Active Surveillance for Taiwanese Men with Localized Prostate Cancer: Intermediate-Term Outcomes and Predictive Factors.

PURPOSE: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. MATERIALS AND METHODS: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. RESULTS: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years). CONCLUSIONS: AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion.

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.

3-N-butylphthalide protects against high-fat-diet-induced obesity in C57BL/6 mice and increases metabolism in lipid-accumulating cells.

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.

Effect of Ginkgo biloba Extract (EGb-761) on Recovery of Erectile Dysfunction in Bilateral Cavernous Nerve Injury Rat Model.

OBJECTIVE: To investigate whether the therapeutic effect of Ginkgo biloba extract (GBE) in a rat model can improve erectile dysfunction after bilateral cavernous nerve injury. METHODS: Forty-three male Sprague-Dawley rats underwent cavernous nerve crush injury and were randomized into 4 groups, including: vehicle only, high-dose GBE, medium-dose GBE, and low-dose GBE. Eight animals underwent sham operation. Four weeks later, erectile function was assessed by cavernous nerve electrostimulation, and penile tissue was collected for histologic analysis. RESULTS: Significant recovery of erectile function was observed in the high-dose GBE group in a dose-dependent manner as compared with the vehicle-only group (P <.001). The high-dose GBE group had a significant increase in neurofilament-1 expression (P <.001), preservation of neural nitric oxide synthase nerve fibers of the dorsal penile nerve (P <.05), and increased smooth muscle cell content (P <.001) compared with the vehicle-only group. In addition, high-dose GBE markedly augments the smooth muscle-to-collagen ratio (P <.05) and reduces the apoptotic index. CONCLUSION: Administration of GBE increases neuron survival and preserves the neural nitric oxide synthase nerve fiber and contents of the corpus cavernosum after bilateral cavernous nerve injury. These implications indicate the beneficial effects of GBE use in the repair of the cavernous nerve and recovery of erectile function after radical prostatectomy.

Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson's disease therapy.

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta as well as motor impairment. Aggregation of α-synuclein in neuronal cells plays a key role in this disease. At present, therapeutics for PD provides moderate symptomatic benefits, but it is not able to delay the development of the disease. Current efforts toward the treatment of PD are to identify new drugs that slow or arrest the progressive course of PD by interfering with a disease-specific pathogenetic process in PD patients. Irisflorentin derived from the roots of Belamcanda chinensis (L.) DC. is an herb which has been used for the treatment of inflammatory disorders in traditional Chinese medicine. The purpose of the present study was to assess the potential for irisflorentin to ameliorate PD in Caenorhabditis elegans models. Our data reveal that irisflorentin prevents α-synuclein accumulation in the transgenic Caenorhabditis elegans model and also improves dopaminergic neuron degeneration, food-sensing behavior, and life-span in a 6-hydroxydopamine-induced Caenorhabditis elegans model, thus indicating its potential as a anti-parkinsonian drug candidate. Irisflorentin may exert its effects by promoting rpn-3 expression to enhance the activity of proteasomes and down-regulating egl-1 expression to block apoptosis pathways. These findings encourage further investigation on irisflorentin as a possible potent agent for PD treatment.

Irisflorentin modifies properties of mouse bone marrow-derived dendritic cells and reduces the allergic contact hypersensitivity responses.

Irisflorentin is an isoflavone component derived from the roots of Belamcanda chinensis (L.) DC. In traditional Chinese medicine, this herb has pharmacological properties to treat inflammatory disorders. Dendritic cells (DCs) are crucial modulators for the development of optimal T-cell immunity and maintenance of tolerance. Aberrant activation of DCs can induce harmful immune responses, and so agents that effectively improve DC properties have great clinical value. We herein investigated the effects of irisflorentin on lipopolysaccharide (LPS)-stimulated maturation of mouse bone marrow-derived DCs in vitro and in the contact hypersensitivity response (CHSR) in vivo. Our results demonstrated that treatment with up to 40 µM irisflorentin does not cause cellular toxicity. Irisflorentin significantly lessened the proinflammatory cytokine production (tumor necrosis factor-α, interleukin-6, and interleukin-12p70) by LPS-stimulated DCs. Irisflorentin also inhibited the expression of LPS-induced major histocompatibility complex class II and costimulatory molecules (CD40 and CD86) on LPS-stimulated DCs. In addition, irisflorentin diminished LPS-stimulated DC-elicited allogeneic T-cell proliferation. Furthermore, irisflorentin significantly interfered with LPS-induced activation of IκB kinase, c-Jun N-terminal kinase, and p38, as well as the nuclear translocation of NF-κB p65. Subsequently, treatment with irisflorentin obviously weakened 2,4-dinitro-1-fluorobenzene-induced delayed-type hypersensitivity. These findings suggest new insights into the role of irisflorentin as an immunotherapeutic adjuvant through its capability to modulate the properties of DCs.

