo. Our data suggests that regorafenib modulates immune function by regulating both tumor and immune cells. Specifically, regorafenib induced the polarization of macrophages toward the proinflammatory M1 phenotype by suppressing the production of plasminogen activator inhibitor 1 (PAI-1), a macrophage regulator. In addition, regorafenib suppressed the secretion of PAI-1 from ex vivo human HNSCC organoids., Significance: Regorafenib enhances M1/M2 macrophage polarization and suppresses PAI-1 secretion from cancer cells, leading to a shift from M2 to M1 macrophages in the HNSCC tumor microenvironment., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Auditory hallucinations are the most frequently occurring psychotic symptom in schizophrenia. Continuous theta burst stimulation (cTBS) has been used as an adjuvant treatment for auditory hallucinations. This meta-analysis focused on randomized controlled clinical trials (RCTs) to assess the efficacy of adjuvant cTBS on auditory hallucinations in schizophrenia., Methods: We performed a comprehensive search of four international databases from their inception to January 14, 2024, to identify relevant RCTs that assessed the effects of adjuvant cTBS on auditory hallucinations. The key words included "auditory hallucinations", "continuous theta burst stimulation" and "transcranial magnetic stimulation". Inclusion criteria included patients with auditory hallucinations in schizophrenia or schizoaffective disorder. The Revised Cochrane risk-of-bias tool for randomized trials (RoB1) were used to evaluate the risk of bias and the Review Manager Software Version 5.4 was employed to pool the data., Results: A total of 4 RCTs involving 151 patients with auditory hallucinations were included in the analysis. The Cochrane risk of bias of these studies presented "low risk" in all items. Preliminary analysis showed no significant advantage of adjuvant cTBS over sham stimulation in reducing hallucinations [4 RCTs, n = 151; SMD: -0.45 (95%CI: -1.01, 0.12), P = 0.13; I 2  = 61%]. Subgroup analysis revealed that patients treated with adjuvant cTBS for more than 10 stimulation sessions and total number of pulses more than 6000 [3 RCTs, n = 87; SMD: -4.43 (95%CI: -8.22, -0.63), P = 0.02; I 2  = 47%] had a statistically significant improvement in hallucination symptoms. Moreover, the rates of adverse events and discontinuation did not show any significant difference between the cTBS and sham group., Conclusions: Although preliminary analysis did not revealed a significant advantage of adjuvant cTBS over sham stimulation, subgroup analysis showed that specific parameters of cTBS appear to be effective in the treatment of auditory hallucinations in schizophrenia. Further large-scale studies are needed to determine the standard protocol of cTBS for treating auditory hallucinations., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024534045., 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 © 2024 Ye, Chen, Wei, Zhan, Li, Zhang, Huang and Yang.)

