The role of miR-155 in urologic malignancies.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a crucial role in regulating gene expression across multiple levels. They are involved in a wide range of physiological processes, including proliferation, differentiation, apoptosis, and cell cycle control. In recent years, miRNAs have emerged as pivotal regulatory molecules in the development and progression of tumors. Among these, miR-155 has garnered significant attention due to its high expression in various diseases, particularly urologic malignancies. Since an extensive corpus of studies having focused on the roles of miR-155 in various urologic malignancies, it is essential to summarize the current evidence on this topic through a comprehensive review. Altered miR-155 expression is related to various physiological and pathological processes, including immune response, inflammation, tumor development and treatment resistance. Notably, alterations in miR-155 expression have been observed in urologic malignancies as well. The up-regulation of miR-155 expression is commonly observed in urologic malignancies, contributing to their progression by targeting specific proteins and signaling pathways. This article provides a comprehensive review of the significant role played by miR-155 in the development of urologic malignancies. Furthermore, the potential of miR-155 as a biomarker and therapeutic target in urologic malignancies is also discussed.

Heparanase inhibitor OGT 2115 induces prostate cancer cell apoptosis via the downregulation of MCL­1.

Heparanase (HPSE), an endo-ß-D-glucuronidase, cleaves heparan sulfate and serves an important role in the tumor microenvironment and thus in tumorigenesis. HPSE is known to promote tumor cell evasion of apoptosis. However, the underlying mechanism of this requires further study. In the present study, the results demonstrated that myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, and HPSE were upregulated in prostate cancer tissues compared with adjacent normal tissues. In addition, the HPSE inhibitor, OGT 2115, inhibited PC-3 and DU-145 prostate cancer cell viability in a dose-dependent manner, with IC50 values of 20.2 and 97.2 µM, respectively. Furthermore, annexin V/PI double-staining assays demonstrated that OGT 2115 induced apoptosis in prostate cancer cells. OGT 2115 treatment markedly decreased MCL-1 protein expression levels, whereas RNA interference-mediated downregulation of MCL-1 and OGT 2115 drug treatment synergistically induced apoptosis in PC-3 and DU-145 cells. In vivo, OGT 2115 40 mg/kg (ig) significantly inhibited PC-3 cell xenograft growth in nude mice and increased the positive TUNEL staining rate of xenograft tissues. It was therefore hypothesized that MCL-1 was an important signaling molecule in OGT 2115-induced apoptosis. The results of the present study also demonstrated that the proteasome inhibitor, MG-132, markedly inhibited the downregulation of MCL-1 protein expression levels induced by OGT 2115. However, the protein synthesis inhibitor, cycloheximide, did not affect the role of OGT 2115 in regulating MCL-1. In summary, the results of the present study demonstrated that the proapoptotic activity of OGT 2115 was achieved by downregulating MCL-1.

Cigarette Smoke Mediates Nasal Epithelial Barrier Dysfunction via TNF-α.

BACKGROUND: Extensive data suggest that exposure to cigarette smoke can induce pulmonary epithelial barrier dysfunction. However, the effects of cigarette smoke on the nasal epithelial barrier are still unclear. Here, we investigated the consequence and mechanism of cigarette smoke on the nasal epithelial barrier. METHODS: Sprague Dawley rats were exposed to cigarette smoke for 3 or 6 months, and changes in inflammatory markers and nasal barrier function were evaluated. Moreover, underlying mechanisms were explored. Finally, normal human bronchial epithelial cells were cultured with or without tumor necrosis factor-alpha (TNF-α) in vitro, and the levels of continuity and tight junction-associated proteins were measured. RESULTS: In vivo experiments showed that the nasal mucosal barrier function of rats exposed to cigarette smoke was disturbed. Indeed, proteins associated with tight junctions were decreased, and the levels of inflammatory factors, such as IL-8, IL-6, and TNF-α, were dramatically increased in comparison to those of control animals. In vitro, TNF-α was shown to disrupt the continuity of proteins associated with tight junctions and to downregulate the expression of these proteins in bronchial epithelial cells. CONCLUSIONS: We found that cigarette smoke disrupted the nasal mucosal barrier, and the extent of the damage was correlated with the duration of cigarette smoke exposure. We showed that TNF-α can disrupt the continuity and attenuate the expression of tight junction proteins in human bronchial epithelial cells. Therefore, cigarette smoke may induce nasal epithelial barrier dysfunction through TNF-α.

