June 2024
Translational Oncology
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June 2024
Translational Oncology
June 2024
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3 Reads
Journal of Clinical Oncology
5048 Background: In the CHART trial, rezvilutamide plus ADT significantly improved radiographic PFS and OS compared with bicalutamide plus ADT in patients with high-volume mHSPC (Gu et al., Lancet Oncol 2022). Here, we report the PRO results from the CHART trial. Methods: Eligible patients were men ≥18 years old with high-volume mHSPC and without previous chemotherapy or other localized treatment for prostate cancer. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. PROs were exploratory endpoints and were assessed in all randomized patients by using the Brief Pain Inventory-Short Form (BPI-SF) and Functional Assessment of Cancer Therapy-Prostate (FACT-P). PROs were collected within 7 days prior to the first dose, on Day 1 of each cycle (28 days) in Cycles 2–12, once every 2 cycles in Cycles 13–36, once every 4 cycles afterwards, and on Day 30 after the last dose. Results: Between Jun 28, 2018, and Aug 6, 2020, a total of 654 patients were randomly assigned to receive either rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). The data cutoff for this PRO analysis was Feb 28, 2022, and the median follow-up was 29.3 months (IQR 21.0–33.3). Baseline pain scores and functional status scores were comparable between the two study groups. The median time to progression of pain (both intensity and interference) was not reached in either group. The 25th percentile for the time to average pain progression was 25.8 months (95% CI 14.8–31.4) in the rezvilutamide plus ADT group and 11.7 months (95% CI 8.7–22.1) in the bicalutamide plus ADT group (HR 0.79, 95% CI 0.58–1.08; p=0.133). Patients in the rezvilutamide group exhibited a longer time to pain interference progression compared to the bicalutamide group (25th percentile, 20.2 months [95% CI 12.9–31.3] vs 10.2 months [95% CI 7.4–11.1]; HR 0.70 [95% CI 0.52–0.93]; p=0.015). Regarding functional status, the time to deterioration of the FACT-P total score was prolonged in the rezvilutamide plus ADT group compared to the bicalutamide plus ADT group (25th percentile, 12.8 months [95% CI 7.4–20.3] vs 6.0 months [95% CI 4.6–9.2]; HR 0.66, 95% CI 0.50–0.86; p=0.002). Additionally, the rezvilutamide plus ADT group exhibited delayed deterioration in all FACT-P subscale scores compared to the bicalutamide plus ADT group. Conclusions: Rezvilutamide plus ADT demonstrated superiority over bicalutamide plus ADT in delaying pain progression and functional status deterioration in high-volume mHSPC. Clinical trial information: NCT03520478 .
May 2024
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1 Read
BMC Microbiology
Background The study aims to analyze the epidemiology of preservation fluid (PF) contamination and investigate the impact of PF contamination and possible donor-derived infections(p-DDI) on early postoperative prognosis in kidney transplant (KT) recipients. Methods A total of 256 PF samples were collected for microbiological evaluation from all KT recipients who received deceased donor donations in our hospital from June 2018 to August 2022. Data on the baseline and clinical characteristics of these PF corresponding to recipients and donors were extracted from the electronic medical record. It mainly included the early postoperative complications and prognosis of KT recipients. Results From June 2018 to August 2022, 597 kidney transplants were performed in our center, with 260 recipients receiving kidney transplantation from donation after citizens’ death. A total of 256 samples of PF were collected, of which 64.5% (165/256) were culture positive, and 24.6% (63/165) of the culture-positive PF were polymicrobial contamination. A total of 238 strains were isolated, of which coagulase-negative staphylococci (CoNS) had the highest proportion of 34.0% (81/238), followed by Klebsiella pneumoniae with 20.6% (49/238) and Escherichia coli with 8.8% (21/238). Recipients with culture-positive PF had a significantly higher incidence of postoperative infection (55.8% vs. 20.9%, P < 0.001) and DGF (38.2% vs. 24.2%, P = 0.023). In addition, the incidence of p-DDI was 12.9% (33/256). CRKP was the most common pathogen causing p-DDI. The recipients who developed p-DDI had a higher rate of graft loss (9.1% vs. 0.4%, P < 0.001), mortality (12.1% vs. 3.1%, P = 0.018), and longer postoperative hospital stay (30 days (19.5–73.5) vs. (22 days (18–32), P < 0.05) compared with recipients who did not develop p-DDI. Conclusions Culture-positive PF is potentially significant for KT recipients, and p-DDI may increase the risk of poor prognosis for recipients. Prophylactic anti-infective treatment should be actively performed for highly virulent or multidrug-resistant (MDR) pathogens (especially Carbapenem-resistant Klebsiella pneumoniae, CRKP) in PF to avoid the occurrence of p-DDI.
