Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer.

Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell-mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor-T cell therapy may represent a promising strategy for patients with EphA10-positive tumors.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

The association between the severity of periodontitis and osteonecrosis of the jaw in patients with different cancer locations: a nationwide population-based study.

OBJECTIVES: To determine the relation between the severity of periodontitis and osteonecrosis of the jaw (ONJ) occurrence among different cancer locations and estimate the effect of dental care on ONJ prevention in cancer patients. MATERIALS AND METHODS: This population-based cross-sectional study was conducted through the Longitudinal Health Insurance Database, Taiwan. Patients with malignancies were collected and subdivided into groups according to their different cancer locations, the severity of periodontitis, and dental care. Multivariable logistic regression analysis was performed to assess the associations between ONJ and ONJ-related factors. RESULTS: A total of 8,234 ONJ patients and 32,912 control patients were investigated. Lip, oral cavity, and pharynx malignancies had the highest ONJ risk among all cancer locations (OR from 3.07 to 9.56, P < 0.01). There is a linear relationship between different severities of periodontitis and ONJ. Patients with radiotherapy and severe periodontitis had the highest ONJ risk (adjusted OR, 9.56; 95% CI, 5.34-17.1). Patients with good dental care had a lower ONJ risk. CONCLUSIONS: The periodontal condition and cancer location showed a significant impact on the risk of developing ONJ after adjusting for bisphosphonate use. Good dental care could decrease the risk of ONJ in cancer patients. The severity of periodontitis might be a target to predict the potency of ONJ. CLINICAL RELEVANCE: Dentists must be vigilant about the increased risk of ONJ in cancer patients with periodontitis, especially in the head and neck cancer population. Good dental care is advised for cancer patients with severe periodontitis.

Complete intraureteral stent placement reduces stent-related symptoms: Systemic review and meta-analysis.

PURPOSE: The distal coil of a double-J ureteral stent is considered the major cause of stent-related symptoms. We noticed that some recent studies investigated whether complete intraureteral stent placement (CIU-SP) reduced these symptoms. The current systemic review and meta-analysis aimed to evaluate the safety and the effectiveness of CIU-SP, as compared to conventional stent placement (C-SP). METHODS: We retrieved relevant trials published before December 2021 from three databases, including PubMED, Embase, and Web of Science. The following medical subject heading were used ((complete intraureteral stent) OR (suture stent)) AND (symptom OR pain) AND (randomized OR randomised). The above search was limited to English language publication. RESULTS: We identified six prospective randomized trials, all of which investigated a short-term (1-2 weeks) stent placement following uncomplicated ureteroscopic lithotripsy. The meta-analysis revealed that CIU-SP significantly reduced stent-related symptoms: CIU-SP had lower USSQ (Ureteral Stent Symptom Questionnaire) Urinary Symptom Index score (MD -5.13; 95%CI [-5.82,-4.44]; P < 0.00001), lower USSQ Pain Index score (MD -4.21; 95%CI [-5.25,-3.17]; P < 0.00001), and lower VAS pain scale (MD -1.93; 95%CI [-2.17,-1.69]; p < 0.00001). Besides, patients with CIU-SP were less likely to have pain (RR 0.78; 95%CI [0.67,0.91]; p = 0.001). There was no significant difference regarding the USSQ General Health and Work Performance. Both CIU-SP and C-SP had similarly few complications of Clavien-Dindo grade ≥2. CONCLUSION: This meta-analysis reveals that CIU-SP significantly decreases stent-related urinary symptoms and pain. Based on the current evidence, CIU-SP is ready to be applied in clinical practice, at least in those requiring short-term stent placement following uncomplicated ureteroscopic lithotripsy.

Impacts of nocturia on quality of life, mental health, work limitation, and health care seeking in China, Taiwan and South Korea (LUTS Asia): Results from a cross-sectional, population-based study.

