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Hao-Kuang Wang,1– 3 Yu-Ting Su,4 Yu-Cheng Ho,3,5 Yung-Kuo Lee,6 Tian-Huei Chu,6 Kuang-Ti Chen,7 Cheng-Chun Wu3,5 1Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City, Taiwan; 2School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 3Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 4Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, Taiwan; 5School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 6Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan; 7Department of Veterinary Medicine, Nation Chung-Hsing University, Taichung City, TaiwanCorrespondence: Cheng-Chun Wu, School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan, Tel +886-7-6151100-7961, Fax +886-7-6155150, Email chengchunwu@isu.edu.twBackground: Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood–brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown.Methods: The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury.Results: The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia.Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.Keywords: HDAC1, stroke, blood-brain barrier, TNF-α, IL-1β, ROS, mNSS, cylinder test

Yu-Ying Wu,1,2 I-Fan Lin,1,3 Po-Yuan Chen,1,2 Cheng-Kai Lin,1,2 Cheng-Chun Wu,1 Cheng-Loong Liang,1,2 Yi-Che Lee,1,4 Chi-Wei Lin,1,5 Wei-Leng Chin,1,5 Hao Kuang Wang1,2,6 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 5Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, TaiwanCorrespondence: Hao Kuang WangDepartment of Neurosurgery, E-Da Hospital/ I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, TaiwanTel +866-975106080Email ed101393@gmail.comBackground: Osteoporotic fractures are a significant cause of morbidity and mortality affecting population worldwide. All guidelines recommended vertebral fracture assessment by dual-energy X-ray absorptiometry (DXA). This study aimed at evaluation of any associated benefits of screening with DXA in patients who had received vertebroplasty in Taiwan.Methods: Data were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. We retrospectively compared the data of patients, who were admitted for vertebroplasty, whether they received DXA screening or not. The outcomes of interest were recurrence of spinal fracture and mortality during a follow-up period of 10 years.Results: From this Taiwan national database, the screening rate of osteoporosis in patient who received vertebroplasty was 11.7%. The mean age in the non-DXA screened cohort (n=32,986) was 74.03± 12.21 years (71.98% female). In the DXA screened cohort (n=4361), the mean age was 76.43± 9.19 years (79.91% female). During the 10-year follow-up period, after matching, non-DXA patients had significantly higher mortality rates than their DXA counterparts, which were 42.37% and 37.73% (p-value < 0.0001), respectively. The re-fracture rates between non-DXA and DXA patients were not significantly different at 17.26% and 16.89% (p-value = 0.1766), respectively.Conclusion: The rate of DXA screening before patients receiving vertebroplasty was extremely low, at 11.7%. Our results showed that DXA screening before vertebroplasty in spinal fractures patients had lower mortality. From this national retrospective cohort study, routine screening of osteoporosis in spinal fracture patients can lead to reduction in mortality.Keywords: osteoporosis, vertebroplasty, DXA, mortality

Hao-Kuang Wang,1,2 Jui-Sheng Chen,1,3,4 Chien-Yu Hsu,1 Yu-Ting Su,5 Tzu-Ching Sung,2 Cheng-Loong Liang,1,6 Aij-Lie Kwan,3,7 Cheng-Chun Wu6 1Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan; 2School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Neurosurgery, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan; 5Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 7Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, TaiwanCorrespondence: Cheng-Chun WuSchool of Medicine, College of Medicine, I-Shou University, Kaohsiung, TaiwanTel +886-7-6151100-7961Fax +886-7-6155150Email chengchunwu@isu.edu.twIntroduction: Cerebral ischemia is a leading cause of disability and death worldwide. However, an effective therapeutic approach for the condition remains undiscovered. The previously proposed growth factor-based therapy has been inefficient due to its inability to pass through the blood–brain barrier. B355252, a newly developed small molecule, exhibited a potential neuroprotective effect in vivo. However, its exact efficacy in cerebral ischemia remains unclear.Methods: We adopt an endothelin-1 stereotaxic intracranial injection to induced cerebral ischemia in rat. We further conducted 2,3,5-triphenyltetrazolium chloride (TTC) staining, immunofluorescent staining, enzyme-linked immunosorbent assay (ELISA), and behavioral tests to evaluate the efficacy of B355252 in neuroprotection, anti-inflammation, and behavioral outcome improvements.Results: We identified that B355252 could protect ischemic neurons from neuronal loss by attenuating DNA damage, reducing ROS production and the LDH level, and preventing neuronal apoptosis. Moreover, inflammatory responses in astrocytic and microglial gliosis, as well as IL-1β and TNF-α levels, were ameliorated. Consequently, the behavioral outcomes of ischemic rats in neurologic responses and fore paw function recovery were improved.Discussion: Overall, our study verified the in vivo therapeutic potential of B355252. The study findings further support its application in the development of a therapeutic approach for stroke.Keywords: stroke, NGF, B355252, stroke, DNA damage, inflammation, mNSS, cylinder test