Diagnosis of early hepatic steatosis would allow timely intervention. B-mode ultrasound imaging was in question for detecting early steatosis, especially with a variety of concomitant parenchymal disease. This study aimed to use the surgical specimen as a reference standard to elucidate the clinical performance of ultrasonic echogenicity and backscatter parametric and nonparametric statistics in real-world scenarios. Ultrasound radio-frequency (RF) signals of right liver lobe and patient data were collected preoperatively. Surgical specimen was then used to histologically determine staging of steatosis. A backscatter nonparametric statistic (h), a known backscatter parametric statistic, i.e., the Nakagami parameter (m), and a quantitative echo intensity (env) were calculated. Among the 236 patients included in the study, 93 were grade 0 (<5% fat) and 143 were with steatosis. All the env, m and h statistics had shown significant discriminatory power of steatosis grades (AUC = 0.643-0.907 with p-value < 0.001). Mann-Whitney U tests, however, revealed that only the backscatter statistics m and h were significantly different between the groups of grades 0 and 1 steatosis. The two-way ANOVA showed a significant confounding effect of the elevated ALT on env (p-value = 0.028), but no effect on m or h. Additionally, the severe fibrosis was found to be a significant covariate for m and h. Ultrasonic signals acquired from different scanners were found linearly comparable., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: Low muscle mass and obesity are associated with mobility disability, cardiometabolic diseases, and loss of independence. Three skeletal muscle indices (SMIs) are proposed to adjust the body size of individuals. However, it is unknown which index is better correlated with mobility. Additionally, it remains unclear whether low muscle mass or abdominal obesity has a greater impact on the mobility and cardiometabolic health of older adults., Objectives: This study explored the association between different SMIs {appendicular skeletal muscle mass [ASM] adjusted by body height [Ht], body weight [Wt], or body mass index [BMI (kg/m 2 )]} and mobility/cardiometabolic health. The roles of low muscle mass and abdominal obesity in the mobility and cardiometabolic health of individuals were also identified., Methods: Four-hundred and twenty-seven community-dwelling middle-aged and older adults underwent body composition assessments [dual-energy x-ray absorptiometry and waist circumference (WC)], grip strength, and mobility (timed up-and-go test and chair stand test). Spearman's rank correlation coefficient and regression models were used to examine research questions. This study was registered in the Thai Clinical Trials Registry (registration number: TCTR20210521007)., Results: All SMIs were positively correlated with the grip strength (ASM/Ht 2 : r = 0.392; ASM/Wt: r = 0.439; ASM/BMI: r = 0.569). Regarding mobility, only ASM/Ht 2 wasn't relevant. After adjusting for age, sex, and WC, ASM/BMI was the only SMI associated with grip strength (β = 0.274). When age and sex were controlled, WC, but not SMI, was associated with mobility and cardiometabolic health., Conclusions: ASM/Ht 2 did not correlate with mobility in middle-aged and older adults, whereas ASM/Wt and ASM/BMI did. Abdominal obesity has a greater impact on mobility and cardiometabolic health than low muscle mass in middle-aged and older adults. We recommend using ASM/BMI to identify the low muscle mass of individuals. In addition, clinicians should note the important role of abdominal obesity when considering mobility in middle-aged and older adults., Competing Interests: The authors report no conflicts of interest., (© 2024 The Author(s).)

Objective: To investigate the clinicopathological and molecular genetic characteristics of Crohn's disease (CD). Methods: A retrospective analysis was conducted on 52 CD patients who underwent surgical resection at the First Affiliated Hospital of Nanjing Medical University between January 2014 and June 2023. Clinical presentations and histopathological features were assessed. Whole-genome sequencing was performed on 17 of the samples, followed by sequencing and pathway enrichment analyses. Immunohistochemistry was used to assess the expression of frequently mutated genes. Results: Among the 52 patients, 34 were males and 18 were females, male-to-female ratio was 1.9∶1.0, with a median age of 45 years at surgery and 35 years at diagnosis. According to the Montreal classification, A3 (51.9%,27/52), B2 (61.5%, 32/52), and L3 (50.0%,26/52) subtypes were the most predominant. Abdominal pain and diarrhea were the common symptoms. Histopathological features seen in all 52 patients included transmural inflammation, disruption of cryptal architecture, lymphoplasmacytic infiltration, varying degrees of submucosal fibrosis and thickening, increased enteric nerve fibers and neuronal proliferation. Mucosal defects, fissure ulcers, abscesses, pseudopolyps, and adenomatous proliferation were also observed in 51 (98.1%), 38 (73.1%), 28 (53.8%), 45 (86.5%), and 28 (53.8%) cases, respectively. Thirty-one (59.6%) cases had non-caseating granulomas, and 3 (5.8%) cases had intestinal mucosal glandular epithelial dysplasia. Molecular analysis showed that 12/17 CD patients exhibited mutations in at least one mucin family gene (MUC2, MUC3A, MUC4, MUC6, MUC12, MUC17), and MUC4 was the most frequently mutated in 7/17 of cases. Immunohistochemical stains showed reduced MUC4 expression in epithelial cells, with increased MUC4 expression in the epithelial surface, particularly around areas of inflammatory cell aggregation; and minimal expression in the lower half of the epithelium. Conclusions: CD exhibits diverse clinical and pathological features, necessitating a comprehensive multidimensional analysis for diagnosis. Mutations and expression alterations in mucin family genes, particularly MUC4, may play crucial roles in the pathogenesis of CD.