BACKGROUND: While nocturia has been proposed to be related to various systemic diseases and even mortality, there has been little information of the impact of nocturia in other aspects of physical and mental well-being. We evaluated the impact of nocturia on quality of life (QoL), mental health, work limitation, and health-care seeking behavior. METHODS: An internet-based self-administered survey was distributed among individuals aged ≥40 years with the ability to use a computer and to read the local language. Survey questions included demographic details, International Continence Society symptom definitions and the international prostate symptom score. Impact on nocturia on health-related QoL physical and mental health domain, Hospital Anxiety and Depression Scale (HADS) score and Work Limitations Questionnaire (WLQ) measures was evaluated. RESULTS: There were 8284 participants (women, 51%) of whom 34% were aged ≥60 years. Prevalence of nocturia ≥2 was 35% in men and 37% in women. Across both genders, QoL decreased with increasing frequency of nocturia. Besides nocturia, hypertension, presence of neurological disorder, lower urinary tract symptom measures and female gender were also associated with HADS anxiety and depression scores of ≥8. Nocturia significantly impacted work ability across WLQ measures. Though the utilization of prescription medications increased with the increase in frequency of nocturia, it was also noted that up to 30% of participants who reported nocturia frequency of ≥3 did not seek any treatment for their complaints. CONCLUSION: Nocturia significantly affects QoL, work productivity, and mental well-being. However, healthcare utilization remains low and warrants increased awareness and education in the patients, caregivers and physicians.

RNase 7 Inhibits Uropathogenic Escherichia coli-Induced Inflammation in Bladder Cells under a High-Glucose Environment by Regulating the JAK/STAT Signaling Pathway.

Antimicrobial peptides (AMPs), which are natural antibiotics, protect against pathogens invading the urinary tract. RNase 7 with antimicrobial properties has rapid and powerful suppressive effects against Gram-positive and Gram-negative bacterial infections. However, its detailed antibacterial mechanisms have not been fully determined. Here, we investigate whether RNase 7 had an impact on bladder cells under uropathogenic Escherichia coli (UPEC) infection in a high-glucose environment using in vitro GFP-UPEC-infected bladder cell and PE-labeled TLR4, STAT1, and STAT3 models. We provide evidence of the suppressive effects of RNase 7 on UPEC infection and UPEC-induced inflammatory responses by regulating the JAK/STAT signaling pathway using JAK inhibitor and STAT inhibitor blocking experiments. Pretreatment with different concentrations of RNase 7 for 24 h concentration-dependently suppressed UPEC invasion in bladder cells (5 µg/mL reducing 45%; 25 µg/mL reducing 60%). The expressions of TLR4, STAT1, and STAT3 were also downregulated in a concentration-dependent manner after RNase 7 pretreatment (5 µg/mL reducing 35%, 54% and 35%; 25 µg/mL reducing 60%, 75% and 64%, respectively). RNase 7-induced decrease in UPEC infection in a high-glucose environment not only downregulated the expression of TLR4 protein and the JAK/STAT signaling pathway but also decreased UPEC-induced secretion of exogenous inflammatory IL-6 and IL-8 cytokines, although IL-8 levels increased in the 25 µg/mL RNase 7-treated group. Thus, inhibition of STAT affected pSTAT1, pSTAT3, and TLR4 expression, as well as proinflammatory IL-6 and IFN-γ expression. Notably, blocking JAK resulted in the rebound expression of related proteins, especially pSTAT1, TLR4, and IL-6. The present study showed the suppressive effects of RNase 7 on UPEC infection and induced inflammation in bladder epithelial cells in a high-glucose environment. RNase 7 may be an anti-inflammatory and anti-infective mediator in bladder cells by downregulating the JAK/STAT signaling pathway and may be beneficial in treating cystitis in DM patients. These results will help clarify the correlation between AMP production and UTI, identify the relationship between urinary tract infection and diabetes in UTI patients, and develop novel diagnostics or possible treatments targeting RNase 7.

Association between aphasia and risk of dementia after stroke.