Fong-Yu Cheng,1 Yuan-Yow Chiou,2,3 Shih-Yuan Hung,4,5 Tsun-Mei Lin,6 Hao-Kuang Wang,7 Chi-Wei Lin,8 Hung-Hsiang Liou,9 Min-Yu Chang,5 Hsi-Hao Wang,5 Yi-Che Lee4,5,10 1Department of Chemistry, Chinese Culture University, Taipei, Taiwan; 2Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 5Division of Nephrology, Department of Internal Medicine, E-DA Hospital, Kaohsiung, Taiwan; 6Department of Laboratory Medicine, E-DA Hospital, Kaohsiung, Taiwan; 7Department of Neurosurgery, E-DA Hospital, Kaohsiung, Taiwan; 8Department of Medical Education, E-DA Hospital, Kaohsiung, Taiwan; 9Division of Nephrology, Department of Internal Medicine, Hsin-Jen Hospital, New Taipei City, Taiwan; 10Division of Nephrology, Department of Internal Medicine, E-DA Dachang Hospital, Kaohsiung, TaiwanCorrespondence: Yi-Che LeeDivision of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan, R.O.CTel +886-7-6150011 Ext 5121Email pipijer@gmail.comPurpose: Vitamin D3 is useful for the treatment of peritoneal dialysis (PD)-related peritoneal damage, but its side effects, such as hypercalcemia and vascular calcification, limit its applicability. Thus, we developed vitamin D-loaded magnetic nanoparticles (MNPs) and determined their therapeutic efficacy and side effects in vivo.Materials and Methods: Alginate-modified MNPs were combined with 1α, 25 (OH)2D3 to generate vitamin D-loaded nanoparticles. The particles were conjugated with an antibody against peritoneum-glycoprotein M6A (GPM6A). The particles’ ability to target the peritoneum was examined following intraperitoneal administration to mice and by monitoring their bio-distribution. We also established a PD animal model to determine the therapeutic and side effects of vitamin D-loaded MNPs in vivo.Results: Vitamin D-loaded MNPs targeted the peritoneum better than vitamin D3, and had the same therapeutic effect as vitamin D3 in ameliorating peritoneal fibrosis and functional deterioration in a PD animal model. Most importantly, the particles reduced the side effects of vitamin D3, such as hypercalcemia and body weight loss, in mice.Conclusion: Vitamin D-loaded MNPs could be an ideal future therapeutic option to treat PD-related peritoneal damage.Keywords: peritoneal dialysis, nanoparticles, vitamin D, fibrosis

Cheng-Kai Lin,1,2 Po-Yuan Chen,1,2 Yu-ying Wu,1,2 Cheng-Chun Wu,1 Han-Jung Chen,1,2 Cheng-Loong Liang,1,2 Yi-Che Lee,1,3 Chi-Wei Lin,1,4 Chao-Ming Hung,1,5,* Hao-Kuang Wang1,2,6,* 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 5Department of General Surgery, E-Da Cancer Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Chao-Ming Hung; Hao-Kuang WangDepartment of Neurosurgery, E-Da Hospital/I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 82445, TaiwanTel +866-975106080Email ed100647@edah.org.tw; ed101393@gmail.comBackground: Statin treatment improves clinical outcomes in patients with ischemic strokes, although there is no evidence regarding the safety of statin therapy in patients with intracerebral hemorrhage (ICH). This study aimed at evaluating the effects of continuing statin treatment after ICH.Methods: Data were obtained from the National Health Insurance Research Database in Taiwan. We retrospectively compared the data of patients with and without statin exposure after ICH. The outcomes of interest were recurrence of hemorrhagic stroke and mortality during a follow-up period of 10 years.Results: During the 10-year follow-up period, the mortality rate was 32.73% in the statin group and 42.77% in the non-statin group. Statin therapy in patients with acute ICH with dyslipidemia can decrease mortality.Conclusion: Statin therapy reduced the risk of 10-year mortality in patients who experienced acute hemorrhagic stroke.Keywords: statin, hemorrhagic stroke, mortality