Objective: Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD., Method: 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations., Results: Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups ( P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes ( B = -0.610, t = -5.299, P < 0.001)., Conclusion: Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients., 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 © 2024 Ye, Zhao, Liu, Luo, Xiong, Zhan, Li, Wei, Chen and Yang.)

Competing Interests: Declaration of competing interest The authors have no competing interest to declare.

Preservation of executive function, like inhibition, closely links to the quality of life in senior adults. Although neuroimaging literature has shown enhanced inhibitory function followed by aerobic exercise, current evidence implies inconsistent neuroplasticity patterns along different time durations of exercise. Hence, we conducted a 12-week exercise intervention on 12 young and 14 senior volunteers and repeatedly measured the inhibitory functionality of distinct aspects (facilitation and interference effects) using the numerical Stroop task and functional Magnetic Resonance Imaging. Results showcased improved accuracy and reduced reaction times (RT) after 12-week exercise, attributed to frontoparietal and default mode network effects. In young adults, the first phase (0 to six weeks) exercise increased the activation of the right superior medial frontal gyrus, associated with reduced RT in interference, but in the second intervention phase (six to twelve weeks), the decreased activation of the left superior medial frontal gyrus positively correlated with reduced RT in facilitation. In senior adults, the first six-week intervention led to reduced activations of the inferior frontal gyrus, inferior parietal gyrus, and default mode network regions, associated with the reduced RT in interference. Still, in the second intervention phase, only the visual area exhibited increased activity, associated with reduced RT in interference. Except for the distinctive brain plasticity between the two phases of exercise intervention, the between-group comparison also presented that the old group gained more cognitive benefits within the first six weeks of exercise intervention; however, the cognitive improvements in the young group occurred after six weeks of intervention. Limited by the sample size, these preliminary findings corroborated the benefits of aerobic exercise on the inhibitory functions, implying an age × exercise interaction on the brain plasticity for both facilitation and interference., (© 2024. The Author(s).)

Objective: The aim of this study is to investigate the clinical value of radiomics based on non-enhanced head CT in the prediction of hemorrhage transformation in acute ischemic stroke (AIS)., Materials and Methods: A total of 140 patients diagnosed with AIS from January 2015 to August 2022 were enrolled. Radiomic features from infarcted areas on non-enhanced CT images were extracted using ITK-SNAP. The max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select features. The radiomics signature was then constructed by multiple logistic regressions. The clinicoradiomics nomogram was constructed by combining radiomics signature and clinical characteristics. All predictive models were constructed in the training group, and these were verified in the validation group. All models were evaluated with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA)., Results: Of the 140 patients, 59 experienced hemorrhagic transformation, while 81 remained stable. The radiomics signature was constructed by 10 radiomics features. The clinicoradiomics nomogram was constructed by combining radiomics signature and atrial fibrillation. The area under the ROC curve (AUCs) of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the training group were 0.64, 0.86, and 0.86, respectively. The AUCs of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the validation group were 0.63, 0.90, and 0.90, respectively. The DCA curves showed that the radiomics signature performed well as well as the clinicoradiomics nomogram. The DCA curve showed that the clinical application value of the radiomics signature is similar to that of the clinicoradiomics nomogram., Conclusion: The radiomics signature, constructed without incorporating clinical characteristics, can independently and effectively predict hemorrhagic transformation in AIS patients., 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 © 2024 Huang, Chen, Chen, Cai, Lin, Lin, Chen, Yang, Li and Wang.)

