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The diagnostic rate of prostate cancer (PCa) remains suboptimal, particularly for patients whose serum prostate-specific antigen (PSA) concentration is less than 10 ng/mL. Single-cell sequencing, machine learning, and Mendelian randomization have emerged in recent years as excellent methods for identifying tumour markers. We identified 3 genes (RAB3B, SPON2, and SLC4A4) through single-cell sequencing and a machine learning screen. Among them, RAB3B (Ras-related protein, Rab-3B) had a higher area under the diagnostic curve for PSA < 10 ng/mL PCa (0.763) than the other two genes did. Mendelian randomization analysis revealed that the occurrence of PCa led to an increase in circulating levels of the RAB3B protein. Western blot and immunohistochemical analyses demonstrated that RAB3B was overexpressed in PCa tumour. Subsequently, elevated levels of RAB3B were detected in the culture medium of PCa cells. Furthermore, urinary RAB3B protein levels were significantly increased in PCa patients. For patients with PSA levels < 10 ng/mL, urinary RAB3B exhibited an area under the receiver operating characteristic curve (AUC) of 0.733 for PCa diagnosis, outperforming both PSA concentration (AUC = 0.682) and age (AUC = 0.651). Notably, the AUC of the multivariate model urine RAB3B + PSA + Age is 0.8. GSEA at al analysis and functional experiments, including gain-of-function and loss-of-function studies revealed that RAB3B promotes the proliferation and migration of PCa cells. In summary, urinary RAB3B, discovered through a multiomics approach, is a promising biomarker that is complementary to serum PSA, and together these factors can improve diagnostic decision-making in the PSA grey zone.

Acute antibody-mediated rejection (AAMR) is an important cause of cardiac allograft dysfunction, and more effective strategies need to be explored to improve allograft prognosis. Interleukin (IL)-6/IL-6R signaling plays a key role in the activation of immune cells including B cells, T cells and macrophages, which participate in the progression of AAMR. In this study, we investigated the effect of IL-6/IL-6R signaling blockade on the prevention of AAMR in a mouse model. We established a mouse model of AAMR for cardiac transplantation via presensitization of skin grafts and addition of cyclosporin A, and sequentially analyzed its features. Tocilizumab, anti-IL-6R antibody, and recipient IL-6 knockout were used to block IL-6/IL-6R signaling. We demonstrated that blockade of IL-6/IL-6R signaling significantly attenuated allograft injury and improved survival. Further mechanistic research revealed that signaling blockade decreased B cells in circulation, spleens, and allografts, thus inhibiting donor-specific antibody production and complement activation. Moreover, macrophage, T cell, and pro-inflammatory cytokine infiltration in allografts was also reduced. Collectively, we provided a highly practical mouse model of AAMR and demonstrated that blockade of IL-6/IL-6R signaling markedly alleviated AAMR, which is expected to provide a superior option for the treatment of AAMR in clinic.

[This corrects the article DOI: 10.3389/fimmu.2021.778359.].

Metastatic prostate cancer (PCa) remains incurable and causes considerably diminished overall survival. Despite significant progress in pharmacotherapy, the disease prognosis remains unchanged. Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness in treating various advanced malignancies, but their efficacy in metastatic PCa is relatively limited. Previous studies have confirmed the immunosuppressive role of tumor-infiltrating B cells (TIL-Bs) in the PCa microenvironment, which accounts for their poor immunogenic potency. In this study, we demonstrated that an oral kinase agent, ibrutinib, strongly potentiated anti-PD-1 checkpoint blockade efficacy and successfully controlled tumor growth in a murine orthotopic PCa model constructed using a metastatic and hormone-independent cell line (RM-1). We identified close relationships between TIL-Bs, Bruton’s tyrosine kinase (BTK), and immunosuppressive molecules by bioinformatics and histological analysis. An in vitro study showed that a low dose of ibrutinib significantly inhibited B cell proliferation and activation as well as IL-10 production through the BTK pathway. Moreover, ibrutinib-treated B cells promoted CD8+ T cell proliferation and inhibitory receptor (IR) expression. However, the same dose of ibrutinib was insufficient to induce apoptosis in cancer cells. An in vivo study showed that ibrutinib monotherapy failed to achieve tumor regression in murine models but decreased B cell infiltration and inhibited activation and IL-10 production. More importantly, CD8+ T cell infiltration increased with high IR expression. Ibrutinib synergized with anti-PD-1 checkpoint blockade enormously improved antitumor immunity, thereby reducing tumor volume in the same scenario. These data set the scene for the clinical development of ibrutinib as an immunogenic trigger to potentiate anti-PD-1 checkpoint blockade for metastatic PCa immunotherapy.