Yi-Che Lee,1–3 Chih-Ting Huang,4 Fong-Yu Cheng,5 Shih-Yuan Hung,3,6 Tsun-Mei Lin,7 Yen-Chang Tsai,4 Chih-I Chen,8 Hao-Kuang Wang,9 Chi-Wei Lin,10 Hung-Hsiang Liou,11 Min-Yu Chang,3 Hsi-Hao Wang,3 Yuan-Yow Chiou4,12 1Division of Nephrology, Department of Internal Medicine, E-DA Dachang Hospital/ I-Shou University, Kaohsiung, Taiwan; 2School of Medicine, College of Medicine; 3Division of Nephrology, Department of Internal Medicine, E-DA Hospital/ I-Shou University, Kaohsiung, Taiwan; 4Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Chemistry, Chinese Culture University, Taipei, Taiwan; 6School of Medicine for International Students; 7Department of Laboratory Medicine; 8Division of Colorectal Surgery, Department of Surgery; 9Department of Neurosurgery; 10Department of Medical Education, E-DA Hospital/ I-Shou University, Kaohsiung, Taiwan; 11Division of Nephrology, Department of Medicine, Hsin-Jen Hospital, New Taipei City, Taiwan; 12Department of Pediatrics, National Cheng Kung University Hospital, Tainan, TaiwanCorrespondence: Yi-Che LeeDivision of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 82445, Taiwan, ROCTel +886-7-6150011 ext. 5121Email pipijer@gmail.com Yuan-Yow ChiouInstitute of Clinical Medicine, Department of Pediatrics, National Cheng Kung University Hospital, Medical College, No. 138, Sheng-Li Road, Tainan City 701, Taiwan, ROCTel +886-6-2353535 ext. 4184Fax +886-6-2753083Email yuanyow@mail.ncku.edu.twPurpose: Vitamin D is a novel potential therapeutic agent for peritoneal dialysis (PD)-related peritoneal fibrosis, but it can induce hypercalcemia and vascular calcification, which limits its applicability. In this study, we create nanotechnology-based drug delivery systems to investigate its therapeutics and side effects.Materials and methods: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) and L-α-phosphatidylcholine (PC), which packages with 1α,25(OH)2D3, were used to construct vitamin D nanoliposomes. To confirm the function and safety of vitamin D nanoliposomes, peritoneal mesothelial cells were treated with TGF-β1 and the reverse was attempted using vitamin D nanoliposomes. Antibodies (Ab) against the peritoneum-glycoprotein M6A (GPM6A) Ab were conjugated with vitamin D nanoliposomes. These particles were implanted into mice by intraperitoneal injection and the animals were monitored for the distribution and side effects induced by vitamin D.Results: Vitamin D nanoliposomes were taken up by the mesothelial cells over time without cell toxicity and it also provided the same therapeutic effect in vitro. In vivo study, fluorescent imaging showed vitamin D nanoliposomes allow specific peritoneum target effect and also ameliorate vitamin D side effect.Conclusion: Nanoliposomes vitamin D delivery systems for the prevention of PD-related peritoneal damage may be a potential clinical strategy in the future.Keywords: peritoneal dialysis, nanoliposome, vitamin D, fibrosis

Shu-Hui Lin,1,2,* Hsin-Kai Wang,3,4,* Kun-Tu Yeh,1,5 Hui-Chun Tai,1,6 Hui-Yi Wang,1 Lan-Ru Huang,2 Chun-Wen Chiu,7 Chia-Min Chung,8,9 Bharath Kumar Velmurugan101Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan; 3Public Health Bureau, Tainan City Government, Tainan, Taiwan; 4Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan; 5School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 6Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan; 8Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 9Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 10Toxicology and Biomedicine Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam*These authors contributed equally to this work Purpose: c-MYC has been noted in many tumor types, but its functional significance and clinical utility in oral squamous cell carcinoma (OSCC) are not well known. Here we studied the expression of c-MYC in correlation to clinical outcome in patients with oral squamous cell carcinoma.Methods: The current study, using immunohistochemical staining, first examined c-MYC expression in OSCC patients and further correlated its expression with clinicopathological parameters.Results: c-MYC was expressed in the majority of OSCC patients (n=133). The c-MYC expression is associated with histological grade (P=0.0205) of patients with oral squamous cell carcinoma. Multivariate Cox regression analysis revealed that TN stage (P0.05). Multiplicative-scale interaction between T stage (III/IV) and low c-MYC expression on mortality risk was identified (P=0.0233). Kaplan–Meier survival analysis demonstrated that oral cancer patients (T III/IV stage) with high c-MYC expression had better survival than those with low and medium c-MYC expression (P=0.0270).Conclusion: Our data indicate that c-MYC is a potential biomarker that can be used as a therapeutic target for treating OSCC patients with T stage (III/IV).Keywords: T stage, c-MYC, OSCC, biomarker, survival

Bharath Kumar Velmurugan,1 Hsin-Kai Wang,2,3 Chia-Min Chung,4,5 Chien-Hsun Lee,6 Lan-Ru Huang,7 Kun-Tu Yeh,6,7* Shu-Hui Lin6,8*1Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 2Public Health Bureau, Tainan City Government, Tainan City, Taiwan; 3Jenteh Junior College of Medicine, Nursing and Management, Taiwan; 4Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 5Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 7School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan *These authors contributed equally to this workIntroduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure.Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated.Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan–Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival.Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.Keywords: CIP2A, OSCC: prognosis, survival, Taiwan

