Thiazolidinedione enhances the efficacy of anti-PD-1 monoclonal antibody in murine melanoma.

Several clinical studies observed a surprising beneficial effect of obesity on enhancing immunotherapy responsiveness in patients with melanoma, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here, we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug commonly used to treat diabetes by sequestering fatty acids in metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-programmed cell death protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, an initially immunotherapy-sensitive murine melanoma model. We observed a transition from high to intermediate PD-1 expression in tumor-infiltrating CD8+ T cells. Moreover, TZD inhibited PD-1 expression in mouse and human T cells treated in vitro. In addition to its direct impact on immune cells, TZD also decreased circulating insulin concentrations, while insulin induced T cell exhaustion in culture. In TZD-treated mice, we observed higher fatty acid concentrations in the tumor microenvironment, with fatty acids protecting against exhaustion in culture. Together, these data are consistent with an indirect mechanism of TZD inhibiting T cell exhaustion. Finally, we analyzed imaging data from patients with melanoma before and after anti-PD-1 treatment, confirming the beneficial effect of increased subcutaneous fat on anti-PD-1 responsiveness in patients. We also found that the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the canonical activator of lipid uptake and adipogenesis activated by TZD, correlated with overall survival time. Taken together, these data identify a new adjuvant to enhance immunotherapy efficacy in YUMMER1.7 melanoma mice, and discover a new metabolism-based prognostic marker in human melanoma.NEW & NOTEWORTHY Zhang et al. demonstrate that the diabetes drug rosiglitazone improves the efficacy of immunotherapy in mouse melanoma. This effect is both direct and indirect: TZD directly reduces PD-1 expression in CD8+ T cells (i.e., reduces exhaustion), and indirectly reduces exhaustion by lowering insulin levels and increasing local fat. Finally, they demonstrate that hallmarks of TZD action (such as PPARγ expression and subcutaneous fat content) correlate with improved immunotherapy efficacy in humans with melanoma.

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

On the Effect of Electroacupuncture in Promoting Healing after High Tibial Osteotomy.

Purpose: To explore the clinical effect of electroacupuncture in promoting the healing of the osteotomy area after high tibial osteotomy. Methods: 50 patients with knee osteoarthritis who underwent open wedge high tibial osteotomy (OWHTO) were selected and randomly divided into the observation group and control group. The control group got the common postoperative treatment, and the observation group was added electroacupuncture from the 3rd day after the operation on the basis of the control group. The electroacupuncture acupoints were selected SP10, ST34, ST32, EX-LE2, ST40,KI6, KI3, SP6, and ST41, once a day, and 14 days were a course of treatment. And then we contrasted the index of the Lane-Sandhu X-ray score, the skin incision healing time, the swelling subsided time, Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index Score (WOMAC), and Lysholm in different time. Results: The Lane-Sandhu X-ray score of the observation group was better than that of the control group at all time points (P < 0.05), and the time to achieve bone healing was about 2 weeks earlier than that of the control group. The skin healing and swelling were the subsided time in the osteotomy area. Both were better than the control group, and the difference was statistically significant (P < 0.05). The VAS score, WOMAC score, and Lysholm score of the two groups were significantly improved compared with preoperatively, and the difference was statistically significant (P < 0.05). The improvement of the observation group's VAS score, WOMAC score, and Lysholm score at 1 week, 4 weeks, and 8 weeks after the end of the treatment course was better than that of the control group, and the difference was statistically significant (P < 0.05). Conclusion: Electroacupuncture can quicken the healing of bone tissue and surrounding soft tissues in the osteotomy area after high tibial osteotomy, and at the same time, it can help the relief of knee joint pain and improve knee joint function.

Ascorbic acid induced TET2 enzyme activation enhances cancer immunotherapy efficacy in renal cell carcinoma.