A reactive oxygen species-related signature to predict prognosis and aid immunotherapy in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant disease containing tumor-infiltrating lymphocytes. Reactive oxygen species (ROS) are present in the tumor microenvironment and are strongly associated with cancer development. Nevertheless, the role of ROS-related genes in ccRCC remains unclear. Methods: We describe the expression patterns of ROS-related genes in ccRCC from The Cancer Genome Atlas and their alterations in genetics and transcription. An ROS-related gene signature was constructed and verified in three datasets and immunohistochemical staining (IHC) analysis. The immune characteristics of the two risk groups divided by the signature were clarified. The sensitivity to immunotherapy and targeted therapy was investigated. Results: Our signature was constructed on the basis of glutamate-cysteine ligase modifier subunit (GCLM), interaction protein for cytohesin exchange factors 1 (ICEF1), methionine sulfoxide reductase A (MsrA), and strawberry notch homolog 2 (SBNO2) genes. More importantly, protein expression levels of GCLM, MsrA, and SBNO2 were detected by IHC in our own ccRCC samples. The high-risk group of patients with ccRCC suffered lower overall survival rates. As an independent predictor of prognosis, our signature exhibited a strong association with clinicopathological features. An accurate nomogram for improving the clinical applicability of our signature was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the signature was closely related to immune response, immune activation, and immune pathways. The comprehensive results revealed that the high-risk group was associated with high infiltration of regulatory T cells and CD8+ T cells and more benefited from targeted therapy. In addition, immunotherapy had better therapeutic effects in the high-risk group. Conclusion: Our signature paved the way for assessing prognosis and developing more effective strategies of immunotherapy and targeted therapy in ccRCC.

Epigenetic dysregulation of autophagy in sepsis-induced acute kidney injury: the underlying mechanisms for renoprotection.

Sepsis-induced acute kidney injury (SI-AKI), a common critically ill, represents one of the leading causes of global death. Emerging evidence reveals autophagy as a pivotal modulator of SI-AKI. Autophagy affects the cellular processes of renal lesions, including cell death, inflammation, and immune responses. Herein, we conducted a systematic and comprehensive review on the topic of the proposed roles of autophagy in SI-AKI. Forty-one relevant studies were finally included and further summarized and analyzed. This review revealed that a majority of included studies (24/41, 58.5%) showed an elevation of the autophagy level during SI-AKI, while 22% and 19.5% of the included studies reported an inhibition and an elevation at the early stage but a declination of renal autophagy in SI-AKI, respectively. Multiple intracellular signaling molecules and pathways targeting autophagy (e.g. mTOR, non-coding RNA, Sirtuins family, mitophagy, AMPK, ROS, NF-Kb, and Parkin) involved in the process of SI-AKI, exerting multiple biological effects on the kidney. Multiple treatment modalities (e.g. small molecule inhibitors, temsirolimus, rapamycin, polydatin, ascorbate, recombinant human erythropoietin, stem cells, Procyanidin B2, and dexmedetomidine) have been found to improve renal function, which may be attributed to the elevation of the autophagy level in SI-AKI. Though the exact roles of autophagy in SI-AKI have not been well elucidated, it may be implicated in preventing SI-AKI through various molecular pathways. Targeting the autophagy-associated proteins and pathways may hint towards a new prospective in the treatment of critically ill patients with SI-AKI, but more preclinical studies are still warranted to validate this hypothesis.

The positive relationship between androgen receptor splice variant-7 expression and the risk of castration-resistant prostate cancer: A cumulative analysis.

Background: At present, androgen deprivation therapy (ADT) is still the standard regimen for patients with metastatic and locally advanced prostate cancer (PCa). The level of androgen receptor splice variant-7 (AR-V7) in men with castration-resistant prostate cancer (CRPC) has been reported to be elevated compared with that in patients diagnosed with hormone-sensitive prostate cancer (HSPC). Aim: Herein, we performed a systematic review and cumulative analysis to evaluate whether the expression of AR-V7 was significantly higher in patients with CRPC than in HSPC patients. Methods: The commonly used databases were searched to identify the potential studies reporting the level of AR-V7 in CRPC and HSPC patients. The association between CRPC and the positive expression of AR-V7 was pooled by using the relative risk (RR) with the corresponding 95% confidence intervals (CIs) under a random-effects model. For detecting the potential bias and the heterogeneity of the included studies, sensitivity analysis and subgroup analysis were performed. Publication bias was assessed Egger's and Begg's tests. This study was registered on PROSPERO (ID: CRD42022297014). Results: This cumulative analysis included 672 participants from seven clinical trials. The study group contained 354 CRPC patients, while the other group contained 318 HSPC patients. Pooled results from the seven eligible studies showed that the expression of positive AR-V7 was significantly higher in men with CRPC compared to those with HSPC (RR = 7.55, 95% CI: 4.61-12.35, p < 0.001). In the sensitivity analysis, the combined RRs did not change substantially, ranging from 6.85 (95% CI: 4.16-11.27, p < 0.001) to 9.84 (95% CI: 5.13-18.87, p < 0.001). In the subgroup analysis, a stronger association was detected in RNA in situ hybridization (RISH) measurement in American patients, and those studies were published before 2011 (all p < 0.001). There was no significant publication bias identified in our study. Conclusion: Evidence from the seven eligible studies demonstrated that patients with CRPC had a significantly elevated positive expression of AR-V7. More investigations are still warranted to clarify the association between CRPC and AR-V7 testing. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.