Cheng-Loong Liang,1 Hao-Kwan Wang,1 Fei-Kai Syu,2 Kuo-Wei Wang,1 Kang Lu,1 Po-Chou Liliang1 1Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan; 2Department of Pharmacy, China Medical University Hospital, Taichung City, Taiwan Purpose: Postvertebral augmentation vertebral compression fractures are common; repeated vertebral augmentation is usually performed for prompt pain relief. This study aimed to evaluate the incidence and risk factors of repeat vertebral augmentation.Methods: We performed a retrospective, nationwide, population-based longitudinal observation study, using the National Health Insurance Research Database (NHIRD) of Taiwan. All patients who received vertebral augmentation for vertebral compression fractures were evaluated. The collected data included patient characteristics (demographics, comorbidities, and medication exposure) and repeat vertebral augmentation. Kaplan–Meier and stratified Cox proportional hazard regressions were performed for analyses.Results: The overall incidence of repeat vertebral augmentation was 11.3% during the follow-up until 2010. Patients with the following characteristics were at greater risk for repeat vertebral augmentation: female sex (AOR=1.24; 95% confidence interval [CI]: 1.10–2.36), advanced age (AOR=1.60; 95% CI: 1.32–2.08), diabetes mellitus (AOR=4.31; 95% CI: 4.05–5.88), cerebrovascular disease (AOR=4.09; 95% CI: 3.44–5.76), dementia (AOR=1.97; 95% CI: 1.69–2.33), blindness or low vision (AOR=3.72; 95% CI: 2.32–3.95), hypertension (AOR=2.58; 95% CI: 2.35–3.47), and hyperlipidemia (AOR=2.09; 95% CI: 1.67–2.22). Patients taking calcium/ vitamin D (AOR=2.98; 95% CI: 1.83–3.93), bisphosphonates (AOR=2.11; 95% CI: 1.26–2.61), or calcitonin (AOR=4.59; 95% CI: 3.40–5.77) were less likely to undergo repeat vertebral augmentation; however, those taking steroids (AOR=7.28; 95% CI: 6.32–8.08), acetaminophen (AOR=3.54; 95% CI: 2.75–4.83), or nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR=6.14; 95% CI: 5.08–7.41) were more likely to undergo repeat vertebral augmentation.Conclusion: We conclude that the incidence of repeat vertebral augmentation is rather high. An understanding of risk factors predicting repeat vertebral augmentation provides valuable basis to improve health care for geriatric populations. Keywords: vertebroplasty, kyphoplasty, comorbidity, bisphosphonate, old ageTwo Letters to the Editor have been recieved and published İlhan et alWilson et al

Lu K, Liliang PC, Wang HK, Chen JS, Chen TY, Huang R, Chen HJ. J Pain Res. 2016;9:917–924. Page 917, author affiliation list, the authors have requested for the affiliations to be listed as shown below. Kang Lu1Po-Chou Liliang1Hao-Kuang Wang1Jui-Sheng Chen1Te-Yuan Chen1Ruyi Huang2Han-Jung Chen1,3 1Department of Neurosurgery, E-Da Hospital, I-Shou University, 2Department of Family Medicine, E-Da Hospital, I-Shou University, 3Department of Neurosurgery, E-Da Cancer Hospital, College of Medicine, I-Shou University, Kaohsiung, TaiwanRead the original article

Background: Inflammatory events may contribute to the pathogenesis of dementia and interleukin-1 (IL-1) may exert both neurotoxic and neuroprotective effects. We investigated whether IL-1alpha -889 C/T and IL-1beta -511 C/T promoter polymorphisms are associated with the risk of Alzheimer's disease (AD) and vascular dementia (VaD). Methods: AD patients (n = 219) and VaD patients (n = 82), who fulfilled the criteria of the NINCDS-ADRDA and NINDS-AIREN, and ethnic-matched and nondemented controls (n = 209) were analyzed by means of genotype association method. Results: No significant difference in the genotype distribution of the analyzed single nucleotide polymorphisms was found between AD or VaD cases and controls. However, the frequency of the IL-1alpha -889 CT genotype was notably lower in VaD patients aged over 70 years than the age-matched controls (9.1 vs. 22.9%, p = 0.036) andtheIL-1alpha -889 CT genotype demonstrated a trend toward decrease in risk of developing VaD (odds ratio: 0.34; 95% confidence interval: 0.12-0.83, p = 0.026). Multivariate analysis revealed that the IL-1beta -511T-carrying genotype slightly strengthens the negative association of the IL-1alpha -889 CT genotype with VaD (odds ratio: 0.26; 95% confidence interval: 0.08-0.79, p = 0.024). Conclusion: Our data suggest a protective role of the IL-1alpha -889 CT genotype in VaD susceptibility among Taiwanese aged over 70 years. Copyright (c) 2007 S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