Exploring the regulatory mechanism of PD-L1 in renal cancer is one of the key strategies to improve the response of renal cancer patients to checkpoint blockade therapy. In this study, the synergistic effect of ascorbic acid (vitamin C) supplementation and the impact of TET2 depletion on anti-PD-L1 therapy were determined in xenograft model experiments. Lymphocyte infiltration and chemokine expression were determined using flow cytometry and qRT-PCR. To determine the downstream targets of TET2, we performed hMeDip-seq and RNA-seq analyses. The molecular mechanism was further confirmed by hMeDip-qPCR, MeDip-qPCR, bisulfite sequencing, Western blotting, qRT-PCR and xenograft model experiments in vitro and in vivo. The present study demonstrated that ascorbic acid enhanced the efficacy of immunotherapy and that the loss of TET2 function enabled renal cancer cells to evade antitumor immunity. Ascorbic acid treatment significantly increased the intratumoral infiltration of T cells and the expression of cytokines and chemokines, while the loss of TET2 impaired the infiltration of T cells and the expression of cytokines and chemokines. TET2 was recruited to IRF1 by IFN-γ-STAT1 signaling, thereby maintaining IRF1 demethylation and ultimately inducing PD-L1 expression. These results suggest a new strategy of stimulating TET activity to improve immunotherapy for renal cell carcinoma.

The efficacy and safety of Serenoa repens extract for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome: a multicenter, randomized, double-blind, placebo-controlled trial.

PURPOSE: To perform a placebo-controlled trial to evaluate the efficacy and safety of Serenoa repens extract (SRE) for the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, clinical phase 4 study of 221 patients with CP/CPPS across 11 centers. Participants were randomly assigned in a 2:1 ratio to receive SRE or placebo for 12 weeks. The primary efficacy endpoint was the change in total score on the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI). Secondary efficacy endpoints included improvements within each domain of NIH-CPSI, clinical response rate, and International Index of Erectile Function 5 items (IIEF-5). RESULTS: In total, 226 patients were enrolled and randomized between January 2017 and June 2018. Of these 221 patients were included in the intent-to-treat analysis: 148 in the SRE group and 73 patients in the placebo group. Compared to the placebo, SRE led to statistically significant improvements in the NIH-CPSI total score and sub-scores. The significant improvements of NIH-CPSI scores were established after 2 weeks from the first dose, and continued to the end of the treatment. Furthermore, a significantly higher rate of patients achieved a clinical response in the SRE group compared with that in the placebo group (73.0% vs 32.9%, P < 0.0001). Only minor adverse events were observed across the entire study population. CONCLUSIONS: SRE was effective, safe, and clinically superior to placebo for the treatment of CP/CPPS. ChiCTR-IPR-16010196, December 21, 2016 retrospectively registered.

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

[Investigation on sea of marrow and the application of Naohu (GV 17)].

The theory on four seas is a kind of view to explain the longitudinal and horizontal distribution relationship of meridians and collaterals by ancient scholars. The authors were attempted to explore it by taking the theory on sea of marrow as example in terms of literature analysis. In Lingshu: Hailun (Chapter 33 of Miraculous Pivot), it is recorded that sea of marrow flows into two locations, but they are not the acupoint sites for treatment. Based on the comprehensive literature investigation, it is known that such two sites to which sea of marrow flows refer to a kind of boundaries so that the range of sea of marrow is determined, the function of it explored, and the controversy on "heart dominating mind" and "brain governing spirit" solved. It is defined that the function of sea of marrow is the macro-conception of shen (mind, spirit) that is modulated by vital movement information. Additionally, in association with meridian literature analysis, as well as acupoint textual research, it finally focuses on Naohu (GV 17) that is the critical point in the application of the theory on sea of marrow. In clinical application of such theory, the importance should be attached to the governor vessel, Naohu (GV 17) and their spatial system of bone.

Efficacy and Safety of Serenoa repens Extract Among Patients with Benign Prostatic Hyperplasia in China: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of Serenoa repens among patients with benign prostatic hyperplasia (lower urinary tract symptoms/benign prostatic hyperplasia [LUTS/BPH]) in China. METHODS: We conducted a double blind, placebo-controlled study of 354 patients with LUTS/BPH from 19 institutions, to evaluate the efficacy and safety of Serenoa repens. Participants were randomly assigned (1:1) into the Serenoa repens extract (320 mg) or placebo groups for 24 weeks. Primary efficacy parameters were changes in International Prostate Symptom Score and peak urinary flow from baseline to each assessment. Secondary efficacy parameters included improvement of storage symptom and voiding symptom scores, prostate volume, urinary frequency, and total prostate-specific antigen level. Other parameters assessed were quality of life score, a four-item male sexual function questionnaire score, and International Index of Erectile Function score across the consecutive double-blind visits. RESULTS: Statistically significant improvement in the peak urinary flow, International Prostate Symptom Score, scores of storage symptoms and voiding symptoms, quality of life score, four-item male sexual function questionnaire score, and International Index of Erectile Function score were observed in the Serenoa repens extract group compared with those in the placebo group (P <.05). Two (1.18%) of 169 patients in the placebo group and 3 (1.89) of 159 patients in the Serenoa repens extract group experienced 1 or more adverse events. CONCLUSION: The Serenoa repens extract was effective, safe, well-tolerated, and clinically and statistically superior to placebo in the target LUTS/BPH population.