[Research Advances on the Relationship between Overt Hyperthyroidism and Risk of Erectile Dysfunction].

Studies have demonstrated the detrimental effects of overt hyperthyroidism on sexual functioning.Here,we comprehensively reviewed the studies that focused on the association between overt hyperthyroidism and erectile dysfunction (ED).After the systematic searching for relevant studies,we find that overt hyperthyroidism is significantly associated with the high risk of ED.The prevalence of ED in patients with hyperthyroidism ranges from 3.05% to 85%,while that in general population is 2.16% to 33.8%.A study reported that the erectile functioning of the hyperthyroidism patients was improved (International Index of Erectile Function:22.1±6.9 vs. 25.2±5.1) after the achievement of euthyroidism.The underlying mechanism of the increase in the risk of ED by overt hyperthyroidism might be correlated to the dysfunction of hypothalamus-pituitary-thyroid axis,dysregulation of sex hormones,abnormal expression of thyroid hormone receptors,and psychiatric or psychological disturbances (e.g.,depression,anxiety,and irritability).Since limited clinical trials have been conducted,additional well-designed cohorts with sizable samples are warranted to elucidate the evidence and mechanism of hyperthyroidism predisposing to ED.The present review indicates that overt hyperthyroidism and the risk of ED are associated,which reminds the clinicians should assess the thyroid stimulating hormone in hyperthyroidism patients presenting with ED,especially in those without positive conventional laboratory findings for causing ED.

Minimally invasive surgery for pediatric renal and ureteric stones: A therapeutic update.

The incidence of pediatric urolithiasis (PU) is growing worldwide. The corresponding therapeutic methods have become a research hot spot in pediatric urology. PU has the characteristics of abnormal metabolism, easy recurrence, and immature urinary system development, which make its treatment different from that of adults. Pediatric urologists should select the optimal treatment modality to completely remove the stones to prevent recurrence. Currently, the curative treatments of PU include extracorporeal shock wave lithotripsy (ESWL), ureteroscopy, retrograde intrarenal surgery, percutaneous nephrolithotomy (PCNL), laparoscopic, robot-assisted laparoscopic, and open surgery. This review aims to conduct a therapeutic update on the surgical interventions of both pediatric renal and ureteric stones. It accentuates that pediatric surgeons or urologists should bear in mind the pros and cons of various minimally invasive surgical treatments under different conditions. In the future, the treatment of PU will be more refined due to the advancement of technology and the development of surgical instruments. However, a comprehensive understanding of the affected factors should be taken into account by pediatric urologists to select the most beneficial treatment plan for individual children to achieve precise treatment.

Low prognostic nutritional index is associated with poor outcome in middle-aged and elderly patients with non-metastatic nasopharyngeal carcinoma: a retrospective cohort study.