Mesophotic coral ecosystems (MCEs), located at depths ranging from 30-150 m, host some of the most diverse yet least explored marine bioresources, particularly significant for the discovery of new bioactive molecules. The fungus Beauveria sp. NBUF147, associated with an Irciniidae sponge from the mesophotic zone at a depth of 82 m, underwent chemical investigation that led to the identification of one new sterol, beautoide A (1), and one reported sterol, 3β,5α,9α-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (2). Their structures were determined from analysis of spectroscopic data and X-ray crystallography. Evaluation of biological activity in prednisolone-induced osteoporotic zebrafish showed that 1 was anti-osteoclastogenic in vivo at 3.0 μM., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Human milk oligosaccharides (HMOs) exhibit prebiotic, antimicrobial, and immunomodulatory properties and confer significant benefits to infants. Branched HMOs are constructed through diverse glycosidic linkages and prominently feature the lacto-N-biose (LNB, Gal-β1,3-GlcNAc) motif with fucose and/or sialic acid modifications, displaying structural complexity that surpasses that of N- and O-glycans. However, synthesizing comprehensive libraries of branched HMO is challenging due to this complexity. Although a few systematic synthetic strategies have emerged, many of them rely on labor-intensive chemical methodologies or exploit the substrate specificity of human N-acetylglucosaminyltransferase 2 (hGCNT2). In this study, we capitalized on the substrate promiscuities of hGCNT2 and bacterial glycosyltransferases (GTs) to construct a universal tetrasaccharide core in a highly efficient manner. This core was systematically and flexibly extended to generate diverse branched HMOs utilizing the promiscuity of bacterial GTs coupled with N-trifluoroacetyl glucosamine (GlcNTFA), which facilitated sugar chain elongation. The GlcNTFA residues were subsequently converted into various N-modified glucosamines through straightforward chemical manipulations to modulate the activities of additional GTs during glycan extension. These masked amino groups were ultimately reverted to N-acetyl groups, facilitating the synthesis of a broad range of asymmetric and multiantennary HMOs featuring LNB moieties, including many previously inaccessible structures., (© 2024 Wiley-VCH GmbH.)

Neck pain due to cervical facet joint pain has a prevalence of 36-60% in chronic neck pain. Pulsed radiofrequency for such pain has been verified. After proper patient selection, pulsed radiofrequency of the cervical facet joints provide long-term pain relief in a routine clinical setting. In the patient selection, clinical and sagittal alignment parameters are rarely discussed for the outcome. In the present study, we analyzed the factors from the clinical data and sagittal alignment parameters and investigated the associated predictors of pulsed radiofrequency for cervical facet joint pain. There were 204 patients with cervical facet joint pain who received a medial branch block and pulsed radiofrequency between 2015 and 2020 after excluding patients with neurological symptoms and other confounding factors. The patients were classified into good and poor outcome groups based on the improvement of the pain score(visual analog scale). Clinical and radiological data were analyzed. Multivariable logistic model showed that the predictors were cervical lordosis including two methods (odds ratio [OR] 0.92, 95% confidence interval [CI]: 0.89-0.96 for C2-C7 Cobb angle; OR 0.91, 95% CI: 0.88-0.95 for the angle measured by the Jackson method), ossification of the nuchal ligament, number of diseased facet joints, anterior cervical discectomy with fusion, and adjacent facet joint after anterior cervical discectomy with fusion. With the results, we demonstrated that the outcome were related to cervical lordosis including two methods, formation of ossification of nuchal ligament, the number of diseased facet joints, post anterior cervical discectomy with fusion, and adjacent facet joint post anterior cervical discectomy with fusion. The corresponding optimal cutoff for discriminating a poor outcome was 7° for the C2-C7 Cobb angle and - 2° for the angle measured using the Jackson method., Competing Interests: Declarations Ethics approval The study was approved by the Institutional Review Board of E-Da hospital (EMRP-111-065). Competing interests The authors declare no competing interests. Medical writing, editorial, and other assistance No., (© 2024. The Author(s).)