Land degradation is a major threat to ecosystem. Long-term conventional farming practices can lead to severe soil degradation and a decline in crop productivity, which are challenging for both local and global communities. This study was conducted to clarify the responses on soil physicochemical properties and microbial communities to changes in farming practices. Slope land orchards under three agricultural management practices-conventional farming (CF), organic farming (OF), and ecofriendly farming (EFF)-were included in this study. We found that soil carbon stock increased by 3.6 and 5.1 times in surface soils (0-30 cm) under EFF and OF treatments, respectively. EFF and OF significantly increased the contents of total nitrogen by 0.33-0.46 g/kg, ammonia-N by 3.0-7.3 g/kg, and microbial biomass carbon by 0.56-1.04 g/kg but reduced those of pH by 0.6 units at least, and available phosphorous by 104-114 mg/kg. The application of phosphorous-containing herbicides and chemical fertilizers might increase the contents of phosphorous and nitrate in CF soil. High abundances of Acidobacteria and Actinobacteria were observed in EFF and OF soils, likely because of phosphorous deficiency in these soils. The abundance of fungi in OF soil indicated that plants' demand for available soil phosphorous induced the fungus-mediated mineralization of organic phosphorous. High abundances of Gammaproteobacteria , Planctomycetes , Firmicutes , and Nitrospirae were observed in CF soil, possibly because of the regular use of herbicides containing phosphorous and chemical fertilizers containing high total nitrogen contents., 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 © 2024 Chen, Liao, Tzou, Lin, Chang and Jien.)

Successful management of obesity can be challenging if individuals constantly experience cravings. The present study investigated the effects of a high-protein diet, including a high-protein drink consumed immediately after high-intensity interval training (HIIT), on appetite and weight loss in obese middle-aged individuals. A total of 52 obese middle-aged individuals (58.2 ± 4.11 years old) were randomly assigned to one of three groups: the exercise group (E, n=19), exercise and high-protein diet group (ED, n=21), and a control group (n=12). The E and ED groups engaged in cycling HIIT (comprising 90 % of peak heart rate (HR peak ) for 3 min, followed by 70 % of HR peak for 3 min, for a total of 5 cycles) three times a week for 3 months. The ED group consumed a high-protein drink immediately after HIIT and had a daily protein intake of 1.6g/kg. Body composition and eating behavior were assessed before and after the intervention. Additionally, appetite levels were measured before and after each exercise session, before dinner, and before bedtime during three phases of the intervention: the first phase (weeks 3-4), the second phase (weeks 5-8), and the third phase (weeks 9-12). Results showed that only the ED group experienced a decrease in body mass index (from 27.4 ± 4.28 to 26.8 ± 4.09 kg/m 2 , p=0.04). Appetite significantly increased after exercise in both E and ED groups (p values for the three phases ranged from 0.04 to 0.001 for the E group and from 0.042 to 0.003 for the ED group). The desire to eat significantly increased after exercise in the E group (phase 1: p = 0.026; phase 2: p = 0.011; phase 3: p = 0.003), but not in the ED group. Furthermore, the frequency of late-night snacking decreased in the ED group (the score changed from 2.4 ± 0.86 to 2.7 ± 0.80, p = 0.034). Notably, the E group tended to have a higher pre-dinner appetite score than the ED group in the third phase (p = 0.063). In summary, a high daily protein intake, combined with the consumption of high-protein drinks after exercise, resulted in reduced post-exercise appetite and a decrease in the frequency of late-night snacking., Competing Interests: Declaration of Competing Interest 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. Published by Elsevier Inc.)