BACKGROUND AND PURPOSE: Although findings from published studies suggest post-stroke aphasia is associated with an increased risk of dementia, few studies have evaluated its association in a nationally representative cohort with long-term follow-up. No studies have reported data by type of stroke. Therefore, we examined the association between post-stroke aphasia and the risk of developing dementia. METHODS: Using claims data from Taiwan's universal health insurance program, a cohort of patients ≥18 years old with an initial hospitalization for stroke in 2002-2005 were identified and followed up until December 31, 2016. Patients with newly diagnosed aphasia during stroke hospitalization or within 6 months of discharge were defined as the aphasia group. Cox proportional hazards models were used to estimate hazard ratios (HRs) for developing overall, vascular, and non-vascular dementia in patients with and without post-stroke aphasia. RESULTS: During a median follow-up period of 7.9 and 8.6 years for the aphasia (n=17063) and non-aphasia groups (n=105940), respectively, overall dementia incidence was similar, whereas vascular dementia incidence was higher in the aphasia group (7.52 vs. 5.52 per 1000 person-years). The adjusted HRs (95% confidence intervals) were 1.11 (1.06-1.17), 1.42 (1.31-1.53), and 0.94 (0.88-1.01) for overall, vascular, and non-vascular dementia, respectively. The association between aphasia and the risk of vascular dementia did not differ by stroke type (P for interaction=0.43). The analysis of 16856 propensity score-matched pairs revealed similar results. CONCLUSION: Patients with post-stroke aphasia have an increased risk of developing vascular dementia irrespective of the type of stroke.

Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway.

JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 µg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.

The impact of timing and modalities of dental prophylaxis on the risk of 5-fluorouracil-related oral mucositis in patients with head and neck cancer: a nationwide population-based cohort study.

PURPOSE: This study investigated the impact of dental prophylaxis on 5-fluorouracil (5-FU)-related oral mucositis (OM) according to the head and neck cancer (HNC) locations and treatment times. METHODS: A total of 13,969 HNC participants, including 482 5-FU-related OM subjects and 13,487 comparisons were enrolled from the Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan between 2000 and 2008. All subjects were stratified into subgroups based on the times to perform chlorhexidine use, scaling, and fluoride application before 5-FU administration. The dental prophylaxis related to 5-FU-related OM was estimated by multiple logistic regression and represented with odds ratio (OR) and 95% confidence interval (CI). RESULTS: Fluoride gel application and scaling significantly impacted on OM development (p < 0.001), and the joint effect of fluoride gel and scaling induced 5-FU-related OM (OR = 3.46, 95% CI = 2.39-5.01). The risk of OM was raised 2.25-fold as scaling within 3 weeks before 5-FU-related chemotherapy (95% CI = 1.81-2.81), and a 3.22-fold increased risk of OM while fluoride gel was applied during 5-FU-related treatment (95% CI = 1.46-7.13). CONCLUSION: Dental prophylaxis significantly affected 5-FU-related OM in the HNC population. A short interval between dental scaling or fluoride application and 5-FU administration may be associated with higher prevalence of OM. Scaling simultaneously combined with chlorohexidine promoted 5-FU-related OM in specific HNC patients excluding the oral cancer and nasopharyngeal cancer population. Proper timing of the prophylactic dental treatments prior to 5-FU therapy could reduce the risk to develop 5-FU-related OM.

Bidirectional relationship between temporomandibular disorder and ankylosing spondylitis: a population-based cohort study.

OBJECTIVES: This study aimed to determine the relation between temporomandibular disorder (TMD) and ankylosing spondylitis (AS) bidirectionally and ascertain the important comorbidities for AS occurrence in TMD patients. MATERIALS AND METHODS: We conducted this population-based cohort study through Longitudinal Health Insurance Database, Taiwan. Study 1 investigated the risk of TMD in AS patients. Study 2 assessed the risk of AS in TMD patients. RESULTS: In total, 3204 AS patients and 12,816 age-matched and gender-matched comparisons were enrolled in study 1. The TMD incidence in the AS cohort was 2.88-fold higher when compared with the comparisons (1.54 vs. 0.53 per 10,000 person-years). After adjusting for age, gender, and comorbidity, the AS cohort had a 2.66-fold (95% CI = 1.79-3.97) increased risk of TMD occurrence (P < 0.0001). The second study recruited 4998 TMD patients and 19,991 age-matched and gender-matched comparisons. Both TMD and comparison cohorts showed similar AS risk (HR = 1.49, 95% CI = 0.91-2.43, P = 0.1108) in the adjusted model. Study 2 identified a 3.66-fold increased risk of AS occurrence in TMD patients with comorbidity, including parapsoriasis, rheumatoid arthritis, osteoporosis, Cushing's syndrome, and climacteric arthritis (P < 0.012). CONCLUSIONS: AS appears to significantly impact the occurrence of TMD. TMD might play a synergic role in AS development. CLINICAL RELEVANCE: Clinicians have to be vigilant about the increased risk of TMD in AS patients and take care of AS disease activity and prognosis. The symptoms and signs of TMD could be a predictor of AS in patients with the aforementioned comorbidities.