Time-resolved x-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Among human milk oligosaccharides (HMOs), linear HMOs are synthesized through mature but varied routes. Although branched HMOs can be synthesized by chemical, enzymatic, or chemoenzymatic methods, these methods cannot be easily applied to the synthesis of asymmetric multiantennary oligosaccharides. Herein, we developed a controllable method to synthesize asymmetric biantennary HMOs. In our synthetic route, GlcNAcβ1,3(GlcN3β1,6)Glaβ1,4Glc was first chemically synthesized as the core tetrasaccharide, which contains β1,6GlcN3 as the "stop" sugar in transferase-catalyzed glycosylation. The desired sugars at the GlcNAcβ1-3Gal arm can be assembled using galactosyltransferase, N -acetylglucosaminyltransferase, and fucosyltransferase. Then, the Staudinger reduction and acetylation were used to transform GlcN3 to GlcNAc and assemble sugars by initiating the "go" process. By manipulating transferase-catalyzed glycosylations, 22 natural asymmetric biantennary oligosaccharides were synthesized., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Gallbladder cancer (GBC) is highly aggressive and has poor prognosis, with most patients only diagnosed at an advanced stage. Furthermore, treatment options are limited, and their effect is unsatisfactory. Bromodomain-containing protein (BRD) is an epigenetic regulator that plays a carcinogenic role in several tumors, including squamous cell lung cancer, acute myeloid leukemia, synovial sarcoma, and malignant rhabdomyosarcoma. However, the expression, biological function, and molecular mechanisms of action of BRD9 in GBC are still unknown. Kaplan-Meier analysis, qRT-PCR, and analysis of clinical features were used to assess the clinical significance of BRD9 in GBC. Cell Counting Kit-8 and colony formation assays were performed to determine the effects of BRD9 on cell growth. The functional role of BRD9 in GBC was explored using qRT-PCR, western blotting, siRNA, and CHIP-qPCR. mRNA sequencing was performed to explore the underlying mechanisms of BRD9, and a nude mouse model of GBC was established to explore the anti-tumor effects of the BRD9 inhibitor I-BRD9 in vivo. BRD9 expression was elevated in GBC tissues compared with adjacent non-tumor tissues, and high BRD9 expression was associated with poor prognosis in patients with GBC. BRD9 knockdown by siRNA significantly decreased cell growth. Targeting BRD9 with I-BRD9 inhibited the proliferation of GBC cells without significant toxic effects. Additionally, I-BRD9 treatment suppressed CST1 expression in GBC cell lines, thereby inhibiting the PI3K-AKT pathway. The transcription factor FOXP1 was found to interact with BRD9 to regulate CST1 expression. Collectively, these results suggest that BRD9 may be a promising biomarker and therapeutic target for GBC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Animal experiments involving nude mice met the requirements and were approved by Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (Animal experiment approval number: XHEC–NSFC–2021-093, approval date: February 24, 2021). The study was approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiaotong University School of Medicine. Informed consent was obtained from the patients for this study. Consent for publication All authors have seen and approved the manuscript and consent publication., (© 2024. The Author(s).)

Competing Interests: The authors declare no conflicts of interest.