May 2024
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7 Reads
International Journal of Oncology
Clear cell renal cell carcinoma (ccRCC), the most common type of renal cell carcinoma (RCC), is not sensitive to traditional radiotherapy and chemotherapy. The polyphenolic compound Gallic acid (GA) can be naturally found in a variety of fruits, vegetables and plants. Autophagy, an intracellular catabolic process, regulates the lysosomal degradation of organelles and portions in cytoplasm. It was reported that autophagy and GA could affect the development of several cancers. Therefore, the aim of the present study was to evaluate the effects of GA on ccRCC development and clarify the role of autophagy in this process. In the present study, the effects of GA on the proliferation, migration and invasion of ccRCC cells were investigated in vitro by Cell Counting Kit‑8, colony formation, flow cytometry, wound healing and Transwell migration assays, respectively. Additionally, the effects of GA on ccRCC growth and metastasis were evaluated using hematoxylin‑eosin and immunohistochemical staining in vivo. Moreover, it was sought to explore the underlying molecular mechanisms using transmission electron microscopy, western blotting and reverse transcription‑quantitative PCR analyses. In the present study, it was revealed that GA had a more potent viability inhibitory effect on ccRCC cells (786‑O and ACHN) than the effect on normal renal tubular epithelial cell (HK‑2), which demonstrated that GA selectively inhibits the viability of cancer cells. Furthermore, it was identified that GA dose‑dependently inhibited the proliferation, migration and invasion of ccRCC cells in vitro and in vivo. It was demonstrated that GA promoted the release of autophagy markers, which played a role in regulating the PI3K/Akt/Atg16L1 signaling pathway. All the aforementioned data provided evidence for the great potential of GA in the treatment of ccRCC.
May 2024
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2 Reads
Background Ceftazidime-avibactam is a treatment option for carbapenem-resistant gram-negative bacilli (CR-GNB) infections. However, the risk factors associated with ceftazidime-avibactam (CAZ-AVI) treatment failure in kidney transplant (KT) recipients and the need for CAZ-AVI-based combination therapy remain unclear. Methods From June 2019 to December 2023, a retrospective observational study of KT recipients with CR-GNB infection treated with CAZ-AVI was conducted, with the primary outcome being 30-day mortality and secondary outcomes being clinical cure, microbiological cure, and safety. Risk factors for 30-day mortality and clinical failure were also investigated. Results A total of 81 KT recipients treated with CAZ-AVI were included in this study. Forty recipients (49.4%) received CAZ-AVI monotherapy, with a 30-day mortality of 22.2%. The clinical cure and microbiological cure rates of CAZ/AVI therapy were 72.8% and 66.7%, respectively. CAZ-AVI alone or in combination with other medications had no effect on clinical cure or 30-day mortality. Multivariate logistic regression analysis revealed that a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR]: 4.517; 95% confidence interval [CI]: 1.397-14.607; P = 0.012) was an independent risk factor for 30-day mortality. Clinical cure was positively associated with the administration of CAZ-AVI within 48 hours of infection onset (OR: 11.009; 95% CI: 1.344-90.197; P=0.025) and negatively associated with higher APACHE II scores (OR: 0.700; 95% CI: 0.555-0.882; P=0.002). Four (4.9%) recipients experienced recurrence within 90 days after the initial infection, 3 (3.7%) recipients experienced CAZ-AVI-related adverse events, and no CAZ-AVI resistance was identified. Conclusion CAZ-AVI is an effective medication for treating CR-GNB infections following kidney transplantation, even as monotherapy. Optimization of CAZ/AVI therapy (used within 48 hours of infection onset) is positively associated with potential clinical benefit. Further larger-scale studies are needed to validate these findings.
April 2024
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20 Reads
Cell Death Discovery
Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2α plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2α-dependent lipid accumulation and tumor progression. HIF-2α promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2α knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2α pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.