The Effects of Tgfb1 and Csf3 on Chondrogenic Differentiation of iPS Cells in 2D and 3D Culture Environment.

Mesenchymal stem (MS) cells, embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells are known for their ability to differentiate into different lineages, including chondrocytes in culture. However, the existing protocol for chondrocyte differentiation is time consuming and labor intensive. To improve and simplify the differentiation strategy, we have explored the effects of interactions between growth factors (transforming growth factor ß1 (Tgfb1) and colony stimulating factor 3 (Csf3), and culture environments (2D monolayer and 3D nanofiber scaffold) on chondrogenic differentiation. For this, we have examined cell morphologies, proliferation rates, viability, and gene expression profiles, and characterized the cartilaginous matrix formed in the chondrogenic cultures under different treatment regimens. Our data show that 3D cultures support higher proliferation rate than the 2D cultures. Tgfb1 promotes cell proliferation and viability in both types of culture, whereas Csf3 shows positive effects only in 3D cultures. Interestingly, our results indicate that the combined treatments of Tgfb1 and Csf3 do not affect cell proliferation and viability. The expression of cartilaginous matrix in different treatment groups indicates the presence of chondrocytes. We found that, at the end of differentiation stage 1, pluripotent markers were downregulated, while the mesodermal marker was upregulated. However, the expression of chondrogenic markers (col2a1 and aggrecan) was upregulated only in the 3D cultures. Here, we report an efficient, scalable, and convenient protocol for chondrogenic differentiation of iPS cells, and our data suggest that a 3D culture environment, combined with tgfb1 and csf3 treatment, promotes the chondrogenic differentiation.

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson's Disease Models In Vivo and In Vitro.

Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3.

BACKGROUND: UPEC can internalize clonally in prostate to form biofilm-like intracellular bacterial communities (IBCs) for recurrent or chronic infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells. METHODS: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC infection. RESULTS: This study revealed that testosterone effectively suppresses UPEC infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 µg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC infection, and found the significant restoring in both the sizes of IBCs and bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their infection to prostate cells. CONCLUSIONS: Overall, our study demonstrates that testosterone suppresses the initial infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after infection. These results indicate a critical role for STAT3 in facilitating UPEC infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

The application of stem cell therapy and brown adipose tissue transplantation in metabolic disorders.

The discovery of brown fat in adult humans has led to increased research of the thermogenic function of this tissue in various metabolic diseases. In addition, high levels of brown fat have been correlated with lower body mass index values. Therefore, increasing brown fat mass and/or activity through methods such as the browning of white fat is considered a promising strategy to prevent and treat obesity-associated diseases. Cell-based approaches using mesenchymal stromal cells and brown adipose tissue (BAT) have been utilized to directly increase BAT mass/activity through cell and tissue implantation into animals. In addition, recent studies evaluating the transplantation of human embryonic stem cells and induced pluripotent stem (iPS) cells have shown promising results in terms of positive metabolic function. In this comprehensive review, we provide a summary of the research over the past 10 years with regard to stem cell therapy and brown fat tissue transplantation for the effective treatment of metabolic syndrome. Recent advancements in stem cell methods have allowed for the production of brown adipocytes from human iPS cells, which represent an unlimited source of cellular material with which to study adipocyte development. In addition, this process is expected to be used to further explore drug- and cell-based therapies to treat obesity-related metabolic complications.

The predictive value of serum testosterone level on the functional outcomes after acute ischemic stroke in males.

INTRODUCTION: We aimed to evaluate the predictive value of sex hormone levels on 3-month functional outcomes after acute ischemic stroke (AIS) in males. MATERIALS AND METHODS: A total of 110 male AIS patients were included in this prospective study. Serum levels of testosterone and estradiol were measured at admission. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) were measured at admission and after 3 months. A mRS score ≥3 was considered as a poor functional outcome. RESULTS: The median age of the 110 subjects was 62.0 [23.3] years (range 35-93 years). Univariate logistic regression revealed that bioavailable testosterone, free testosterone, age, NIHSS at admission, mRS at admission, and prior ischemic stroke were associated with a poor functional outcome (mRS score ≥3) at 3 months. In multivariate analysis, only age, NIHSS at admission, and mRS at admission were independent predictors. CONCLUSIONS: After controlling the covariates, bioavailable and free testosterone levels are not associated with the 3-month mRS in male patients with AIS. Age, NIHSS at admission, and mRS at admission are robust predictors for the functional outcomes.