Most x-ray sources are inherently polychromatic. Polychromatic ("pink") x-rays provide an efficient way to conduct diffraction experiments as many more photons can be used and large regions of reciprocal space can be probed without sample rotation during exposure-ideal conditions for time-resolved applications. Analysis of such data is complicated, however, causing most x-ray facilities to discard >99% of x-ray photons to obtain monochromatic data. Key challenges in analyzing polychromatic diffraction data include lattice searching, indexing and wavelength assignment, correction of measured intensities for wavelength-dependent effects, and deconvolution of harmonics. We recently described an algorithm, Careless, that can perform harmonic deconvolution and correct measured intensities for variation in wavelength when presented with integrated diffraction intensities and assigned wavelengths. Here, we present Laue-DIALS, an open-source software pipeline that indexes and integrates polychromatic diffraction data. Laue-DIALS is based on the dxtbx toolbox, which supports the DIALS software commonly used to process monochromatic data. As such, Laue-DIALS provides many of the same advantages: an open-source, modular, and extensible architecture, providing a robust basis for future development. We present benchmark results showing that Laue-DIALS, together with Careless, provides a suitable approach to the analysis of polychromatic diffraction data, including for time-resolved applications., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Due to the specific loads that occur in combat sports athletes' forearm muscles, we decided to compare the immediate effect of monotherapy with the use of compressive heat (HT), cold (CT), and alternating therapy (HCT) in terms of eliminating muscle tension, improving muscle elasticity and tissue perfusion and forearm muscle strength. This is a single-blind, randomized, experimental clinical trial. Group allocation was performed using simple 1:1 sequence randomization using the website randomizer.org. The study involved 40 40 combat sports athletes divided into four groups and four therapeutic sessions lasting 20 min. (1) Heat compression therapy session (HT, n = 10) (2) (CT, n = 10), (3) alternating (HCT, n = 10), and sham, control (ShT, n = 10). All participants had measurements of tissue perfusion (PU, [non-reference units]), muscle tension (T-[Hz]), elasticity (E-[arb- relative arbitrary unit]), and maximum isometric force (Fmax [kgf]) of the dominant hand at rest (Rest) after the muscle fatigue protocol (PostFat.5 min), after therapy (PostTh.5 min) and 24 h after therapy (PostTh.24 h). A two-way ANOVA with repeated measures: Group (ColdT, HeatT, ContrstT, ControlT) × Time (Rest, PostFat.5 min, PostTh.5 min, Post.24 h) was used to examine the changes in examined variables. Post-hoc tests with Bonferroni correction and ± 95% confidence intervals (CI) for absolute differences (△) were used to analyze the pairwise comparisons when a significant main effect or interaction was found. The ANOVA for PU, T, E, and Fmax revealed statistically significant interactions of Group by Time factors (p < 0.0001), as well as main effects for the Group factors (p < 0.0001; except for Fmax). In the PostTh.5 min. Period, significantly (p < 0.001) higher PU values were recorded in the HT (19.45 ± 0.91) and HCT (18.71 ± 0.67) groups compared to the ShT (9.79 ± 0.35) group (△ = 9.66 [8.75; 10.57 CI] > MDC (0.73) , and △ = 8.92 [8.01; 9.83 CI] > MDC (0.73) , respectively). Also, significantly (p < 0.001) lower values were recorded in the CT (3.69 ± 0.93) compared to the ShT (9.79 ± 0.35) group △ = 6.1 [5.19; 7.01 CI] > MDC (0.73) . For muscle tone in the PostTh.5 m period significantly (p < 0.001) higher values were observed in the CT (20.08 ± 0.19 Hz) group compared to the HT (18.61 ± 0.21 Hz), HCT (18.95 ± 0.41 Hz) and ShT (19.28 ± 0.33 Hz) groups (respectively: △ = 1.47 [1.11; 1.83 CI] > MDC (0.845) ; △ = 1.13 [0.77; 1.49 CI] > MDC (0.845) , and △ = 0.8 [0.44; 1.16 CI], < MDC (0.845) ). The highest elasticity value in the PostTh.5 m period were observed in the CT (1.14 ± 0.07) group, and it was significantly higher than the values observed in the HT (0.97 ± 0.03, △ = 0.18 [0.11; 0.24 CI] > MDC (0.094) , p < 0.001), HCT (0.90 ± 0.04, △ = 0.24 [0.17; 0.31 CI] > MDC (0.094) , p < 0.001) and ShT (1.05 ± 0.07, △ = 0.094 [0.03; 0.16 CI] = MDC (0.094) , p = 0.003) groups. For Fmax, there were no statistically significant differences between groups at any level of measurement. The results of the influence of the forearm of all three therapy forms on the muscles' biomechanical parameters confirmed their effectiveness. However, the effect size of alternating contrast therapy cannot be confirmed, especially in the PostTh24h period. Statistically significant changes were observed in favor of this therapy in PU and E measurements immediately after therapy (PostTh.5 min). Further research on contrast therapy is necessary., (© 2024. The Author(s).)

The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study presents the first room-temperature crystal structure of mouse VDAC-1 (mVDAC-1), which is a significant step toward understanding the channel's gating mechanism. The new structure, obtained at a 3.3 Å resolution, demonstrates notable differences from the previously determined cryogenic structure, particularly in the loop regions, which may be critical for the transition between the 'open' and 'closed' states of VDAC-1. Comparative analysis of the root-mean-square deviation (R.M.S.D.) and B-factors between the cryogenic and room-temperature structures suggests that these conformational differences, although subtle, are important for VDAC's functional transitions. The application of electric field-stimulated X-ray crystallography (EF-X) is proposed as a future direction to resolve the 'closed' state of VDAC-1 by inducing voltage-driven conformational changes in order to elucidate the dynamic gating mechanism of VDAC-1. Our findings have profound implications for understanding the molecular basis of VDAC's role in mitochondrial function and its regulation under physiological conditions.

The current standard method for amino acid signal identification in protein NMR spectra is sequential assignment using triple-resonance experiments. Good software and elaborate heuristics exist, but the process remains laboriously manual. Machine learning does help, but its training databases need millions of samples that cover all relevant physics and every kind of instrumental artifact. In this communication, we offer a solution to this problem. We propose polyadic decompositions to store millions of simulated three-dimensional NMR spectra, on-the-fly generation of artifacts during training, a probabilistic way to incorporate prior and posterior information, and integration with the industry standard CcpNmr software framework. The resulting neural nets take [ 1 H, 13 C] slices of mixed pyruvate-labeled HNCA spectra (different CA signal shapes for different residue types) and return an amino acid probability table. In combination with primary sequence information, backbones of common proteins (GB1, MBP, and INMT) are rapidly assigned from just the HNCA spectrum.