MultiParametric Magnetic Resonance Imaging-Based Nomogram for Predicting Prostate Cancer and Clinically Significant Prostate Cancer in Men Undergoing Repeat Prostate Biopsy.

OBJECTIVE: To develop and internally validate nomograms based on multiparametric magnetic resonance imaging (mpMRI) to predict prostate cancer (PCa) and clinically significant prostate cancer (csPCa) in patients with a previous negative prostate biopsy. MATERIALS AND METHODS: The clinicopathological parameters of 231 patients who underwent a repeat systematic prostate biopsy and mpMRI were reviewed. Based on Prostate Imaging and Reporting Data System, the mpMRI results were assigned into three groups: Groups "negative," "suspicious," and "positive." Two clinical nomograms for predicting the probabilities of PCa and csPCa were constructed. The performances of nomograms were assessed using area under the receiver operating characteristic curves (AUCs), calibrations, and decision curve analysis. RESULTS: The median PSA was 15.03 ng/ml and abnormal DRE was presented in 14.3% of patients in the entire cohort. PCa was detected in 75 patients (32.5%), and 59 (25.5%) were diagnosed with csPCa. In multivariate analysis, age, prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE), and mpMRI finding were significantly independent predictors for PCa and csPCa (all p < 0.01). Of those patients diagnosed with PCa or csPCa, 20/75 (26.7%) and 18/59 (30.5%) had abnormal DRE finding, respectively. Two mpMRI-based nomograms with super predictive accuracy were constructed (AUCs = 0.878 and 0.927, p < 0.001), and both exhibited excellent calibration. Decision curve analysis also demonstrated a high net benefit across a wide range of probability thresholds. CONCLUSION: mpMRI combined with age, PSA, PV, and DRE can help predict the probability of PCa and csPCa in patients who underwent a repeat systematic prostate biopsy after a previous negative biopsy. The two nomograms may aid the decision-making process in men with prior benign histology before the performance of repeat prostate biopsy.

High Incidence of Incidental Prostate Cancer in Transurethral Resection of Prostate Specimens in China. The Value of Pathologic Review.

OBJECTIVE: To identify the incidence and clinicopathologic features of prostate cancer incidentally detected in patients undergoing transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH), and to estimate the clinical value of pathologic review of all TURP specimens. STUDY DESIGN: A pathologic review was performed on all TURP specimens for each patient from May 1, 2004, to June 30, 2014, in our institute. A total of 1,024 men (ages 46-98) were identified by pathology specimen. Those with a known diagnosis of prostate cancer prior to TURP (n = 16) were excluded from the analysis. The tumor volume, Gleason score, pathologic stage, serum prostate-specific antigen (PSA) level, and follow-up data were evaluated for those who were found to have prostate cancer. RESULTS: A total of 87 (8.6%) patients (ages 50-88) were found to have prostate cancer. Significant prostate cancer was found in 25 patients. From May 1, 2004, to May 31, 2009, 30 (6.1%) patients (ages 57-83) were found to have prostate cancer. From June 1, 2009, to June 30, 2014, 57 (11.0%) patients (ages 50-88) were found to have prostate cancer. CONCLUSION: Our series demonstrates that 8.6% of patients were found to have prostate cancer and that the incidence was increasing in recent years. Even in some patients with T1a disease, the tumors were significant. The pathologic review of TURP specimens is valuable in China.

Analysis of Advantages and Disadvantages of the Location Methods of International Auricular Acupuncture Points.

