Nucleocytoplasmic shuttling of BEFV M protein-modulated by lamin A/C and chromosome maintenance region 1 through a transcription-, carrier- and energy-dependent pathway.

This study demonstrates for the first time that the matrix (M) protein of BEFV is a nuclear targeting protein that shuttles between the nucleus and the cytoplasm in a transcription-, carrier-, and energy-dependent manner. Experiments performed in both intact cells and digitonin-permeabilized cells revealed that M protein targets the nucleolus and requires carrier, cytosolic factors or energy input. By employing sequence and mutagenesis analyses, we have determined both nuclear localization signal (NLS) 6KKGKSK11 and nuclear export signal (NES) 98LIITSYL TI106 of M protein that are important for the nucleocytoplasmic shuttling of M protein. Furthermore, we found that both lamin A/C and chromosome maintenance region 1 (CRM-1) proteins could be coimmunoprecipitated and colocalized with the BEFV M protein. Knockdown of lamin A/C by shRNA and inhibition of CRM-1 by leptomycin B significantly reduced virus yield. Collectively, this study provides novel insights into nucleocytoplasmic shuttling of the BEFV M protein modulated by lamin A/C and CRM-1 and by a transcription- and carrier- and energy-dependent pathway.

Robotic partial nephrectomy for renal tumor: The pentafecta outcomes of a single surgeon experience.

PURPOSE: This study investigated the oncological and functional surgical outcomes for patients with renal tumor who underwent robot-assisted partial nephrectomy (PN) by a single surgeon in Taiwan from 2006 to 2019. METHODS: This retrospective study assessed patients who underwent robot-assisted PN for renal tumor. Patient data were analyzed for age, sex, body mass index, operative time and total ischemic time, surgical margin (positive/negative), and surgical complications. To evaluate functional and oncological outcomes, achievement of trifecta, and pentafecta criteria was used. Trifecta criteria were defined as a negative surgical margin, no postoperative complications, warm ischemia time <25 min. Pentafecta criteria were the trifecta criteria, >90% preservation of estimated glomerular filtration rate (eGFR) preservation, and no stage progression of chronic kidney disease at 1-year follow-up. RESULTS: Of 101 patients who received robot-assisted PN, the most common type of renal tumor was clear cell renal cell carcinoma (RCC) (38%), followed by angiomyolipoma (26%). Patient characteristics were mean age 54.59 ± 13.8 years; mean RENAL Nephrometry score 6.63 ± 2.16; mean operative time 102.34 ± 50.06 min; and warm ischemia time 20.01 ± 14.12 min. The mean eGFR was 104.43 ± 31.73 mL/min/1.73 m2 preoperatively and 89.39 ± 32.3 mL/min/1.73 m2 postoperatively. Pathologic evaluation showed malignant tumors in 57 patients, among whom achievement of trifecta criteria occurred for 39 (68.42%) and pentafecta criteria for 18 (31.57%). Operation time was the only predictor for pentafecta achievement. CONCLUSION: Robotic PN is a safe and effective approach for patients with renal tumor that can preserve most renal function and achieve oncological control. Pentafecta criteria can be used to more clearly define the surgical outcome of RAPN.

Oncolytic Avian Reovirus σA-Modulated Upregulation of the HIF-1α/C-myc/glut1 Pathway to Produce More Energy in Different Cancer Cell Lines Benefiting Virus Replication.

Our previous reports proved that the structural protein σA of avian reovirus (ARV) is an energy activator which can regulate cellular metabolism that is essential for virus replication. This study has further demonstrated that the ARV protein σA is able to upregulate the HIF-1α/myc/glut1 pathway in three cancer cell lines (A549, B16-F10, and HeLa) to alter the metabolic pathway of host cells. Quantitative real-time RT-PCR and Western blotting results have revealed that σA protein could enhance both mRNA and the protein levels of HIF-1α, c-myc, and glut1 in these cancer cell lines. In this work, ATeam immunofluorescence staining was used to reveal that knockdown of HIF-1α, c-myc, and glut1 by shRNAs decreased cellular ATP levels. Our data reveal that the ARV σA protein can downregulate lactate fermentation and upregulate glutaminolysis. The σA protein upregulates glutaminase, which converts glutamate into the TCA cycle intermediate α-ketoglutarate, activating the TCA cycle. In the lactate fermentation pathway, ARV σA protein suppresses lactate dehydrogenase A (LDHA), implying the Warburg effect does not occur in these cancer cell lines. This study provides a novel finding revealing that ARV σA protein upregulates glycolysis and glutaminolysis to produce energy using the HIF-1α/c-myc/glut1 pathway to benefit virus replication in these cancer cell lines.