March 2024
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34 Reads
Chronic prostatitis and Pelvic Pain syndrome (CP/CPPS) is an autoimmune inflammatory disease characterized by pelvic or perineal pain and infiltration of inflammatory cells in the prostate. C-X-C chemokine receptor type 7 (CXCR7), also known as the atypical chemokine receptor 3 (ACKR3) receptor, are atypical chemokine receptors. Having been shown to play a key role in inflammatory processes, whether CXCR7 influences the role of autoimmune prostate and immune regulation and its mechanism of action are unclear. In this study, a mouse model of experimental autoimmune prostatitis was constructed by subcutaneous injection of antigen, and CXCR7 agonist was administered to investigate the effects of CXCR7 on the proportion of immune cells and fibrosis in CP/CPPS. Western blotting, immunohistochemical staining and Immunofluorescence, flow cytometry, and masson staining were used to study the possible regulatory mechanisms. CXCR7 agonists can significantly reduce pain and prostatic inflammation, and in vivo flow studies have shown that they affect the TH17/Treg cell ratio. To elucidate the potential mechanisms by which CXCR7 influences the pathogenesis of CNP, we conducted simultaneous RNA-seq and non-targeted metabolome sequencing. Our findings suggest that CXCR7 agonists alleviate fibrosis in autoimmune prostatitis by inhibiting the TGFβ/SMAD pathway. This study provides a valuable immunological basis for CNP to intervene CP/CPPS therapy with CXCR7 as the target.
March 2024
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13 Reads
Cell Communication and Signaling
Purpose Prostatitis is a highly prevalent condition that seriously affects men’s physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target. Methods Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated. Results SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-β. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse. Conclusions The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.
March 2024
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4 Reads
The Prostate
Background Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. Methods The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200, or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti‐inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO‐1 inhibitor zinc protoporphyrin on prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin‐eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation‐related cytokines, such as interleukin (IL)−1β, IL‐6, and tumor necrosis factor were detected by enzyme‐linked immunosorbent assay. The regulation of Nrf2/HO‐1 signaling pathway and the expression of NLRP3 inflammasome‐related protein in EAP mice were detected by western blot analysis assay. Results Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO‐1 signal pathway. Nrf2/HO‐1 pathway inhibitors can inhibit NaB ‐mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti‐inflammatory effect can also be blocked by Nrf2/HO‐1 pathway. Conclusions NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO‐1 pathway. NaB has the potential as an effective agent in the treatment of EAP.
February 2024
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29 Reads
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1 Citation
ImmunoTargets and Therapy
Background The specific involvement of the CD8+ T effector memory RA (TEMRA) subset in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has largely not been explored in the literature. Methods Targeted single-cell RNA sequencing (scRNA-seq) profiles were generated from peripheral blood mononuclear cells (PBMCs) obtained from two CP/CPPS patients and two healthy controls (HCs) in our recent study. Pseudotime series algorithms were used to reveal the differentiation trajectory, CellChat analysis was used to explore the communication between individual cells, and the SCENIC program was used to identify potential transcription factors (TFs). Based on the cosine similarity, clusters of differentially expressed genes (DEGs) were considered to be further enriched in different pathways. To confirm the functional role of the critical clusters, flow cytometry was employed. Results The results revealed the molecular landscape of these clusters, with TEMRA cells exhibiting pronounced cytokine-mediated signaling pathway enrichment. Pseudotime trajectory analysis further mapped the evolution from naïve T cells to that of TEMRA cells, elucidating the developmental pathways involved in the immune context. A significant finding from CellChat analysis was the differential expression of ligands and receptors, with CD8+ TEMRA cells showing enhanced signaling, particularly in the CP/CPPS context, compared to HCs. Flow cytometry confirmed these results, revealing a heightened proinflammatory cytokine profile in patients with chronic prostatitis-like symptoms (CP-LS), suggesting that TEMRA cells play a significant role in disease pathogenesis. TF profiling across the T-cell clusters identified key regulators of cellular identity, identifying novel therapeutic targets. Elevated TNF signaling activity in CD8+ TEMRA cells underscored the involvement of these cells in disease mechanisms. Conclusion This study elucidates the pivotal role of the CD8+ TEMRA cell subset in CP/CPPS, which is characterized by increased TNF signaling and proinflammatory factor expression, highlighting potential biomarkers and opening new avenues for therapeutic intervention.
... We used harmony's method to remove the batch efect between samples and selected the top 30 PCs for downscaling and clustering. After the dimensionality reduction clustering the results were projected onto a 2D map using the UMAP method for the next step of cell type identifcation [29,30]. We obtained the cell markers of the relevant cells by referring to previous literature as well as according to the CellMarker database (https://xteam.xbio. ...
