Assessing the predictive value of intraductal carcinoma of the prostate (IDC-P) in determining abiraterone efficacy for metastatic hormone-sensitive prostate cancer (mHSPC) patients.

BACKGROUND: This study explored the value of intraductal carcinoma of the prostate (IDC-P) in predicting the efficacy of abiraterone treatment in metastatic hormone-sensitive prostate cancer (mHSPC) patients. METHODS: A retrospective study of 925 patients who underwent prostate biopsies to detect IDC-P was conducted, with participants divided into two cohorts. The first cohort of 165 mHSPC patients receiving abiraterone treatment was analyzed to compare therapeutic effectiveness between IDC-P positive and negative cases. Utilizing propensity score matching (PSM) to reduce bias, outcomes such as PSA response, progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival were assessed. Additionally, the second cohort of 760 mHSPC patients compared the efficacy of abiraterone with conventional hormone therapy, focusing on differences between IDC-P positive and negative individuals. RESULTS: After PSM, our first cohort included 108 patients with similar baseline characteristics. Among them, 50% (54/108) were diagnosed with IDC-P, with 22.2% (12/54) having IDC-P pattern 1 and 77.8% (42/54) with IDC-P pattern 2. While no notable difference was seen in PSA responses between IDC-P positive and negative patients, IDC-P presence linked to worse clinical outcomes (PSA-PFS: 18.6 months vs. not reached [NR], p = 0.009; rPFS: 23.6 months vs. NR, p = 0.020). Further analysis showed comparable outcomes for IDC-P pattern 1 but significantly worse prognosis for IDC-P pattern 2 (PSA-PFS: 18.6 months vs. NR, p = 0.002; rPFS: 22.4 months vs. NR, p = 0.010). Subgroup analysis revealed IDC-P pattern 2 consistently predicted poorer outcomes across patient subgroups. Remarkably, both IDC-P positive and negative patients gained more from androgen deprivation therapy with abiraterone than conventional treatment, with IDC-P negative patients showing a more significant survival advantage, supported by better hazard ratios (0.47 and 0.66). CONCLUSION: This study found that IDC-P, especially pattern 2, predicts poor prognosis in mHSPC patients on abiraterone therapy. Also, abiraterone's advantage over hormone therapy is reduced in cases with IDC-P compared to those without.

Exploring the Blood Biomarkers and Potential Therapeutic Agents for Human Acute Mountain Sickness Based on Transcriptomic Analysis, Inflammatory Infiltrates and Molecular Docking.

A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. However, the regulation of the immune system in high-altitude environments is extremely complex and remains elusive. This study integrated system bioinformatics methods to screen for changes in immune cell subtypes and their associated targets. It also sought potential therapeutically effective natural compound candidates. The present study observed that monocytes, M1 macrophages and NK cells play a crucial role in the inflammatory response in AMS. IL15RA, CD5, TNFSF13B, IL21R, JAK2 and CXCR3 were identified as hub genes, and JAK2 was positively correlated with monocytes; TNFSF13B was positively correlated with NK cells. The natural compound monomers of jasminoidin and isoliquiritigenin exhibited good binding affinity with JAK2, while dicumarol and artemotil exhibited good binding affinity with TNFSF13B, and all are expected to become a potential therapeutic agents.

Case report: Synchronous prostate cancer and renal cell carcinoma with prostate cancer-origin metastases to adrenal and renal hilar lymph nodes.