Echinocystic Acid Ameliorates Arthritis in SKG Mice by Suppressing Th17 Cell Differentiation and Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Inflammation.

Echinocystic acid (EA), a pentacyclic triterpene, exhibits anti-inflammatory, antioxidant, and analgesic activities to counteract pathological effects in various diseases. Here, we aimed to determine the immunomodulatory effect of EA on zymosan-induced arthritis in SKG mice and how it would influence Th17 differentiation and human rheumatoid arthritis fibroblast-like synoviocytes inflammation. Our results showed that EA (10 and 25 mg/kg) attenuated arthritis symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion, and the high levels of proinflammatory cytokines, such as TNF-α, interleukin (IL)-6, and IL-1ß in paw tissues, and reduced the number of splenic Th17 cells. Mechanistically, we found that in vitro treatment of EA inhibited both IL-6- and transforming growth factor-ß (TGF-ß)-induced Th17 cell differentiation by suppressing the phosphorylation of signal transducers and transcriptional activators, especially STAT3. In line with the in vivo result, EA significantly reduced the protein and mRNA expression of IL-6 and IL-1ß in human RA-FLA cells, MH7A cells. Furthermore, the production of both cytokines was confirmed with the downregulation of mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB) signaling pathways under the stimulation of TNF-α. In conclusion, these findings revealed that EA was capable of amelioration of arthritic disorders in SKG mice through inhibiting Th17 cell differentiation and synovial fibroblast inflammation, supporting that EA is a promising therapeutic candidate for treating RA patients.

Lactoferrin Ameliorates Ovalbumin-Induced Asthma in Mice through Reducing Dendritic-Cell-Derived Th2 Cell Responses.

Asthma is a chronic respiratory disease with symptoms such as expiratory airflow narrowing and airway hyperresponsiveness (AHR). Millions of people suffer from asthma and are at risk of life-threatening conditions. Lactoferrin (LF) is a glycoprotein with multiple physiological functions, including antioxidant, anti-inflammatory, antimicrobial, and antitumoral activities. LF has been shown to function in immunoregulatory activities in ovalbumin (OVA)-induced delayed type hypersensitivity (DTH) in mice. Hence, the purpose of this study was to investigate the roles of LF in AHR and the functions of dendritic cells (DCs) and Th2-related responses in asthma. Twenty 8-week-old male BALB/c mice were divided into normal control (NC), ovalbumin (OVA)-sensitized, and OVA-sensitized with low dose of LF (100 mg/kg) or high dose of LF (300 mg/kg) treatment groups. The mice were challenged by intranasal instillation with 5% OVA on the 21st to 27th day after the start of the sensitization period. The AHR, cytokines in bronchoalveolar lavage fluid, and pulmonary histology of each mouse were measured. Serum OVA-specific IgE and IgG1 and OVA-specific splenocyte responses were further detected. The results showed that LF exhibited protective effects in ameliorating AHR, as well as lung inflammation and damage, in reducing the expression of Th2 cytokines and the secretion of allergen-specific antibodies, in influencing the functions of DCs, and in decreasing the level of Th2 immune responses in a BALB/c mouse model of OVA-induced allergic asthma. Importantly, we demonstrated that LF has practical application in reducing DC-induced Th2 cell responses in asthma. In conclusion, LF exhibits anti-inflammation and immunoregulation activities in OVA-induced allergic asthma. These results suggest that LF may act as a supplement to prevent asthma-induced lung injury and provide an additional agent for reducing asthma severity.