February 2024
... At present, itaconic acid has shown good therapeutic effects in many animal disease models such as sepsis and pulmonary brosis[66-69]. Various itaconic acid derivatives such as 4-OI and dimethyl itaconic acid exhibit similar biological properties [70,71]. Fumaric acid, which has a similar structure to itaconic acid, is already used clinically to treat multiple sclerosis and psoriasis. ...
December 2023
The Prostate
... Similar to the TCGA dataset, patients in both datasets were categorized into high-and low-risk groups based on their median risk scores. Furthermore, we performed the DeLong test to compare the predictive performance of the DRS, as quantified by the AUC, with that of other cell death-related gene signatures [50][51][52][53][54][55]. Statistical significance was set at p < 0.05. ...
November 2023
iMeta
... Obacunone at 25-100 mg/kg/d administered by gavage all effectively attenuated the severity of DSS-induced ulcerative colitis in mice by mitigating the Toll-like receptor 4/nuclear factor-κB signaling hyperactivation and regulating the abnormal composition of the intestinal flora [38]. Obacunone in a dose-dependent manner (10-50 mg/kg/d) alleviated experimental autoimmune prostatitis-induced chronic pelvic pain syndrome and pro-inflammatory depolarization of macrophages within the prostate via, at least partially, deactivating macrophage migration inhibitory factor (MIF) [39]. ...
October 2023
Biochemistry and Biophysics Reports
... Understanding the molecular classifications of RCs could provide directions for successful targeted therapies. The common treatment options for male and female RCs are chemotherapy, immunotherapy, and radiotherapy [28][29][30][31]. PCa is classified into several subtypes with different clinicopathological features based on eight molecular classifications: tomlins, the cancer genome atlas (TCGA), prostate cancer 14-pathway (PCS), 50-gene signature (PAM50), bone-metastatic, epithelial, immune, and multi-omics [28]. ...
November 2023
... Chemotherapy has limited therapeutic effect on metastatic renal cell carcinoma and is often combined with immunosuppressive drugs. With the continuous breakthroughs in targeted therapy and immunotherapy, the treatment of advanced kidney cancer has entered the era of combining targeted therapy and immunotherapy, and the median overall survival of patients has been greatly improved [20][21][22][23]. Currently, commonly used targeted drugs for the treatment of advanced kidney clear cell carcinoma include anti-vascular targeted drugs (sunitinib, sorafenib, pezopanib, axitinib, cabozantinib, lenvatinib, bevacizumab, etc.) and anti-rapamycintargeting protein (mTOR)-targeted drugs (everolimus and tesilomox) [24]. ...
July 2023
European Urology Oncology
... However, cells eventually start to self-destruct if ER stress levels are consistently high. Diseases like diabetes, cancer, and neurodegeneration might be triggered by ER stress and UPR signaling [11][12][13]. It has been demonstrated that ER stress and UPR are essential for the pathogenesis, development, and therapeutic response of many malignancies [14]. ...
April 2023
Journal of Cancer
... Not only these, ferrite is also emerging in cancer treatment. For example, Ahmad et al. found that manganese cobalt ferrite had obvious inhibitory effect on human breast cancer cells [61]; Wang et al. modified manganese-zinc ferrite with polyethylene glycol and showed great synergistic anti-tumor effects in vivo [62]. ...
March 2023
Small
... Furthermore, better efficacy of anti-PD-1/L1 inhibitors was observed in tumours with a high tumour mutational burden (TMB) [30,38,50], which is an additional explanation for their poor efficacy in testicular germ cell tumours, which are known to have low TMB [9]. Despite the overall better therapeutic response in tumours that express PD-L1 either on tumour or immune cells [29,53], the efficacy of anti-PD-1/L1 inhibitors is not at a satisfactory level, especially not in testicular germ cell tumours. This indicates the need to find other therapeutic targets, intending to overcome chemotherapy and immunotherapy resistance. ...
February 2023
Cellular Oncology
... One of the most important factors in protection against infectious complications is a negative preoperative urine culture. However, even if preoperative urine culture is negative in patients undergoing RIRS, postoperative fever has been reported at the rate of 14.6% [4]. In the endourological treatment of kidney stones, stone and renal pelvis culture has been found to have higher efficacy in the prediction of infectious complications than mid-flow urine culture, and even if preoperative midflow urine culture is negative, the complication rates are increased if there is bacterial production in stone or renal pelvis culture [5,6]. ...
February 2023
World Journal of Urology