The aim of the present study was to investigate the protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax. Thirty-six SD rats were randomly divided into three groups (n=12) including sham operation (S) group, ischemia-reperfusion group (I/R) group and ischemic preconditioning (IP) group. After anesthesia with intraperitoneal injection of chloral hydrate, bilateral renal pedicles were clipped for 45 min, followed by perfusion for 6 h to establish the I/R model. Both kidneys in rats of S group were separated and exposed for 45 min, but renal pedicles were not clipped. In IP group, bilateral renal pedicles were clipped for 5 min, followed by perfusion for 5 min, this procedure was repeated 3 times. Then bilateral renal pedicles were clipped for 45 min, followed by perfusion for 6 h. Blood samples were collected and rats were sacrificed to collect renal tissue. Levels of serum creatinine (Cr) and blood urea nitrogen (BUN) were measured. Activity of superoxide dismutase (SOD) was measured by xanthine oxidase assay. Degree of renal injury was evaluated by H&E staining. TUNEL kit was used to detect the number of apoptotic cells in renal tissue. Expression levels of Bcl-2 and Bax were detected by semi-quantitative PCR and western blot analysis at mRNA and protein levels, respectively. Results showed that levels of Cr and BUN in I/R and IP groups were significantly higher than those in S group, and levels of Cr and BUN in I/R group were significantly higher than that in IP group (P<0.05). Activity of SOD in I/R group and IP group were significantly lower than those in S group, and activity of SOD in I/R group were significantly lower than those in IP group (P<0.05). H&E staining showed that, compared with S group, renal injury in the I/R and IP groups was more serious than that in the S group, and I/R group was more serious than the IP group (P<0.05). TUNEL apoptosis assay showed that number of apoptotic cells in IP and I/R groups were significantly higher than that in the S group (P<0.01). Semi-quantitative PCR and western blot analysis showed that, compared with the S group, expression levels of Bcl-2 mRNA and protein were significantly decreased, expression levels of Bax mRNA and protein were significantly increased, and the ratio of Bcl-2/Bax was significantly decreased in the IP and I/R groups (P<0.01). Compared with the I/R group, expression level of Bcl-2 was significantly increased, the level of Bax was significantly deceased, and the ratio of Bcl-2/Bax was significantly increased in the IP group (P<0.01). As a result, ischemic preconditioning can protect rats with renal ischemia-reperfusion injury possibly by increasing the expression level of Bcl-2 and decreasing the expression level of Bax.

To identify the cooperation of authors, countries, institutions and explore the hot spots regarding research of renal cell carcinoma with venous tumor thrombus. Relevant articles were obtained from the Web of Science Core database (WoSC) from 1999 to 2024. CiteSpace was used to perform the analysis and visualization of scientific productivity and emerging trends. Network maps were generated to evaluate the collaborations between different authors, countries, institutions, and keywords. A total of 2180 related articles were identified. We observed an increased enthusiasm in related fields during the past two decades. The USA dominated the field in all countries, and the University of Miami was the core institution. Ciancio G might have a significant influence with more publications and co-citations. Current research hotspots in this field mainly included thrombectomy, tyrosine kinase inhibitors, immune checkpoint inhibitors, vena cava inferior, and microvascular invasion. Thrombectomy complications, thrombectomy survival outcome, and preoperative neoadjuvant immunotherapy represented the frontiers of research in this field, undergoing an explosive phase. This is the first bibliometric study that comprehensively visualize the research trends and status of RCC with VTT. We hope that this work will provide new ideas for advancing the scientific research and clinical application.