Background: Prevalence of psychotic-like experiences (PLEs) - reports of hallucinations and delusional thinking not meeting criteria for psychotic disorder - varies substantially across ethnoracial groups. What explains this range of PLE prevalence? Despite extensive research, the clinical significance of PLEs remains unclear. Are PLE prevalence and clinical severity differentially associated across ethnoracial groups?, Methods: We examined the lifetime prevalence and clinical significance of PLEs across ethnoracial groups in the Collaborative Psychiatric Epidemiology Surveys ( N = 11 139) using the Composite International Diagnostic Interview (CIDI) psychosis symptom screener. Outcomes included mental healthcare use (inpatient, outpatient), mental health morbidity (self-perceived poor/fair mental health, suicidal ideation or attempts), and impairment (role interference). Individuals with outcome onsets prior to PLE onset were excluded. We also examined associations of PLEs with CIDI diagnoses. Cox proportional-hazards regression and logistic regression modeling identified associations of interest., Results: Contrary to previous reports, only Asian Americans differed significantly from other U.S. ethnoracial groups, reporting lower lifetime prevalence (6.7% v. 8.0-11.9%) and mean number (0.09 v. 0.11-0.18) of PLEs. In multivariate analyses, PLE clinical significance showed limited ethnoracial variation among Asian Americans, non-Caribbean Latinos, and Afro-Caribbeans. In other groups, mental health outcomes showed significant ethnoracial clustering by outcome (e.g. hospitalization and role interference with Caribbean-Latino origin), possibly due to underlying differences in psychiatric disorder chronicity or treatment barriers., Conclusions: While there is limited ethnoracial variation in U.S. PLE prevalence, PLE clinical significance varies across U.S. ethnoracial groups. Clinicians should consider this variation when assessing PLEs to avoid exaggerating their clinical significance, contributing to mental healthcare disparities.

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo , ex vivo , and in vitro . Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3 + Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3 + Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25 + Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3 + Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3 + Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