Surgical niche for the treatment of erectile dysfunction.

Penile erection implicates arterial inflow, sinusoidal relaxation and corporoveno-occlusive function. By far the most widely recognized vascular etiologies responsible for organic erectile dysfunction can be divided into arterial insufficiency, corporoveno-occlusive dysfunction or mixed type, with corporoveno-occlusive dysfunction representing the most common finding. In arteriogenic erectile dysfunction, corpora cavernosa show lower oxygen tension, leading to a diminished volume of cavernosal smooth muscle and consequential corporoveno-occlusive dysfunction. Current studies support the contention that corporoveno-occlusive dysfunction is an effect rather than the cause of erectile dysfunction. Surgical interventions have consisted primarily of penile revascularization surgery for arterial insufficiency and penile venous surgery for corporoveno-occlusive dysfunction, whatever the mechanism. However, the surgical effectiveness remained debatable and unproven, mostly owing to the lack of consistent hemodynamic assessment, standardized select patient and validated outcome measures, as well as various surgical procedures. Penile vascular surgery has been disclaimed to be the treatment of choice based on the currently available guidelines. However, reports on penile revascularization surgery support its utility in treating arterial insufficiency in otherwise healthy patients aged <55 years with erectile dysfunction of late attributable to arterial occlusive disease. Furthermore, it is noteworthy that penile venous surgery might be beneficial for selected patients with corporoveno-occlusive dysfunction, especially with a better understanding of the innovated venous anatomy of the penis. Penile vascular surgery might remain a viable alternative for the treatment of erectile dysfunction, and could have found its niche in the possibility of obtaining spontaneous, unaided and natural erection.

The association between dental therapy timelines and osteoradionecrosis: a nationwide population-based cohort study.

OBJECTIVES: The study aimed to investigate the timeline association with specific dental therapy and osteoradionecrosis (ORN) in oral cancer patients. MATERIALS AND METHODS: A total of 7394 oral cancer patients, including 198 ORN subjects, were retrieved from a Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan and were analyzed with the Cox proportional hazard regression to compare the ORN risk of individual dental treatments under different dental treatments. RESULTS: The initial dental treatment time significantly impacted on the risk of ORN in oral cancer patients (P<0.05). Pre-radiotherapy endodontic treatment and post-radiotherapy scaling or subgingival curettage increased ORN prevalence (hazard ratio [HR], 2.28 and 1.77, respectively). Endodontic treatment within 2 weeks to 1 month prior to radiotherapy increased the ORN risk by 5.83-fold. Dental scaling or subgingival curettage initialized from three to 6 months post-radiotherapy raised the ORN prevalence by 2.2-fold. Exodontia initialized within 2 weeks before radiotherapy (HR=1.49) or 1 to 3 months after radiotherapy (HR=2.63) greatly increased ORN prevalence. To perform oral surgery from 3 months pre-radiotherapy to 6 months after radiotherapy increased the 1.85-fold ORN risk. The chemotherapy combined oral surgery increased the ORN prevalence by 2.55-fold. CONCLUSIONS: Timing of dental treatment, including pre-radiotherapy endodontic treatment, post-radiotherapy scaling or subgingival curettage, and oral surgery or exodontia before and after radiotherapy, could closely relate to ORN development in oral cancer patients. CLINICAL RELEVANCE: Choosing right time to perform appropriate dental treatment could effectively reduce oral infection and ORN risk.

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson's Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line.

The movement disorder Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

Prosthetic design related to peri-implant bone resorption in microvascular free fibular flap among patients with oral cancer: A retrospective clinical study.