Serum lipopolysaccharide-binding protein levels and cardiovascular events in hemodialysis patients: A prospective cohort study.

INTRODUCTION: Patients with end-stage kidney disease (ESKD) exhibit an elevated cardiovascular risk. Chronic inflammation is one of the main mechanisms of cardiovascular disease (CVD). Lipopolysaccharide has been proposed as a link between systemic inflammation and CVD. Herein, we evaluated whether lipopolysaccharide-binding protein (LBP), a surrogate marker of lipopolysaccharide and consequent inflammation, is associated with cardiovascular events in ESKD. METHODS: We performed a prospective cohort study of maintenance haemodialysis patients. Baseline serum LBP levels were categorized into tertiles and also modelled continuously for analyses. Cox regression methods were used to evaluate the association of serum LBP levels with cardiovascular events. RESULTS: A total of 360 haemodialysis patients were included in this analysis. During a median follow-up of 3.1 years, 90 (25.0%) patients had cardiovascular events. Patients in the upper tertile of serum LBP levels had a significantly greater risk of cardiovascular events [hazard ratio (HR) 4.87; 95% confidence intervals (CI), 2.12-11.15] than those in the lower tertile, independent of age, sex, hypertension, diabetes, CVD, dialysis vintage, body mass index, non-high-density lipoprotein cholesterol, albumin, phosphorus, high-sensitivity C-reactive protein, and interleukin-6. The association was consistent regardless of whether competing risk of death was accounted for (subdistribution HR 4.87; 95% CI, 1.96-12.11 for upper versus lower tertiles) or serum LBP was analysed as a continuous variable (HR 1.30; 95% CI, 1.02-1.66 per 1 SD increment). CONCLUSIONS: Serum LBP levels were independently associated with cardiovascular events in heomodialysis patients. LBP might serve as a novel biomarker for CVD in ESKD.

Oncolytic avian reovirus σA-modulated fatty acid metabolism through the PSMB6/Akt/SREBP1/acetyl-CoA carboxylase pathway to increase energy production for virus replication.

We have demonstrated previously that the σA protein of avian reovirus (ARV) functions as an activator of cellular energy, which upregulates glycolysis and the TCA cycle for virus replication. To date, there is no report with respect to σA-modulated regulation of cellular fatty acid metabolism. This study reveals that the σA protein of ARV inhibits fatty acids synthesis and enhance fatty acid oxidation by upregulating PSMB6, which suppresses Akt, sterol regulatory element-binding protein 1 (SREBP1), acetyl-coA carboxylase α (ACC1), and acetyl-coA carboxylase ß (ACC2). SREBP1 is a transcription factor involved in fatty acid and cholesterol biosynthesis. Overexpression of SREBP1 reversed σA-modulated suppression of ACC1 and ACC2. In this work, a fluorescence resonance energy transfer-based genetically encoded indicator, Ateams, was used to study σA-modulated inhibition of fatty acids synthesis which enhances cellular ATP levels in Vero cells and human cancer cell lines (A549 and HeLa). By using Ateams, we demonstrated that σA-modulated inhibition of Akt, SREBP1, ACC1, and ACC2 leads to increased levels of ATP in mammalian and human cancer cells. Furthermore, knockdown of PSMB6 or overexpression of SREBP1 reversed σA-modulated increased levels of ATP in cells, indicating that PSMB6 and SREBP1 play important roles in ARV σA-modulated cellular fatty acid metabolism. Furthermore, we found that σA R155/273A mutant protein loses its ability to enter the nucleolus, which impairs its ability to regulate fatty acid metabolism and does not increase ATP formation, suggesting that nucleolus entry of σA is critical for regulating cellular fatty acid metabolism to generate more energy for virus replication. Collectively, this study provides novel insights into σA-modulated inhibition of fatty acid synthesis and enhancement of fatty acid oxidation to produce more energy for virus replication through the PSMB6/Akt/SREBP1/ACC pathway.

Promotion of Smoking Cessation Using the Transtheoretical Model: Short-Term and Long-Term Effectiveness for Workers in Coastal Central Taiwan.