BACKGROUND: Prognostic nutritional index (PNI) and age are effective prognostic factors for patients with non-metastatic nasopharyngeal carcinoma (NPC), and an interaction between them may exist. However, the age cutoff value is generally set at 45 years in current studies. The clinical implications of PNI in middle-aged and elderly patients are unclear. Therefore, we aimed to uncover this issue. PATIENTS AND METHODS: We retrospectively collected data from 132 middle-aged and elderly (≥ 45 years old) patients with non-metastatic NPC. The association between covariates and the PNI was analyzed using 2 or t-test. The effect of PNI on the prognosis was evaluated using univariate and multivariate Cox regression analyses. Unadjusted and multivariate-adjusted models were applied. Stratified and interactive analyses were performed to investigate the potential source of heterogeneity. RESULTS: Median age (61.0 years versus 59.5 years) and the proportion of patients aged ≥ 60 years (57.6% versus 50.0%) in the low-PNI group were higher than those in the high-PNI group (P > 0.05). The patients with a low PNI had shorter overall survival (OS) (hazard ratio (HR) = 0.86, 95% confidence interval (CI) = 0.80-0.93; P < 0.001) and progression-free survival (PFS) (HR = 0.93, 95% CI = 0.87-0.99; P = 0.034). The results remained stable after three adjusted models of covariates, including age (P < 0.05). No significant interactions were observed in middle-aged (45-59 years) and elderly (≥ 60 years) subgroups for OS and PFS (P for interaction > 0.05). CONCLUSION: Although there is an interaction between PNI and age, PNI is an independent prognostic factor in middle-aged and elderly patients with non-metastatic NPC.

MicroRNA-21: A Critical Pathogenic Factor of Diabetic Nephropathy.

Diabetic nephropathy (DN), one of the most common and intractable microvascular complications of diabetes, is the main cause of terminal renal disease globally. MicroRNA-21 (miR-21) is a kind of miRNA early identified in human circulation and tissues. Mounting studies have demonstrated that miR-21 plays an important role in the development and progression of DN. This collaborative review aimed to present a first attempt to capture the current evidence on the relationship between miR-21 and DN. After a systematic search, 29 relevant studies were included for comprehensively and thoroughly reviewing. All these eligible studies reported that miR-21 was up-regulated in DN, whether in serum or renal tissues of human or animal models. MiR-21 exhibited its pathogenic roles in DN by forming a complex network with targeted genes (e.g. MMP-9, Smad7, TIMP3, Cdk6, FOXO1, IMP3, and MMP2) and the signaling cascades (e.g. Akt/TORC1 signaling axis, TGF-ß/NF-κB signaling pathways, TGF-ß/SMAD pathway, CADM1/STAT3 signaling, and AGE-RAGE regulatory cascade), which resulted in epithelial-to-mesenchymal transition, extracellular matrix deposition, cytoskeletal remodeling, inflammation, and fibrosis. This review highlights that miR-21 is a pivotal pathogenic factor in the development of DN. It may serve as an attractive potential diagnostic, prognostic, and predictive biomarker for DN in clinical practice after further confirmation of the clinicopathological features and molecular mechanisms of miR-21-mediated DN.

Molecular mechanisms underlying the renal protective effects of coenzyme Q10 in acute kidney injury.

Coenzyme Q10 (CoQ10), an endogenous antioxidant, has been reported frequently to exert an outstanding protective effect on multiple organ injury, including acute kidney injury (AKI). In this study, we aim to summarize all the current evidence of the protective action of CoQ10 against AKI as there are presently no relevant reviews in the literature. After a systematic search, 20 eligible studies, either clinical trials or experimental studies, were included and further reviewed. CoQ10 treatment exhibited a potent renal protective effect on various types of AKI, such as AKI induced by drugs (e.g., ochratoxin A, cisplatin, gentamicin, L-NAME, and nonsteroidal anti-inflammatory drug), extracorporeal shock wave lithotripsy (ESWL), sepsis, contrast media, and ischemia-reperfusion injury. The renal protective role of CoQ10 against AKI might be mediated by the antiperoxidative, anti-apoptotic, and anti-inflammatory potential of CoQ10. The molecular mechanisms for the protective effects of CoQ10 might be attributed to the regulation of multiple essential genes (e.g., caspase-3, p53, and PON1) and signaling cascades (e.g., Nrf2/HO-1 pathway). This review highlights that CoQ10 may be a potential strategy in the treatment of AKI.

Protective effects of dexmedetomidine in vital organ injury: crucial roles of autophagy.