Background: Synchronous occurrence of prostate cancer (PCa) and renal cell carcinoma (RCC) is uncommon. RCC has a higher tendency to metastasize to the adrenal glands, renal hilar, and retroperitoneal lymph nodes compared to PCa. To date, there are no documented cases existing where metastatic tumors in these regions, observed in patients concurrently with PCa and RCC, have originated from the PCa rather than the RCC. Case presentation: In this case report, we described a 67-year-old male presented with dysuria for two months and left lower extremity edema for three days. Percutaneous biopsies revealed synchronous primary RCC and PCa. However, the origin of the metastatic tumors, especially those involving the adrenal glands, renal hilum, and retroperitoneal regions, remained undetermined. Subsequent surgical procedures identified that the metastatic lesions originated from the PCa, while the RCC was localized. Ultimately, the patient with metastatic hormone-sensitive prostate cancer (mHSPC) received combination therapy with rezvilutamide and goserelin, which resulted in a satisfactory treatment response. Conclusion: In patients with concurrent PCa and RCC, metastatic lesions in the adrenal glands, renal hilar, and retroperitoneal lymph nodes may also originate from the PCa. Accurate identification of the primary tumor and proper staging are critical for the appropriate management of patients with multiple primary malignancies with concurrent metastases.

4-Hydroxybenzoic acid restrains Nlrp3 inflammasome priming and activation via disrupting PU.1 DNA binding activity and direct antioxidation.

Reactive oxygen species (ROS) production is considered central to triggering the nucleotide-binding domain-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation and the subsequent inflammatory responses. Coenzyme Q10 (CoQ10) plays a critical role in maintaining intracellular ROS homeostasis and inhibiting excessive Nlrp3 inflammasome activation. However, direct supplementation of CoQ10 showed unsatisfactory clinical improvement due to its limited absorption and bioavailability. Therefore, stimulating endogenous CoQ10 biosynthesis by supplementing CoQ10 precursors may provide a more promising therapeutic approach. In this study, we described the role of 4-hydroxybenzoic acid (4-HBA), a precursor of CoQ10, in attenuating excessive inflammatory responses. We found that while supplementation of 4-HBA inhibited the priming and activation of Nlrp3 inflammasome, this effect was independent of its metabolic transformation into CoQ10. 4-HBA itself exhibits antioxidative activities. Furthermore, 4-HBA can disrupt the binding activity of PU.1 on the promoters of Tlr4 and Md2, thereby directly suppressing Nlrp3 inflammasome priming during LPS-induced inflammatory responses. Therefore, strategically utilizing 4-HBA or increasing 4-HBA intake may represent a potential strategy for reducing excessive inflammation.

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In the hilly region of Chinese Loess Plateau, rainwater harvesting is a common ecological engineering measure utilized to reduce soil erosion and amplify the efficiency of water resource utilization. However, the effects on rainwater harvesting and the chief influencing factors of biocrusts as a potential material are unclear. In this study, we conducted a field simulation experiment with intensities of 40, 60, 80, and 100 mm·h-1 between bare soil and biocrusts developed in aeolian soils, with bare soil as a control to explore the differences of the initial abstraction time, cumulative rainfall amount, and rainfall harvesting efficiency. We further analyzed the influencing factors of the rainwater harvesting effect. The results showed that the biocrusted soil-surfaces significantly decreased the initial abstraction time. When compared with the cyano biocrusts and bare soil, the reduction of the initial abstraction time of moss biocrusts was decreased by 49.7%-77.5% and 89.7%-110.0% when the rainfall intensities ranged from 40 to 100 mm·h-1 and the slope was 40°. In addition, biocrusted soil surfaces significantly increased the cumulative rainfall amount and rainfall harvesting efficiency. These differences were considerable amongst the dissimilar surface cover types. In comparison to bare soil, when the rainfall intensity was 100 mm·h-1 and the slope was 40°, the cumulative rainfall harvesting efficiency of moss and cyano biocrusts was increased by 29.6% and 7.8%, respectively. Both moss and cyano biocrusts increased rainfall harvesting efficiency of 25.7% and 6.8%, respectively. Variance analysis demonstrated that the rainfall harvesting efficiency was appreciably affected by surface cover type, slope, and rainfall intensity. The interaction between these factors was considerable except for slope and rainfall intensity. Additionally, important considerations for the actual construction included slope length, slope, and biocrust cultivation. In conclusion, biocrusted soil-surfaces have a high rainfall harvesting efficiency, but moss biocrusts have a much greater rain-collecting effect that improves even more as the slope and intensity of the rain increases.