Background: Smoking cessation reduces the risk of severe illnesses in the long run and contributes to improving health. This study evaluated the short-term and long-term effectiveness of workplace smoking cessation intervention implemented using the transtheoretical model. Methods: Participants were assessed at baseline before the intervention and after 6 months and 4 years of follow-ups. Data on changes in participants' perception of smoking prohibition in the workplace, knowledge of the hazards of smoking, attitude towards quitting smoking, and behavior related to tobacco harm prevention were collected. Results: Results showed the prevalence of smoking cessation was 31.5% (95% CI: 25.4-38.1%) after 6 months and 10.7% (95% CI: 6.9-15.6%) after 4 years. At the abovementioned time points, the prevalence of second-hand smoke exposure, and the proportion of people who demonstrated correct knowledge of smoke hazards initially decreased and then increased. The proportion of participants who had seen or received information about tobacco harm prevention provided in the workplace increased from 75.6% at baseline to 95.6% (increased by 20.0%) after 6 months and finally to 97.2% (increased by 21.6%) after 4 years (P < .001). However, the percentage of participants who hoped their workplace continued to provide smoking cessation services rose from 80.0% at baseline to 93.6% (increased by 13.6%) after 6 months and then fell to 78.0% (decreased by 2.0%) after 4 years (P < .001). Conclusion: The short-term effectiveness of the transtheoretical model in promoting workplace smoking cessation is substantial, but in the long-term, effectiveness weakens.

Iatrogenic Vocal Fold Paralysis: A Population-Based Cohort Study in Taiwan.

OBJECTIVE: Iatrogenic vocal fold paralysis is an important issue in laryngology, yet there are few population-based studies regarding the epidemiology. This study used a nationwide population-based claims database (the National Health Insurance Research Database) to investigate the epidemiology of iatrogenic unilateral and bilateral vocal fold paralysis (UVFP/BVFP) among the general adult population in Taiwan. METHOD: This study analyzed patients (20-90 years old) who underwent thyroid, parathyroid, thoracic, cardiac, or anterior cervical spine operations with vocal fold paralysis among adults in Taiwan from January 1, 2007 to December 31, 2013. The codes for vocal fold paralysis were defined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Claims data in the Taiwan National Health Insurance Research Database were used. RESULTS: The most commonly performed operations which were related to vocal fold paralysis in Taiwan were, in descending order of frequency, thyroid, cervical spine, cardiac, thoracic (esophagectomy), and parathyroid operations. The operations that put laryngeal nerves at risk (ONRs) most commonly associated with a diagnosis of UVFP were, in descending order of frequency, thoracic, thyroid, parathyroid, cardiac, and cervical spine. For both UVFP and BVFP, the most commonly associated age group was 51 to 60. For both UVFP and BVFP, the more commonly associated sex was women. Increased length of stay was associated with a higher incidence of UVFP and BVFP. Charlson medical co-morbidity index (CCI) was not associated with UVFP but BVFP was associated with higher Charlson medical co-morbidity scores. CONCLUSIONS: Thyroid operations, age 51 to 60, longer hospital stays are associated with vocal fold paralysis. Overall women are more surgically affected than men. This is the first population-based study of iatrogenic vocal fold paralysis.

Molecular chaperone TRiC governs avian reovirus replication by protecting outer-capsid protein σC and inner core protein σA and non-structural protein σNS from ubiquitin- proteasome degradation.

Avian reoviruses (ARVs) are important pathogens that cause considerable economic losses in poultry farming. To date, host factors that control stabilization of ARV proteins remain largely unknown. In this work we determined that the eukaryotic chaperonin T-complex protein-1 (TCP-1) ring complex (TRiC) is essential for avian reovirus (ARV) replication by stabilizing outer-capsid protein σC, inner core protein σA, and the non-structural protein σNS of ARV. TriC serves as a chaperone of viral proteins and prevent their degradation via the ubiquitin-proteasome pathway. Furthermore, reciprocal co-immunoprecipitation assays confirmed the association of viral proteins (σA, σC, and σNS) with TRiC. Immunofluorescence staining indicated that the TRiC chaperonins (CCT2 and CCT5) are colocalized with viral proteins σC, σA, and σNS of ARV. In this study, inhibition of TRiC chaperonins (CCT2 and CCT5) by the inhibitor HSF1A or shRNAs significantly reduced expression levels of the σC, σA, and σNS proteins of ARV as well as virus yield, suggesting that the TRiC complex functions in stabilization of viral proteins and virus replication. This study provides novel insights into TRiC chaperonin governing virus replication via stabilization of outer-capsid protein σC, inner core protein σA, and the non-structural protein σNS of ARV.