STATEMENT OF PROBLEM: Prosthetic rehabilitation is challenging after tumor excision in patients with oral cancer. Prosthetic parameters may be compromised because of the physical limitations of the oral cavity. Although microvascular free fibular flaps are a common treatment modality for mandibular reconstruction and allow the placement of dental implants, fibular resorption under long-term functional loading is still a controversial issue. Research focusing on how prosthetic design affects fibular resorption around dental implants in an oral cancer population is lacking. PURPOSE: The purpose of this retrospective clinical study was to correlate the success of implant-supported prostheses in microvascular free fibular flaps with occlusal force and fibular resorption around the implants 7 years after functional loading. MATERIAL AND METHODS: The T-Scan III was used to measure occlusal force in 13 participants with oral cancer. Forty-seven successful endosseous dental implants (Biomet 3i) under functional loading in the participants from 2010 to 2017 were analyzed retrospectively. Prosthetic design including fibular length, rehabilitated arch length, and crown-to-implant ratios was estimated from panoramic radiographs. The intergonial distance was used to calibrate the panoramic radiographs to enhance accuracy. To compensate for panoramic distortion, all parameters were represented as a ratio such as fibular length/mandibular width; implant-supported prosthesis length/mandibular dental arch length; implant-supported prosthesis length/maxillary dental arch length; and mandibular dental arch length/maxillary dental arch length. A generalized estimating equation was used for longitudinal analysis to estimate the impact of variables on fibular resorption around the implants. RESULTS: Increased length of the implant-supported prostheses compared with maxillary and mandibular dental arch length significantly impaired the maximal occlusal force (P=.045 and P=.029). The crown-to-implant ratios in the fibular flaps were not correlated with fibular resorption around the implants under long-term functional occlusion (P>.05). The increased ratio of the implant-rehabilitated mandibular to maxillary dental arch length showed a statistically significant tendency to reduce fibular resorption around the implants (P=.007). CONCLUSIONS: Crown-to-implant ratios were not significantly correlated with maximal occlusal force or fibular resorption around dental implants. Increasing the length of the reconstructed mandibular implant-supported prosthesis in the fibular flap will reduce occlusal force. The rehabilitated mandibular dental length should be as long as the maxillary arch for optimum occlusal stress distribution to maintain the peri-implant fibula bone level.

Sialadenitis May Be Associated With an Increased Risk for Osteoradionecrosis: A Nationwide Population-Based Cohort Study.

PURPOSE: The impact of sialadenitis on osteoradionecrosis (ORN) is controversial. The aim of this study was to determine the association between sialadenitis and ORN. MATERIALS AND METHODS: Participants were derived from the Taiwanese Longitudinal Health Insurance Database. From January 1, 2000 to December 31, 2008, cases of sialadenitis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 527.2, 527.3, 527.5 to 527.7, 527.9, and 710.2) and ORN (ICD-9-CM codes 526.89, 526.5, 730.0, and 730.1) were identified. Different treatment modalities, including surgery versus medicine, were used to distinguish the severity of sialadenitis. The primary predictor variable was sialadenitis. The secondary predictor variable was severity of sialadenitis. The primary outcome variable was time to developing ORN. Other study variables were grouped for age, gender, risk factor, and medical treatment. Cox proportional hazard regression was used to investigate the associations between sialadenitis and ORN after adjusting for statistical confounders. RESULTS: The sample was composed of 47,385 patients with a mean age of 46.6 years (standard deviation, 19.9 yr) and 37.2% were men. Twenty percent had a diagnosis of sialadenitis and 1.13% had a diagnosis of ORN. Sialadenitis was associated with an increased risk of ORN (hazard ratio [HR] = 1.93; 95% confidence interval [CI], 1.61-2.31; P < .0001). After adjustment for confounders, sialadenitis was associated with ORN (multivariable HR = 1.83; 95% CI, 1.52-2.19; P < .0001). Severity of sialadenitis was associated with an increased risk of ORN; risks for ORN were 1.79 (95% CI, 1.49-2.16; P < .0001) and 3.52 (95% CI, 1.67-7.44; P < .001) in patients with mild and serious sialadenitis, respectively, compared with the no-sialadenitis cohort. For the joint effect of ORN between sialadenitis and malignancy type, patients with sialadenitis had 11.6-fold risk for ORN (95% CI, 5.58-23.9) compared with patients without malignancy. CONCLUSIONS: Sialadenitis markedly increased the risk to develop ORN. The severity of sialadenitis was positively correlated with the incidence of ORN.