The international standardization of auricular acupuncture points (AAPs) is an important basis for auricular therapy or auricular diagnosis and treatment. The study on the international standardization of AAPs has gone through a long process, in which the location method is one of the key research projects. There are different points of view in the field of AAPs among experts from different countries or regions. By only analyzing the nine representative location methods, this paper tried to offer a proper location method to locate AAPs. Through analysis of the pros and cons of each location method, the location method applied in the WFAS international standard of AAPs is thoroughly considered as an appropriate method. It is important to keep the right direction during developing an International Organization for Standardization (ISO) international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs.

Status and strategies analysis on international standardization of auricular acupuncture points.

OBJECTIVE: To supply literature for developing an international standard of auricular acupuncture points. METHODS: Electronic database searches were conducted in the Chinese National Knowledge Infrastructure and VIP, and the Western databases, Pubmed, the National Science and Technology Library, and the German Journal of Acupuncture, from 1990 to April, 2012. We also searched the documents of international symposiums for auricular acupuncture points (AAPs). Keywords were "auricular points", "auricular acupuncture points", "ear points", or "auriculotherapy". RESULTS: Basic and clinical research on AAPs was performed in China, the United States, France, and Germany. Clinical AAP research was done in Italy, Austria, Switzerland, Spain, the UK, Holland, Japan, Russia, and Africa. However, AAP research was not communicated internationally. The World Federation of Acupuncture-Moxibustion Societies recommended international standard of auricular acupuncture points (ISAAPs). Standardized nomenclature and locations of AAPs would provide a solid basis to draft an international standard organization. CONCLUSION: Experts need to find common points from different countries or regions, provide evidence of different ideas, and list the proposal as a recommendation for an international standard.

[Thoughts and strategies of developing an international standard of nomenclature and location of auricular acupuncture points].

The new development on the international standard of nomenclature and location of auricular acupoints (AAP) was stated in this paper. The similarities and differences of the auricular acupuncture system in various countries were compared in this paper in order to provide suggestions and strategies for international standard of no menclature and location of AAP. In this paper, the international standard of AAP as a common language for international academic exchanges, the guidance for beginners and a basis for further research was mentioned. There were similarities and differences in the nomenclature and location of AAP in China and abroad. It was worthwhile to clarify the similarities and differences in order to promote the process of international standard of AAP. The five basic principles for the international standard of AAP are the basic research of auricular anatomy, the total auricular acupuncture points, principles for nomenclature, the practicality and the accuracy.

[In vitro effect of zilongjin on prostate cancer cell line LNCaP].

OBJECTIVE: To investigate the effect of Zilongjin (ZLJ) on human androgen-dependent type of prostate cancer cell line LNCaP. METHODS: MTT assay, flow cytometry and fluorescence microscopy were used to observe the effect of ZLJ in anti-proliferation, cell cycle arresting and apoptosis induction. RT-PCR was used to examine the effect of ZLJ on expressions of prostate marker gene (PSA), androgen receptor (AR), apoptosis related genes (bcl-2 and bax), and Western blot assay was used to detect the effect on protein expression of bcl-2 and bax. RESULTS: ZLJ could cause apparent inhibition on proliferation, induce G0/G1 phase arresting and apoptosis in time- and dose-dependent manner on LNCaP cells. The concentration for inhibiting cell growth by 50% (IC50) in 72 hrs was 0.79 mg/ml. ZLJ could down-regulate the expression of PSA, AR, bcl-2 genes and lower bcl-2 protein expression, but showed ineffective on bax protein expression. CONCLUSION: ZLJ displays its anti-tumor effects by way of inhibiting the cell proliferation, arresting the G0/G1 phase, inducing apoptosis, down-regulating PSA, AR, bcl-2 gene expression and lowering bcl-2 protein expressions.

Asian trends in prostate cancer hormone therapy.

The first Conference on Asian Trends in Prostate Cancer Hormone Therapy was held in September 2001 to serve as a forum for Asian urologists to compare data on prostate cancer and discuss issues regarding the use of hormone therapy. The conference revealed that due to various cultural and philosophical factors, differences exist in prostate cancer management among the Asian countries. In addition, a lack of databases on hormone therapy was exposed in some countries. It was noted that many decisions in the treatment of prostate cancer are influenced by the strategies adopted in Western countries, and that attempts to formulate uniform guidelines for the Asian region have hitherto been unsuccessful. The main findings of the conference are reported in this review.