The Gastroprotective Effect of Naringenin against Ethanol-Induced Gastric Ulcers in Mice through Inhibiting Oxidative and Inflammatory Responses.

Naringenin is a major flavanone found in grapes, tangelos, blood oranges, lemons, pummelo, and tangerines. It is known to have anti-inflammatory, antioxidant, anticancer, antimutagenic, antifibrogenic, and antiatherogenic pharmacological properties. This study aims to investigate the anti-inflammatory effects of naringenin in ethanol-induced gastric damage in vivo and ethanol-stimulated KATO III cells in vitro. Our results showed that pretreatment with naringenin significantly protected mice from ethanol-induced hemorrhagic damage, epithelial cell loss, and edema with leucocytes. It reduced gastric ulcers (GU) by suppressing ethanol-induced nuclear factor-κB (NF-κB) activity and decreasing the levels of nitric oxide (NO), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and myeloperoxidase (MPO). In addition, pretreatment with naringenin might inhibit the secretion of TNF-α, IL-6, and IL-8, as well as the proteins cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) via the suppression of NF-κB and mitogen-activated protein kinase (MAPK) signaling in ethanol-stimulated stomach epithelial KATO III cells. Together, the results of this study highlight the gastroprotective effect of naringenin in GU of mice by inhibiting gastric secretion and acidity, reducing inflammation and oxidative stress, suppressing NF-κB activity, and restoring the histological architecture. These findings suggested that naringenin has therapeutic potential in the alleviation of ethanol-induced GU.

Verification of the Efficacy of New Diagnostic Criteria for Retropharyngeal Nodes in a Cohort of Nasopharyngeal Carcinoma Patients.

Purpose: A multistage approach to diagnose lateral retropharyngeal nodes (LRPNs) of nasopharyngeal carcinoma (NPC) had been proposed and warranted for validation. Methods: Between 2012 and 2017, the patients with newly diagnosed NPC were enrolled. The responsive nodes or those that progressed during follow-up were positive. The criteria for the multistage approach delimited LRPNs with a minimal axial diameter (MIAD) ≥ 6.1 mm were assessed as positive and if the mean standard uptake value ≥ 2.6, or if the maximal coronal diameter ≥ 25 mm and maximal axial diameter ≥ 8 mm with nodes MIAD < 6.1 mm were also considered as positive. The outcomes were compared with the MIAD cutoff value ≥ 6 mm (traditional method). A chi-squared test was used to compare two areas under the curve of the receiver operating characteristic curves. Results: A total of 67 eligible NPC cases and 155 LRPNs (72 positive and 83 negative) were analyzed. The accuracy, specificity, and sensitivity of the traditional method were 0.91, 0.93, and 0.89, respectively. The values for the multistage approach all reached 0.94. The area under the curve was significantly greater for the multistage approach compared with the traditional method (p = 0.023). Conclusion: The results support the advantage of the multistage approach.

Alantolactone Suppresses Proliferation and the Inflammatory Response in Human HaCaT Keratinocytes and Ameliorates Imiquimod-Induced Skin Lesions in a Psoriasis-Like Mouse Model.