Vital organ injury is one of the leading causes of global deaths. Accumulating studies have demonstrated that dexmedetomidine (DEX) has an outstanding protective effect on multiple organs for its antiinflammatory and antiapoptotic properties, while the underlying molecular mechanism is not clearly understood. Autophagy, an adaptive catabolic process, has been found to play a crucial role in the organ-protective effects of DEX. Herein, we present a first attempt to summarize all the evidence on the proposed roles of autophagy in the action of DEX protecting against vital organ injuries via a comprehensive review. We found that most of the relevant studies (17/24, 71%) demonstrated that the modulation of autophagy was inhibited under the treatment of DEX on vital organ injuries (e.g. brain, heart, kidney, and lung), but several studies suggested that the level of autophagy was dramatically increased after administration of DEX. Albeit not fully elucidated, the underlying mechanisms governing the roles of autophagy involve the antiapoptotic properties, inhibiting inflammatory response, removing damaged mitochondria, and reducing oxidative stress, which might be facilitated by the interaction with multiple associated genes (i.e., hypoxia inducible factor-1α, p62, caspase-3, heat shock 70 kDa protein, and microRNAs) and signaling cascades (i.e., mammalian target of rapamycin, nuclear factor-kappa B, and c-Jun N-terminal kinases pathway). The authors conclude that DEX hints at a promising strategy in the management of vital organ injuries, while autophagy is crucially involved in the protective effect of DEX.

Roles of ARID1A variations in colorectal cancer: a collaborative review.

Colorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6-66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.

MicroRNA-31: a pivotal oncogenic factor in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) continuously constitutes a major challenge for treatment and prognosis due to approximately half of treated OSCC patients dying from locoregional recurrences and distant metastases. MicroRNA-31 (miR-31), an early mammalian miRNA identified, has been gaining importance in the field of OSCC research in recent years. This comprehensive review was conducted for the first time to summarize the current evidence on the association between miR-31 and OSCC. The vast majority of relevant studies (20/21, 95%) demonstrated that miR-31 was an oncogenic factor in the tumorigenesis and progression of OSCC. miR-31 expression is significantly upregulated in plasma, saliva, and tumor tissue of OSCC. miR-31 played an essential role in OSCC development by constituting a complex network with its targeted genes (e.g. RhoA, FIH, ACOX1, VEGF, SIRT3, LATS2, KANK1, and NUMB) and the signaling cascades (e.g. EGF-AKT signaling axis, ERK-MMP9 cascade, Hippo pathway, Wnt signaling, and MCT1/MCT4 regulatory cascade). This review highlights that miR-31 might function as a potential diagnostic, prognostic, and predictive biomarker for OSCC. Further studies are still warranted to better illuminate the clinicopathological features and the molecular mechanisms of miR-31-mediated OSCC development.

Hypospadias and Increased Risk for Psychiatric Symptoms in Both Childhood and Adolescence: A Literature Review.

Hypospadias is one of the most common congenital malformations in boys. Due to abnormal appearance in the penis with abnormal urination and erection, patients with hypospadias were vulnerable to suffering from stress and psychiatric difficulties. The present study aims to summarize all the current evidence of the association between hypospadias and the risk of psychiatric disorders by a comprehensive review. Seventeen clinical studies were identified in the four electronic databases. A total of 953,872 participants were involved, while 15,729 of them were hypospadiac patients and the remaining 938,143 were normal controls. The standard age for surgery for hypospadias ranged from 20.4 months to 21.5 years. Eight out of seventeen (8/17, 47%) included studies explicitly showed that patients with hypospadias had a significantly higher risk of psychosocial disorders (all P < 0.05). Specific types of psychiatric disorders included depression, anxiety, shyness, timidness, isolation, fear of ridicule, attention-deficit hyperactivity, autism spectrum, behavioral/emotional disorders, temper tantrums, emotionality, affective, psychosexual problems, and suicidal tendencies. Based on this review, psychiatric illnesses are frequently detected in hypospadiac patients' childhood, thus proper psychiatric guidance and early interventions from physicians, nurses, and parents may help these children to grow into less affected men.

Risk of osteoporosis and fracture after hysterectomies without oophorectomies: a systematic review and pooled analysis.

The present study provides evidence that women who underwent hysterectomy without oophorectomies are at a higher risk of osteoporosis and bone fractures than the general population. Early interventions for these susceptible women may help to delay or reduce the risk of osteoporosis and bone fractures. INTRODUCTION: Mounting studies have shown that patients with hysterectomy are at high risk of developing osteoporosis or bone fractures, but the evidence from all the relevant studies has not been previously synthesized. The present study aims to investigate whether women with hysterectomy without oophorectomies have a prominently higher prevalence of osteoporosis or fractures than healthy subjects. METHODS: Four electronic databases were systematically searched to identify the eligible studies. The combined effect was assessed by calculating the relative risk (RR) with a 95% confidence interval (CI). More methodologies for this study were available in the PROSPERO (ID: CRD42021227255). RESULTS: Finally, three observational studies offering osteoporosis cases and two retrospective studies reporting fracture cases were included. One eligible study has provided independent data from three groups of fractures. Synthetic results revealed that hysterectomy without oophorectomies was significantly associated with an increased risk of osteoporosis as compared to the general population (combined RR from three studies = 1.47, 95%CI 1.253 to 1.725, P < 0.001; heterogeneity, I2 = 76.2%, P = 0.015). Consistently, the prevalence of fractures was also significantly higher in patients with hysterectomy without oophorectomies than in healthy controls (pooled RR from four studies = 2.333, 95%CI: 1.314 to 4.144, P = 0.004; heterogeneity, I2 = 92.3%, P < 0.001). CONCLUSIONS: This is the first study to quantify the association between hysterectomy without oophorectomies and osteoporosis/fracture risk through a meta-analysis and has subsequently confirmed its positive relationship. Additional large-sample rigorously prospective cohorts are still warranted to validate the present evidence.