Background: Parotid microtumors (size ≤ 1 cm) pose a significant clinical challenge due to their malignant potential and risks associated with surgery. It is imperative to explore the diagnostic workflow that incorporates ultrasound (US) in order to make appropriate clinical decisions with minimal invasiveness., Methods: The patients receiving both US and ultrasound-guided fine needle aspiration (USFNA) for the parotid microtumors in a medical center were retrospectively recruited. The ultrasonic features, cytology of USFNA, and final surgical pathology were analyzed to differentiate the tumor origins and their malignant potential., Results: From August 2009 to March 2016, a total of 92 patients were enrolled in the study. The short axis, long-to-short axis ratio, and presence of an echogenic hilum were found to be significantly useful in distinguishing lymphoid tissue origin from salivary gland origin, which was confirmed by USFNA. An irregular border was predictive for malignant parotid microtumors from both origins. Intra-tumoral heterogeneity was also identified as a significant feature associated with malignant lymph nodes. USFNA was able to confirm all malignant lymph nodes, but it had a false negative rate of 8.5% in parotid microtumors of salivary gland origin. Based on the analysis of US and USFNA results, a diagnostic workflow for parotid microtumors was proposed., Conclusion: US and USFNA can be helpful in classifying the origins of parotid microtumors. US-FNA carries the risk of producing false negative results specifically for microtumors originating from salivary glands, but not lymphoid tissue. The diagnostic workflow, which incorporates both US and USFNA, assists in determining the clinical decision for diagnosing and managing parotid microtumors., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: To elucidate whether pro-inflammatory cytokines might influence the commitment of intervertebral disc (IVD)- and ligamentum flavum (LF)-derived progenitor cells toward either osteogenesis or adipogenesis, specifically Interleukin-1β (IL-1β), IL-19, and IL-20., Methods: Sixty patients with degenerative spondylolisthesis and lumbar or lumbosacral spinal stenosis were included in the study. Injuries to the spine, infections, and benign or malignant tumors were excluded. From nine patient samples, IVD- and LF-derived cells were isolated after primary culture, and two clinical samples were excluded due to mycoplasma infection. The effects of IL-1β, IL-19, as well as IL-20 in regulating osteogenic and adipogenic differentiation in vitro were investigated., Results: Primary IVD- and LF-derived cells were found to have a similar cell morphology and profile of surface markers (CD44, CD90, and CD105) as placenta-derived mesenchymal stem cells (MSCs). Primary IVD/LF cells have a high capacity to differentiate into osteocytes and adipocytes. IL-19 had a tendency to promote adipogenesis. IL-20 inhibited osteogenesis and promoted adipogenesis; IL-1β promoted osteogenesis but inhibited adipogenesis., Conclusion: IL-1β, IL-19, and IL-20 impact the adipogenic and osteogenic differentiation of IVD-derived and LF-derived cells. Modulating the expression of IL-1β, IL-19, and IL-20 provides a potential avenue for controlling cell differentiation of IVD- and LF-derived cells, which might have beneficial effect for degenerative spondylolisthesis and spinal stenosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The prognostic value of exercise capacity has been demonstrated in subjects with established cardiovascular diseases. We aim to evaluate the independence of exercise capacity measured by treadmill exercise test (TET) in predicting long-term outcomes among various comorbidities. This study was conducted from January 2003 to December 2012 in a tertiary medical center in Taiwan. Subjects referred for symptom-limited TET were recruited. Peak achieved metabolic equivalents (METs) were determined by treadmill grade and speed at peak exercise. The main outcomes were cardiovascular and all-cause mortality by linking to the National Death Registry. A total of 18,954 participants (57.8 ± 12.8 years, 62% men) achieved a mean peak METs of 9.2. Subjects in the lowest tertile of peak METs were older, had poorer renal function, lower hemoglobin, and more comorbidities. During a median follow-up of 4.3 years, there were 642 mortalities and 132 cardiovascular deaths. Peak METs significantly predicted cardiovascular death and all-cause mortality in the multivariable Cox regression models [hazard ratio (95% confidence intervals): 0.788 (0.660-0.940) and 0.835 (0.772-0.903), respectively]. The prognostic influence of peak METs consistently appeared in the subgroups, regardless of age, gender, body weight, comorbidities, use of beta-blockers, or the presence of exercise-induced ischemia. The fitness was more predictive of long-term outcomes in young or those with ischemic changes during TET (P for interaction: 0.035 and 0.018, respectively). The benefit of fitness was nonlinearly associated with long-term survival. The prognostic impacts of exercise capacity were universally observed in subjects with or without various comorbidities., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective/hypothesis: Spindle cell carcinoma of the head and neck (HNSpCC) is a rare variant of head and neck squamous cell carcinoma (HNSCC). This study evaluated the clinical characteristics and molecular signatures of such tumors., Study Design: Retrospective analysis., Methods: Medical records of patients diagnosed with HNSpCC from 1996 to 2018 were reviewed. The clinicopathologic features, treatment modalities, and survival status were carefully recorded. Whole exome sequencing (WES) was performed to evaluate the genetic signatures of HNSpCC., Results: We found that among all 71 patients included in this study, the majority of them were male, with tumors developing predominantly in the oral cavity. The 1-, 3-, and 5-year disease-specific survival (DSS) rates were 64.6%, 49.5%, and 43.9%, respectively. A high local recurrence (LR) and distant metastasis (DM) rate (47.9%-25.3%, respectively) were observed. A significant proportion (28.2%) of patients with the worst prognosis had history of previous head and neck cancer (HNC) and had been treated with radiotherapy (RT). WES revealed that those post-RT SpCC shared common mutations with their previous HNC (pre-RT SCC), but gained additional genetic traits, such as hypoxia and cell-ECM interaction that were favorable for survival in an irradiated microenvironment. Distinct genetic landscapes in primary and post-RT SpCC were also found., Conclusions: This study demonstrates that HNSpCC is a unique entity with more aggressive behavior than conventional HNSCC. HNSpCC arising from a previously irradiated field is a predictor of dismal survival. Both genetic and microenvironmental factors contribute to this highly invasive tumor., Level of Evidence: 4 Laryngoscope, 133:2183-2191, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation., Significance: The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth., (©2023 American Association for Cancer Research.)