Ferulic Acid Alleviates Radiation-Induced Immune Damage by Acting on JAK/STAT Signaling Pathway.

The disruption of hematopoietic and immune functions is a significant consequence of the long-term effects of radiation exposure. This study investigated the potential mechanisms by which ferulic acid (FA) acts as a radioprotective agent in mitigating radiation-induced immune damage. C57BL/6J mice were exposed to a dose of 6.0 Gy of 60Co γ irradiation. FA was administered at doses of 25, 50, and 100 mg/kg/d for 7 days before and 30 days following irradiation. We evaluated changes in peripheral blood cells, T and B lymphocytes, natural killer cells in the spleen, and hematopoietic stem/progenitor cells in the bone marrow (BM). Whole-genome transcriptome sequencing of BM was performed to explore potential mechanisms. FA administration resulted in a significant reduction in malonaldehyde levels (p < 0.0001), an increase in catalase and beta-nicotinamide adenine dinucleotide levels in serum (p < 0.05), and enhanced multipotent progenitors (p < 0.01) and common lymphoid progenitors (p < 0.05) in the BM. Additionally, there was an elevation in white blood cell levels, red blood cell levels, and hemoglobin levels in peripheral blood (p < 0.01). Transcriptome analysis indicated that FA reversed the radiation-induced expression of genes related to immunity and inflammation. Enzyme-linked immunosorbent assay experiments further demonstrated that FA reduced interleukin-6 levels in the BM and decreased JAK1, JAK2, and STAT3 protein content (p < 0.01). In conclusion, FA might mitigate hematopoietic and immune damage by modulating the JAK/STAT signaling pathway.

A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.

IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.

Exploring the clinical and diagnostic value of metagenomic next-generation sequencing for urinary tract infection: a systematic review and meta-analysis.

BACKGROUND: A new pathogen detection tool, metagenomic next-generation sequencing (mNGS), has been widely used for infection diagnosis, but the clinical and diagnostic value of mNGS in urinary tract infection (UTI) remains inconclusive. This systematic review with meta-analysis aimed to investigate the efficacy of mNGS in treating UTIs. METHODS: A comprehensive literature search was performed in PubMed, Web of Science, Embase, and the Cochrane Library, and eligible studies were selected based on the predetermined criteria. The quality of the included studies was assessed via the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, and the certainty of evidence (CoE) was measured by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) score. Then, the positive detection rate (PDR), pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve of the summary receiver operating characteristic curve (AUROC) was estimated in Review Manager, Stata, and MetaDisc. Subgroup analysis, meta-regression, and sensitivity analysis were performed to reveal the potential factors that influence internal heterogeneity. RESULTS: A total of 17 studies were selected for further analysis. The PDR of mNGS was markedly greater than that of culture (odds ratio (OR) = 2.87, 95% confidence interval [CI]: 1.72-4.81, p < 0.001, I2 = 90%). The GRADE score presented a very low CoE. Then, the pooled sensitivity was 0.89 (95% CI: 0.86-0.91, I2 = 39.65%, p = 0.06), and the pooled specificity was 0.75 (95% CI: 0.51-0.90, I2 = 88.64%, p < 0.001). The AUROC of the studies analyzed was 0.89 (95% CI: 0.86-0.92). The GRADE score indicated a low CoE. CONCLUSION: The current evidence shows that mNGS has favorable diagnostic performance for UTIs. More high-quality prospective randomized controlled trials (RCTs) are expected to verify these findings and provide more information about mNGS in UTI treatment and prognosis.

Development and validation of a novel nomogram to avoid unnecessary biopsy in patients with PI-RADS category ≥ 4 lesions and PSA ≤ 20 ng/ml.