Psoriasis is an immune-mediated inflammatory disease that affects 2% to 3% of the world population. Alantolactone, a sesquiterpene lactone, was isolated from Inula helenium and Radix inulae and has several biological effects, including antifungal, anthelmintic, antimicrobial, anti-inflammatory, antitrypanosomal, and anticancer properties. This study aimed to evaluate the antipsoriatic potential of alantolactone in vitro and in vivo and to explore its underlying mechanisms. These results showed that alantolactone significantly attenuated IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) cytokine-induced hyperproliferation in HaCaT keratinocytes. Moreover, M5 cytokines significantly upregulated the mRNA levels of TNF-α, IL-6, IL-1ß, and IL-8. However, alantolactone attenuated the upregulation of these inflammatory cytokines. In addition, alantolactone was found to inhibit STAT3 phosphorylation and NF-κB p65 nuclear translocation in HaCaT keratinocytes. Furthermore, alantolactone treatment in mice significantly alleviated the severity of skin lesions (erythema, scaling and epidermal thickness, and inflammatory cell infiltration) and decreased the mRNA expression of inflammatory cytokines (e.g., TNF-α, IL-6, IL-1ß, IL-8, IL-17A, and IL-23) in an IMQ-induced-like mouse model. Therefore, our new findings revealed that alantolactone alleviates psoriatic skin lesions by inhibiting inflammation, making it an attractive candidate for future development as an antipsoriatic agent.

Crassolide Suppresses Dendritic Cell Maturation and Attenuates Experimental Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of ß2-glycoprotein I (ß2GPI)-dependent autoantibodies, with vascular thrombosis or obstetrical complications. Around 20% of APS patients are refractory to current treatments. Crassolide, a cembranoid diterpene extracted from soft corals, is a potential therapeutic candidate. Here, to examine the anti-inflammatory properties of crassolide, we first determined its effects on bone marrow-derived and splenic dendritic cells (DC). Specifically, we applied lipopolysaccharide (LPS) or ß2GPI stimulation and measured the expressions of CD80 and CD86, and secretions of cytokines. We also determined in the OT-II mice, if bone marrow-derived DC was able to stimulate antigen-specific T cells. Moreover, we examined the therapeutic potential of crassolide postimmunization in a murine model of APS that depended on active immunization with ß2GPI. The vascular manifestations were evaluated in terms of fluorescein-induced thrombi in mesenteric microvessels, whereas the obstetric manifestations were evaluated based on the proportion of fetal loss after pregnancy. We also measured blood titers of anti-ß2GPI antibody, splenic cell proliferative responses and cytokine secretions after ß2GPI stimulation ex vivo. Finally, we determined in these mice, hematological, hepatic and renal toxicities of crassolide. Crassolide after LPS stimulation suppressed DC maturation and secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 and IL-23, and downstream T cell activation. Crassolide could partially ameliorate both the vascular and obstetric manifestations of APS in BALB/c mice. Both blood titers of anti-ß2GPI antibody and splenic cell proliferation after ß2GPI stimulation were reduced. Splenic Th1 and Th17 responses were also lowered after ß2GPI stimulation. Finally, within therapeutic doses of crassolide, we found no evidence of its toxicity. In conclusion, we showed the ability of crassolide to suppress DC and downstream T cell responses. Crassolide is therefore a potential candidate for adjunctive therapy in APS.

Clinical implications of multiple glioblastomas: An analysis of prognostic factors and survival to distinguish from their single counterparts.

PURPOSE: Glioblastoma (GBM) has the highest fatality rate among primary malignant brain tumors. GBMs with synchronous multiple foci (multiple GBMs) is rarely diagnosed in the clinical scenario. This study aims to compare the clinical characteristics between multiple and single GBMs and to identify factors associated with the survival of GBM and evaluate their effects. METHODS: We retrospectively reviewed the medical records of patients with primary GBM in a referral medical center in Taiwan who were diagnosed between 2005 and 2016. They were identified from the cancer registry database of the center and followed from the date of diagnosis to october 2018. The primary endpoint of this study was overall survival (OS), and the independent factors for survival were identified through Cox regressions. RESULTS: A total of 48 patients were identified, of whom 44 GBM (92%) and 4 gliosarcoma (GSM) (8%). Preoperative images showed five (10%) patients had multiple brain lesions. GSM showed a high ratio of multiple lesions (50%) than patients with GBM (5%) (p = 0.05). Those with multiple lesions had significantly worse median OS of 8.2 months compared to patients with a single lesion (16 months, p = 0.03). We found that multiple GBMs was a predictor of worse survival (hazard ratio [HR] = 3.57, 95% confidence interval [95%CI]: 1.26-10.13) after adjusting for other significant predictor of radiotherapy (HR = 0.47, 95%CI: 0.23-0.96). CONCLUSION: Patients with multiple GBMs had worse survival compared to those with single GBM. GBM patients without post-operative radiotherapy were also a predictor of worse survival.