Laparoendoscopic single-site (LESS) retroperitoneal partial adrenalectomy using a custom-made single-access platform and standard laparoscopic instruments: technical considerations and surgical outcomes.

BACKGROUND: We previously reported our initial experience with laparoendoscopic single-site (LESS) retroperitoneal partial adrenalectomy using a custom-made single-port device and conventional straight laparoscopic instruments. METHODS: Between December 2010 and February 2012, LESS retroperitoneal partial adrenalectomies were performed in 11 patients. Six patients had aldosterone-producing adenomas (APAs) and five patients had nonfunctioning tumors. A single-port access was created with an Alexis wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA) through an incision of 2-3 cm beneath the tip of the 12th rib. All procedures were performed with straight laparoscopic instruments. RESULTS: All LESS procedures were successfully completed without conversion to traditional laparoscopic conversion. The tumors ranged from 1 cm to 4.7 cm (mean, 2.3 cm). The operative time was 71-257 minutes (mean, 121 minutes). Most patients (n = 8) had minimal blood loss; the other three patients had a blood loss of 150 mL, 100 mL, and 100 mL. The mean hospital stay was 3 days (range, 1-6 days). There were no perioperative or postoperative complications. Pathological examinations revealed negative surgical margins in all specimens. All patients with Conn's syndrome had an improvement in blood pressure and normalization of plasma renin activity and serum aldosterone levels; all patients were free of potassium supplementation. CONCLUSION: Our results clearly demonstrate that LESS retroperitoneal partial adrenalectomy can be performed safely and effectively using a custom-made single-access platform and standard laparoscopic instruments.

Dryocrassin suppresses immunostimulatory function of dendritic cells and prolongs skin allograft survival.

Dendritic cells (DCs) are the major specialized antigen-presenting cells for the development of optimal T-cell immunity. DCs can be used as pharmacological targets to monitor novel biological modifiers for the cure of harmful immune responses, such as transplantation rejection. Dryopteris crassirhizoma Nakai (Aspiadaceae) is used for traditional herbal medicine in the region of East Asia. The root of this fern plant has been listed for treating inflammatory diseases. Dryocrassin is the tetrameric phlorophenone component derived from Dryopteris. Here we tested the immunomodulatory potential of dryocrassin on lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs in vitro and in skin allograft transplantation in vivo. Results demonstrated that dryocrassin reduced the emission of tumor necrosis factor-α, interleukin-6, and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility complex class II, CD40, and CD86 on DCs was also blocked by dryocrassin. Moreover, LPS-stimulated DC-elicited allogeneic T-cell proliferation was alleviated by dryocrassin. In addition, dryocrassin inhibited LPS-induced activation of IκB kinase, JNK/p38 mitogen-activated protein kinase, and the translocation of NF-κB. Treatment with dryocrassin noticeably diminished 2,4-dinitro-1-fluorobenzene-reduced delayed-type hypersensitivity and extended skin allograft survival. Dryocrassin may be one of the potent immunosuppressive agents for transplant rejection via the destruction of DC maturation and function.

n-butylidenephthalide protects against dopaminergic neuron degeneration and α-synuclein accumulation in Caenorhabditis elegans models of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system that impairs motor skills and cognitive function. To date, the disease has no effective therapies. The identification of new drugs that provide benefit in arresting the decline seen in PD patients is the focus of much recent study. However, the lengthy time frame for the progression of neurodegeneration in PD increases both the time and cost of examining potential therapeutic compounds in mammalian models. An alternative is to first evaluate the efficacy of compounds in Caenorhabditis elegans models, which reduces examination time from months to days. n-Butylidenephthalide is the naturally-occurring component derived from the chloroform extract of Angelica sinensis. It has been shown to have anti-tumor and anti-inflammatory properties, but no reports have yet described the effects of n-butylidenephthalide on PD. The aim of this study was to assess the potential for n-butylidenephthalide to improve PD in C. elegans models. METHODOLOGY/PRINCIPAL FINDINGS: In the current study, we employed a pharmacological strain that expresses green fluorescent protein specifically in dopaminergic neurons (BZ555) and a transgenic strain that expresses human α-synuclein in muscle cells (OW13) to investigate the antiparkinsonian activities of n-butylidenephthalide. Our results demonstrate that in PD animal models, n-butylidenephthalide significantly attenuates dopaminergic neuron degeneration induced by 6-hydroxydopamine; reduces α-synuclein accumulation; recovers lipid content, food-sensing behavior, and dopamine levels; and prolongs life-span of 6-hydroxydopamine treatment, thus revealing its potential as a possible antiparkinsonian drug. n-Butylidenephthalide may exert its effects by blocking egl-1 expression to inhibit apoptosis pathways and by raising rpn-6 expression to enhance the activity of proteasomes. CONCLUSIONS/SIGNIFICANCE: n-Butylidenephthalide may be one of the effective neuroprotective agents for PD.