OBJECTIVES: To develop and validate a prediction model for identifying non-prostate cancer (non-PCa) in biopsy-naive patients with PI-RADS category ≥ 4 lesions and PSA ≤ 20 ng/ml to avoid unnecessary biopsy. PATIENTS AND METHODS: Eligible patients who underwent transperineal biopsies at West China Hospital between 2018 and 2022 were included. The patients were randomly divided into training cohort (70%) and validation cohort (30%). Logistic regression was used to screen for independent predictors of non-PCa, and a nomogram was constructed based on the regression coefficients. The discrimination and calibration were assessed by the C-index and calibration plots, respectively. Decision curve analysis (DCA) and clinical impact curves (CIC) were applied to measure the clinical net benefit. RESULTS: A total of 1580 patients were included, with 634 non-PCa. Age, prostate volume, prostate-specific antigen density (PSAD), apparent diffusion coefficient (ADC) and lesion zone were independent predictors incorporated into the optimal prediction model, and a corresponding nomogram was constructed ( https://nomogramscu.shinyapps.io/PI-RADS-4-5/ ). The model achieved a C-index of 0.931 (95% CI, 0.910-0.953) in the validation cohort. The DCA and CIC demonstrated an increased net benefit over a wide range of threshold probabilities. At biopsy-free thresholds of 60%, 70%, and 80%, the nomogram was able to avoid 74.0%, 65.8%, and 55.6% of unnecessary biopsies against 9.0%, 5.0%, and 3.6% of missed PCa (or 35.9%, 30.2% and 25.1% of foregone biopsies, respectively). CONCLUSION: The developed nomogram has favorable predictive capability and clinical utility can help identify non-PCa to support clinical decision-making and reduce unnecessary prostate biopsies.

Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.

Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma.

BACKGROUND: A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown. METHODS: Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation. RESULTS: Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed. CONCLUSIONS: Our study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.

Potential therapeutic effects of traditional Chinese medicine in acute mountain sickness: pathogenesis, mechanisms and future directions.

Background and objectives: Acute mountain sickness (AMS) is a pathology with different symptoms in which the organism is not adapted to the environment that occurs under the special environment of high altitude. Its main mechanism is the organism's tissue damage caused by acute hypobaric hypoxia. Traditional Chinese medicine (TCM) theory focuses on the holistic concept. TCM has made remarkable achievements in the treatment of many mountain sicknesses. This review outlines the pathogenesis of AMS in modern and traditional medicine, the progress of animal models of AMS, and summarizes the therapeutic effects of TCM on AMS. Methods: Using the keywords "traditional Chinese medicine," "herbal medicine," "acute mountain sickness," "high-altitude pulmonary edema," "high-altitude cerebral edema," "acute hypobaric hypoxia," and "high-altitude," all relevant TCM literature published up to November 2023 were collected from Scopus, Web of Science, PubMed, and China National Knowledge Infrastructure databases, and the key information was analyzed. Results: We systematically summarised the effects of acute hypobaric hypoxia on the tissues of the organism, the study of the methodology for the establishment of an animal model of AMS, and retrieved 18 proprietary Chinese medicines for the clinical treatment of AMS. The therapeutic principle of medicines is mainly invigorating qi, activating blood and removing stasis. The components of botanical drugs mainly include salidroside, ginsenoside Rg1, and tetrahydrocurcumin. The mechanism of action of TCM in the treatment of AMS is mainly through the regulation of HIF-1α/NF-κB signaling pathway, inhibition of inflammatory response and oxidative stress, and enhancement of energy metabolism. Conclusion: The main pathogenesis of AMS is unclear. Still, TCM formulas and components have been used to treat AMS through multifaceted interventions, such as compound danshen drip pills, Huangqi Baihe granules, salidroside, and ginsenoside Rg1. These components generally exert anti-AMS pharmacological effects by inhibiting the expression of VEGF, concentration of MDA and pro-inflammatory factors, down-regulating NF-κB/NLRP3 pathway, and promoting SOD and Na + -K + -ATPase activities, which attenuates acute hypobaric hypoxia-induced tissue injury. This review comprehensively analyses the application of TCM in AMS and makes suggestions for more in-depth studies in the future, aiming to provide some ideas and insights for subsequent studies.