Objective: The study aimed to investigate the effects of the level of contraction during isometric shoulder abduction at different abduction angles on muscle thickness and stiffness of the shoulder girdle in asymptomatic individuals., Design: Measurement properties study., Setting: Biomechanics and motion analysis lab., Participants: Twenty individuals volunteered to participate in this study., Main Outcome Measure: The subjects were tested for morphological and mechanical properties, expressed by thickness and stiffness of the supraspinatus tendon and muscle, and upper trapezius muscle. Moreover, acromiohumeral distance was also evaluated using B-mode ultrasound and shear-wave elastography., Intervention: The thickness and stiffness of the supraspinatus and upper trapezius muscle were assessed at 3 angles of abduction (0°, 60°, and 90°) and 3 levels of contraction (0%, 10%, and 20% of the maximal voluntary isometric contraction) using ultrasonography with shear-wave imaging. Moreover, the acromiohumeral distance was measured to establish the occupation ratio during passive movement., Results: The supraspinatus and upper trapezius muscle thickness and stiffness were significantly greater at 60° shoulder abduction compared with 0°, and 90° compared with 60°, as well as significantly greater at 20% maximal voluntary isometric contraction compared with 0% and 10% maximal voluntary isometric contraction. Thickness and stiffness were significantly greater in the supraspinatus compared with the upper trapezius muscle at all 3 angles of shoulder abduction for all 3 level of contractions. The acromiohumeral distance decreased significantly from 0° to 60° and from 60° to 90°., Conclusion: Morphological and mechanical properties of the supraspinatus and upper trapezius muscles depended on the relative level of muscle contraction and the angle of shoulder abduction.

Time-resolved X-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data.

Chemical and conformational changes underlie the functional cycles of proteins. Comparative crystallography can reveal these changes over time, over ligands, and over chemical and physical perturbations in atomic detail. A key difficulty, however, is that the resulting observations must be placed on the same scale by correcting for experimental factors. We recently introduced a Bayesian framework for correcting (scaling) X-ray diffraction data by combining deep learning with statistical priors informed by crystallographic theory. To scale comparative crystallography data, we here combine this framework with a multivariate statistical theory of comparative crystallography. By doing so, we find strong improvements in the detection of protein dynamics, element-specific anomalous signal, and the binding of drug fragments.

Two cases of complicated pain exist: posterior screw fixation and myofascial pain. Intramuscular pulsed radiofrequency (PRF) may be an alternative treatment for such patients. This is a two-stage animal study. In the first stage, two muscle groups and two nerve groups were subdivided into a high-temperature group with PRF at 58 °C and a regular temperature with PRF at 42 °C in rats. In the second stage, two nerve injury groups were subdivided into nerve injury with PRF 42 °C on the sciatic nerve and muscle. Blood and spinal cord samples were collected. In the first stage, the immunohistochemical analysis showed that PRF upregulated brain-derived neurotrophic factor (BDNF) in the spinal cord in both groups of rats. In the second stage, the immunohistochemical analysis showed significant BDNF and tropomyosin receptor kinase B (TrkB) expression within the spinal cord after PRF in muscles and nerves after nerve injury. The blood biomarkers showed a significant increase in BDNF levels. PRF in the muscle in rats could upregulate BDNF-TrkB in the spinal cord, similar to PRF on the sciatica nerve for pain relief in rats. PRF could be considered clinically for patients with complicated pain and this study also demonstrated the role of BDNF in pain modulation. The optimal temperature for PRF was 42 °C.

Introduction: Most adrenal tumors are benign and primary adrenal malignancies are relatively rare. Primary adrenal lymphoma (PAL) is a very rare and highly aggressive malignant tumor with unknown etiology, atypical clinical symptoms, nonspecific imaging manifestations, difficult disease diagnosis and poor prognosis., Case Report: This case report details a 42-year-old woman who was admitted to the hospital with a 1-year-old bilateral adrenal mass and 1-month-old left upper abdominal pain. Enhanced CT of the abdomen showed a right adrenal nodule and a large occupying lesion in the left adrenal region, with a high probability of pheochromocytoma. Intraoperatively, a huge tumor measuring about 12*12*10 cm was found in the left adrenal region, infiltrating the left kidney, spleen and pancreatic tail. Postoperative pathology: lymphocytes were found in the renal capsule and subcapsule, lymphocytes were found in the pancreas; lymphocytes were found in the spleen. Consider a tumor of the lymphohematopoietic system, possibly lymphoma., Conclusion: This case demonstrates that primary adrenal diffuse large B-cell lymphoma (PADLBCL) is highly aggressive, has a poor prognosis, is prone to recurrence, has poor therapeutic outcomes, and is difficult to diagnose. Clinicians should consider the possibility of PADLBCL when encountering huge adrenal-occupying lesions and consider chemotherapy before surgery. Reducing the tumor size before surgery is a more favorable therapeutic approach, thus prolonging the patient life and improving the quality of survival., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)