Acetylcorynoline impairs the maturation of mouse bone marrow-derived dendritic cells via suppression of IκB kinase and mitogen-activated protein kinase activities.

BACKGROUND: Dendritic cells (DCs) are major modulators in the immune system. One active field of research is the manipulation of DCs as pharmacological targets to screen novel biological modifiers for the treatment of inflammatory and autoimmune disorders. Acetylcorynoline is the major alkaloid component derived from Corydalis bungeana herbs. We assessed the capability of acetylcorynoline to regulate lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs. METHODOLOGY/PRINCIPAL FINDINGS: Our experimental data showed that treatment with up to 20 µM acetylcorynoline does not cause cytotoxicity in cells. Acetylcorynoline significantly inhibited the secretion of tumor necrosis factor-α, interleukin-6, and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility complex class II, CD40, and CD86 on DCs was also decreased by acetylcorynoline, and the endocytic capacity of LPS-stimulated DCs was restored by acetylcorynoline. In addition, LPS-stimulated DC-elicited allogeneic T-cell proliferation was blocked by acetylcorynoline, and the migratory ability of LPS-stimulated DCs was reduced by acetylcorynoline. Moreover, acetylcorynoline significantly inhibits LPS-induced activation of IκB kinase and mitogen-activated protein kinase. Importantly, administration of acetylcorynoline significantly attenuates 2,4-dinitro-1-fluorobenzene-induced delayed-type hypersensitivity. CONCLUSIONS/SIGNIFICANCE: Acetylcorynoline may be one of the potent immunosuppressive agents through the blockage of DC maturation and function.

Myricetin attenuates lipopolysaccharide-stimulated activation of mouse bone marrow-derived dendritic cells through suppression of IKK/NF-κB and MAPK signalling pathways.

BACKGROUND: Myricetin is a naturally occurring flavonoid that is found in many fruits, vegetables, teas and medicinal herbs. It has been demonstrated to have anti-inflammatory properties, but, to date, no studies have described the immunomodulatory effects of myricetin on the functions of dendritic cells (DCs). The aim of this study was to evaluate the potential for myricetin to modulate lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs. RESULTS: Our experimental data showed that treatment with myricetin up to 10 µg mL(-1) does not cause cytotoxicity in cells. Myricetin significantly decreased the secretion of tumour necrosis factor-α, interleukin-6 and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility class II, CD40 and CD86 on DCs was also inhibited by myricetin, and the endocytic and migratory capacity of LPS-stimulated DCs was blocked by myricentin. In addition, LPS-stimulated DC-elicited allogeneic T-cell proliferation was reduced by myricetin. Moreover, our results confirmed that myricetin attenuates the responses of LPS-stimulated activation of DCs via suppression of IκB kinase/nuclear factor-κB and mitogen-activated protein kinase-dependent pathways. CONCLUSION: Myricetin has novel immunopharmacological activity, and modulation of DCs by myricetin may be an attractive strategy for the treatment of inflammatory and autoimmune disorders, and for transplantation.

Traumatic brain injury increases the risk of female urinary incontinence.

AIMS: According to our knowledge, no study has attempted to explore the risk of urinary incontinence (UI) after traumatic brain injury (TBI). This study aimed to examine the relationship between TBI in Taiwanese women and their risk of developing UI. METHODS: The study was based on 2,416 female patients newly diagnosed with TBI together with 12,080 matched enrollees without a history of TBI as a comparison group. All patients were tracked for a 1-year period from their index date to identify those who developed subsequent UI. The stratified Cox proportional hazards models were performed to compute the risk of UI between groups. RESULTS: Of 14,496 patients, 104 (4.30%) from the TBI group and 192 (1.59%) from the comparison group had a diagnosis of UI during the follow-up period. The incidence rate of UI was 4.50 (95% CI: 3.69-5.43) per 100 person-years in patients with TBI and 1.62 (95% CI: 1.40-1.86) per 100 person-years in patients without TBI. The stratified Cox proportional analysis showed that after adjusting for socioeconomic status, obesity, hypertension, diabetes, and hysterectomy, the increased UI risk of patients with TBI persisted at about the same level as in the unadjusted analysis (hazard ratio = 2.78; 95% CI = 2.16-3.53). In addition, although patients with severe and moderate TBI had higher incidence rates of UI than patients with mild TBI, the difference did not reach a statistically significant level (P = 0.090). CONCLUSIONS: Our results suggest that an increased risk of UI exists at the first year follow-up in patients with a TBI diagnosis.