Effects of Evodiamine on Behavior and Hippocampal Neurons through Inhibition of Angiotensin-Converting Enzyme and Modulation of the Renin Angiotensin Pathway in a Mouse Model of Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

14-3-3σ downregulation sensitizes pancreatic cancer to carbon ions by suppressing the homologous recombination repair pathway.

This study explored the role of 14-3-3σ in carbon ion-irradiated pancreatic adenocarcinoma (PAAD) cells and xenografts and clarified the underlying mechanism. The clinical significance of 14-3-3σ in patients with PAAD was explored using publicly available databases. 14-3-3σ was silenced or overexpressed and combined with carbon ions to measure cell proliferation, cell cycle, and DNA damage repair. Immunoblotting and immunofluorescence (IF) assays were used to determine the underlying mechanisms of 14-3-3σ toward carbon ion radioresistance. We used the BALB/c mice to evaluate the biological behavior of 14-3-3σ in combination with carbon ions. Bioinformatic analysis revealed that PAAD expressed higher 14-3-3σ than normal pancreatic tissues; its overexpression was related to invasive clinicopathological features and a worse prognosis. Knockdown or overexpression of 14-3-3σ demonstrated that 14-3-3σ promoted the survival of PAAD cells after carbon ion irradiation. And 14-3-3σ was upregulated in PAAD cells during DNA damage (carbon ion irradiation, DNA damaging agent) and promotes cell recovery. We found that 14-3-3σ resulted in carbon ion radioresistance by promoting RPA2 and RAD51 accumulation in the nucleus in PAAD cells, thereby increasing homologous recombination repair (HRR) efficiency. Blocking the HR pathway consistently reduced 14-3-3σ overexpression-induced carbon ion radioresistance in PAAD cells. The enhanced radiosensitivity of 14-3-3σ depletion on carbon ion irradiation was also demonstrated in vivo. Altogether, 14-3-3σ functions in tumor progression and can be a potential target for developing biomarkers and treatment strategies for PAAD along with incorporating carbon ion irradiation.

The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.

The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: This study aimed to summarize the occurrence of immune-related adverse events (irAEs) and further evaluate their association with clinical outcomes in patients with advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs). METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library up to December 2023 was conducted to identify eligible studies. The details of irAEs and data regarding their correlation with clinical outcomes were extracted. R software was used for meta-analysis. RESULTS: A total of 27 studies involving 6148 patients with RCC or UC were included. The pooled overall incidence for any-grade and grade ≥ 3 irAEs was 44.2 % (95 % CI: 38.1 %-50.5 %) and 15.7 % (95 % CI: 11.4 %-21.1 %), respectively. Compared to those without any irAEs, patients with irAEs showed improved PFS (HR = 0.44, 95 % CI: 0.35-0.56, p < 0.01) and OS (HR = 0.47, 95 % CI: 0.42-0.51, p < 0.01), as well as higher ORR (OR = 3.59, 95 % CI: 3.01-4.29, p < 0.01) and DCR (OR = 4.23, 95 % CI: 3.06-5.84, p < 0.01). Subgroup analysis indicated that clinical outcome improvements were associated with the occurrence of irAEs, regardless of tumor type or ICI agent. Notably, patients with cutaneous irAEs, thyroid dysfunction, and grade ≤ 2 irAEs had a higher probability to achieve better survival benefits from ICI-based therapy, while pulmonary irAEs and grade ≥ 3 irAEs seemed to have a negative impact on OS. Additionally, systemic glucocorticoids administration did not affect survival outcomes. CONCLUSION: Our findings suggest that the occurrence of irAEs could be considered as a potential prognostic factor for predicting the efficacy of ICIs in patients with advanced RCC and UC.