Current knowledge of targeted-release budesonide in immunoglobulin A nephropathy: A comprehensive review.

Immunoglobulin A (IgA) nephropathy is a common autoimmune kidney disease. Accumulating studies showed that IgA nephropathy may be partially correlated with mucosal immune system dysfunction. Systemic corticosteroid treatment exerts an essential protective effect against renal deterioration in IgA nephropathy. However, long-term use of corticosteroids may cause systemic side effects. The novel targeted-release formulation (TRF) of budesonide has been shown to deliver the drug to the distal ileum with the aim of minimizing adverse events for patients with IgA nephropathy. In this review, we have summarized all the current evidence of the effects of TRF-budesonide protecting against IgA nephropathy. Three randomized controlled trials (RCTs), one cohort, two case reports, and an ongoing Phase 3 trial (Part B, NCT03643965), were under comprehensive review. These included studies demonstrated that TRF-budesonide could remarkably reduce proteinuria, hematuria, and creatinine, as well as preserve renal function. The local immunosuppressive effects exhibited by TRF-budesonide may represent a novel and promising approach to treating IgA nephropathy. However, the current evidence was only derived from limited trials. Therefore, more well-designed RCTs are still warranted to validate the curable profile of TRF-budesonide in treating IgA nephropathy.

Roles of ferroptosis in urologic malignancies.

Ferroptosis, an iron-dependent form of non-apoptotic cell death, is believed to strongly contribute to the pathogenesis of multiple cancers. Recently, the positive association between ferroptosis and urologic malignancies has drawn considerable attention, while a comprehensive review focused on this issue is absent. Based on this review, ferroptosis has been implicated in the development and therapeutic responses of prostate cancer, kidney cancer, and bladder cancer. Mechanistically, a large number of biomolecules and tumor-associated signaling pathways, including DECR1, PANX2, HSPB1, ACOT8, SUV39H1, NCOA4, PI3K-AKT-mTOR signaling, VHL/HIF-2α pathway, and Hippo/TAZ signaling pathway, have been reported to regulate ferroptosis in urologic cancers. Ferroptosis inducers, such as erastin, ART, CPNPs, and quinazolinyl-arylurea derivatives, exert potential therapeutic effects per se and/or enhance the anticancer response of other anticancer drugs in urologic oncology. A better understanding of ferroptosis may provide a promising way to treat therapy-resistant urologic cancers.

MiR-629-5p Promotes Prostate Cancer Development and Metastasis by Targeting AKAP13.

Prostate cancer (PCa) has become the most frequently occurring cancer among western men according to the latest report, and patients' prognosis is often poor in the event of tumor progression, therefore, many researches are devoted to exploring the molecular mechanism of PCa metastasis. MicroRNAs (miRNA) have proved to play an important role in this process. In present study, by combining clinical samples with public databases, we found that miR-629-5p increased to varying degrees in primary localized PCa tissues and metastatic PCa tissues compared with adjacent normal tissues, and bioinformatics analysis suggested that high level of miR-629-5p was related to poor prognosis. Functionally, miR-629-5p drove PCa cell proliferation, migration and invasion in vitro, and promoted growth of PCa cells in vivo. Moreover, A-kinase Anchor Protein 13 (AKAP13) was screened as a direct target of miR-629-5p, that expression was negatively correlated with the malignant phenotype of tumor cells. In the end, through verification in clinical specimens, we found that AKAP13 could be independently used as a clinical prognostic indicator. Overall, the present study indicates that miR-629-5p plays an oncogenic role in PCa by targeting AKAP13, which provides a new idea for clinical diagnosis and treatment of complex refractory PCa.

Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the "ClinicalTrials.gov" for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.