Early Dutasteride Monotherapy in Patients With Elevated Serum Prostate-Specific Antigen Levels Following Robot-Assisted Radical Prostatectomy.

Background: To evaluate the efficacy of early dutasteride administration in patients with a detectable prostate-specific antigen (PSA) levels after robot-assisted radical prostatectomy (RARP). Methods: We retrospectively analyzed RARP patients whose pathological stage is T2a to T3b without lymph node or distant metastasis from 2007 to 2017. All patients received a daily dose of 0.5 mg of dutasteride when post-RARP PSA levels were increasing but had not achieved biochemical recurrence. PSA levels were monitored every 3 months after dutasteride administration. None of the patients received radiotherapy (RT) or androgen-deprivation therapy (ADT) before taking dutasteride. All follow-ups were begun from RARP to January 2019 or to the date of RT/ADT. Results: Thirty-five patients were included in this analysis. The median followed up was 53.6 months. Twenty-two patients (62.9%) showed a PSA response in which the PSA decreased more than 10% at the first follow-up after dutasteride administration. The Pathological stage > T2 (p = 0.012) and positive surgical margin (p = 0.046) were prognostic factors for a PSA response. Twenty-three out of 35 included patients (65.7%) did not require further RT/ADT. The significant risk factor was the PSA level (p = 0.011) at the beginning of dutasteride treatment. The cut-off value of the PSA level to avoid further RT/ADT was 0.195 ng/ml. Conclusions: Early dutasteride administration showed a significant decline in the PSA levels of patients with pathology stage >T2 and positive surgical margin in our retrospective hypothesis-generating study. If dutasteride was provided before the PSA value increased to 0.195 ng/ml after RARP, it would reduce the probability of acquirement of RT/ADT.

Impact of a home health care program for disabled patients in Taiwan: A nationwide population-based cohort study.

The aim of this study was to evaluate the impact of home health care (HHC) for disabled patients.We conducted a nationwide population-based retrospective cohort study. A total of 5838 disabled patients with HHC were identified to match by propensity score with 15,829 disabled patients without HHC receiving tube or catheter care (tracheostomy tube, nasogastric tube, urinary catheter, cystostomy tube, nephrostomy tube) or stage 3 or 4 pressure sore care from the Taiwanese National Health Insurance Research Database between 2005 and 2009. After 1:1 matching, 2901 subjects in the HHC group and 2901 subjects in the non-HHC group were selected and analyzed. Generalized estimating equations (GEEs) were used to compare the risk of health outcomes (rate of hospitalization and emergency services use) and the healthcare expenditure between the 2 groups.Compared to those in the non-HHC group, the patients in the HHC group had significantly higher risk for hospitalization (odds ratio [OR] = 18.43, 95% confidence interval [CI]: 15.62-21.75, P < .001) and emergency services use (OR = 3.72, 95% CI: 3.32-4.17, P < .001) 1 year before the index date. However, 1 year after the index date, the risk for hospitalization (OR = 1.6, 95% CI: 1.41-1.83, P < .001) and emergency services use (OR = 1.16, 95% CI: 1.04-1.30, P < .05) attenuated significantly. Regarding the comparison of total healthcare expenditure 1 year before and after the index date, our study showed an insignificant decrease of US$1.5 per person per day and a significant increase of US$5.2 per person per day (P < .001) in the HHC and non-HHC groups, respectively.The HHC for disabled patients has a potential role to reduce hospitalization and emergency services use. Besides, the improvement of healthcare quality through HHC was not accompanied by increased healthcare expenditure. The clinical impact of HHC emphasizes the importance for public health officials to promote HHC model to meet the needs of disabled patients.

Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma.

Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time after diagnosis make it a crucial public health issue. Understanding the molecular mechanisms underlying GBM may inspire novel and effective treatments against this type of cancer. At a molecular level, almost all tumor cells exhibit telomerase activity (TA), which is a major means by which they achieve immortalization. Further studies show that promoter mutations are associated with increased TA and stable telomere length. Moreover, some tumors and immortalized cells maintain their telomeres with a telomerase-independent mechanism termed the "alternative lengthening of telomeres" (ALT), which relates to the mutations of the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), the death-domain associated protein (DAXX) and H3.3. By means of the mutations of the telomerase reverse transcriptase (TERT) promoter and ATRX/DAXX, cancers can immortalize and escape cell senescence and apoptosis. In this article, we review the evidence for triggering GBM cell death by targeting telomerase and the ALT pathway, with an extra focus on a plant-derived compound, butylidene phthalide (BP), which may be a promising novel anticancer compound with good potential for clinical applications.

Serum Lipopolysaccharide-Binding Protein is Associated with Chronic Inflammation and Metabolic Syndrome in Hemodialysis Patients.

BACKGROUND: In hemodialysis (HD) patients, impaired gut barrier and alteration in microbiota in the gut is thought to increase the risk of bacterial translocation and chronic inflammation. Lipopolysaccharide-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by microbial products. Our aim is to investigate the relationship between circulating levels of LBP, and various metabolic and inflammatory markers in HD patients. Besides, we also aim to determine its relationship among -patients with different body mass index. PATIENTS AND METHODS: A total of 123 HD patients were stratified into three -tertiles, according to serum LBP level. The LBP and inflammatory markers were determined using immunoassay methods. A bioimpedance spectroscopy device was used for body composition measurement. RESULTS: The serum levels of the two proinflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6, were significantly higher in patients in the upper tertile when compared with the rest of the tertiles. In HD patients, a significant positive correlation was found between serum LBP levels and CRP, IL-6, soluble CD14 (sCD14), and fasting blood glucose levels. Patients with metabolic syndrome and pre-existing cardiovascular disease had higher LBP levels than those without metabolic syndrome. Besides, obese patients were also associated with higher serum LBP levels. Multivariate regression analyses showed that IL-6 level was the strongest correlate of LBP level, followed by hsCRP level and sCD14. CONCLUSIONS: Our study suggested that elevated plasma LBP was associated with metabolic syndrome and obesity. In addition, increased LBP level was correlated positively to markers of inflammation, and sCD14 levels.

Cancer and mTOR inhibitors in kidney transplantation recipients.

BACKGROUND: Previous studies show that mTOR inhibitors decrease the risk of cancer development after kidney transplantation. However, the effect of cumulative doses of mTOR inhibitors on cancer after kidney transplantation is not well known. METHODS: In the current study, patients were registered into a national database in Taiwan. Between year 2000 and 2013, 4,563 patients received kidney transplantation. They were divided into two groups, according to mTOR inhibitors usage. The cumulative dose of mTOR inhibitors was recorded. Patients were followed-up until de novo cancer development, death, or the end of 2014. RESULTS: Patients were divided into two groups: mTOR inhibitors users (study group, n = 828) and mTOR inhibitors non-users (control group, n = 3,735). The median follow-up duration was 7.8 years. The risk of de novo cancer (hazards ratio (HR) 0.80, 95% CI [0.60-1.09], p = 0.16) and risk of death (HR 1.14, 95% CI [0.82-1.60], p = 0.43) was not different between mTOR inhibitor user and non-user groups. Neither high- nor low-dose exposure to mTOR inhibitors was associated with increased risk of cancer or mortality. Analysis of cancer subtypes showed no influence by mTOR inhibitors. In addition, the cause of mortality was not significantly different between the two groups. DISCUSSION: We could not find the association of mTOR inhibitors use and risk of de novo cancer development or mortality in patients with kidney transplantation in Chinese patients. Cumulative exposure to mTOR inhibitors did not change the results.