The mechanism of USP43 in the development of tumor: a literature review.

Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as significant regulators of multiple pathways associated with cancer and other diseases, owing to their capacity to remove ubiquitin from target substrates and modulate signaling. Consequently, they represent potential therapeutic targets for cancer and other life-threatening conditions. USP43 belongs to the DUBs family involved in cancer development and progression. This review aims to provide a comprehensive overview of the existing scientific evidence implicating USP43 in cancer development. Additionally, it will investigate potential small-molecule inhibitors that target DUBs that may have the capability to function as anti-cancer medicines.

Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients.

Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer.

Immune Checkpoint Inhibitor (ICI) Genes and Aging in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical and Genomic Study.

Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein-protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets.

Artificial Intelligence Meets Whole Slide Images: Deep Learning Model Shapes an Immune-Hot Tumor and Guides Precision Therapy in Bladder Cancer.

Background: To construct and validate a deep learning cluster from whole slide images (WSI) for depicting the immunophenotypes and functional heterogeneity of the tumor microenvironment (TME) in patients with bladder cancer (BLCA) and to explore an artificial intelligence (AI) score to explore the underlying biological pathways in the developed WSI cluster. Methods: In this study, the WSI cluster was constructed based on a deep learning procedure. Further rerecognition of TME features in pathological images was applied based on a neural network. Then, we integrated the TCGA cohort and several external testing cohorts to explore and validate this novel WSI cluster and a corresponding quantitative indicator, the AI score. Finally, correlations between the AI cluster (AI score) and classical BLCA molecular subtypes, immunophenotypes, functional heterogeneity, and potential therapeutic method in BLCA were assessed. Results: The WSI cluster was identified associated with clinical survival (P < 0.001) and was proved as an independent predictor (P = 0.031), which could also predict the immunology and the clinical significance of BLCA. Rerecognition of pathological images established a robust 3-year survival prediction model (with an average classification accuracy of 86%, AUC of 0.95) for BLCA patients combining TME features and clinical features. In addition, an AI score was constructed to quantify the underlying logic of the WSI cluster (AUC = 0.838). Finally, we hypothesized that high AI score shapes an immune-hot TME in BLCA. Thus, treatment options including immune checkpoint blockade (ICB), chemotherapy, and ERBB therapy can be used for the treatment of BLCA patients in WSI cluster1 (high AI score subtype). Conclusions: In general, we showed that deep learning can predict prognosis and may aid in the precision medicine for BLCA directly from H&E histology, which is more economical and efficient.

Surgery improves overall and cancer-specific survival of rare urinary cancers; population - based study.

Numerous rare urinary tract (UT) cancers lack adequate understanding of survival and therapeutic options, and nearly all responses to systemic therapy are unsatisfactory, yet clinical research is scarce. METHODS: Between 2010 and 2015, a total of (14,622 patients) with uncommon UT cancer (62.5%) in the overall survival (OS) group and (37.5%) in the cancer specific survival (CSS)group were identified in the SEER database. multimodality therapeutic approach on OS and CSS were compared. RESULTS: In uncommon UT malignancies, OS outperformed CSS in the locoregional stage (P < 0.05), but not in the distant stage (P = 0.34). Non-performed surgery had poor survival in both OS (HR 1.647; 95% CI (1.461-1.856)) and CSS (HR 1.573; 95% CI (1.399-1.769)) respectively (P < 0.05). There were no significant differences in survival in the CSS group between those who received or did not obtain chemotherapy. CONCLUSIONS: The OS group survives substantially longer than the CSS group in the locoregional stage, but not at the distant stage. While both the OS and CSS groups of the locoregional stage were linked with improved survival after surgery, chemotherapy treatment decreased OS but not CSS in patients with uncommon urological cancers. There were no differences in radiation between the OS and CSS.

Laparoscopic retroperitoneal resection of the duodenal gastrointestinal stromal tumors in neurofibromatosis type 1; Case Report and literature review.

Background: Neurofibromatosis type 1, also known as NF1, is a disorder that is passed down in an autosomal dominant manner. It manifests in a wide variety of tumors and affects several organ systems. It is expected that those carrying the NF1 gene will develop a rare mesenchymal tumor known as a gastrointestinal stromal tumor (GIST) more than general population. Case report: This research discusses a 42-year-old female patient with NF1 who was identified with a duodenal GIST but clinically and radiographically misinterpreted as having a retroperitoneal neurofibroma. She had minimally invasive retroperitoneal laparoscopic surgery to remove the tumor and primary anastomosis of the affected duodenal wall. A spindle cell GIST was entirely excised during surgery, as indicated by the pathologist. As a consequence of dialogue at a multidisciplinary team meeting, the patient was discharged from the hospital on the fourth postoperative day and is presently undergoing regular clinical follow-up. Conclusion: Anatomically problematic sites, such as the duodenal GIST in NF1 patients, can be treated safely with the laparoscopic retroperitoneal approach even when retroperitoneal neoplasia arises from the intrabdominal structure and protrudes into the retroperitoneal region.

Glycosylation in Renal Cell Carcinoma: Mechanisms and Clinical Implications.

Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors of the urinary system, accounting for around 2% of all cancer diagnoses and deaths worldwide. Clear cell RCC (ccRCC) is the most prevalent and aggressive histology with an unfavorable prognosis and inadequate treatment. Patients' progression-free survival is considerably improved by surgery; however, 30% of patients develop metastases following surgery. Identifying novel targets and molecular markers for RCC prognostic detection is crucial for more accurate clinical diagnosis and therapy. Glycosylation is a critical post-translational modification (PMT) for cancer cell growth, migration, and invasion, involving the transfer of glycosyl moieties to specific amino acid residues in proteins to form glycosidic bonds through the activity of glycosyltransferases. Most cancers, including RCC, undergo glycosylation changes such as branching, sialylation, and fucosylation. In this review, we discuss the latest findings on the significance of aberrant glycans in the initiation, development, and progression of RCC. The potential biomarkers of altered glycans for the diagnosis and their implications in RCC have been further highlighted.

Clinical value and molecular mechanism of AQGPs in different tumors.

Aquaglyceroporins (AQGPs), including AQP3, AQP7, AQP9, and AQP10, are transmembrane channels that allow small solutes across biological membranes, such as water, glycerol, H2O2, and so on. Increasing evidence suggests that they play critical roles in cancer. Overexpression or knockdown of AQGPs can promote or inhibit cancer cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition and metastasis, and the expression levels of AQGPs are closely linked to the prognosis of cancer patients. Here, we provide a comprehensive and detailed review to discuss the expression patterns of AQGPs in different cancers as well as the relationship between the expression patterns and prognosis. Then, we elaborate the relevance between AQGPs and malignant behaviors in cancer as well as the latent upstream regulators and downstream targets or signaling pathways of AQGPs. Finally, we summarize the potential clinical value in cancer treatment. This review will provide us with new ideas and thoughts for subsequent cancer therapy specifically targeting AQGPs.

Posterior Tibial Nerve Stimulation for Overactive Bladder: Mechanism, Classification, and Management Outlines.

Purpose of the Review. Posterior tibial nerve stimulation (PTNS) techniques have dramatically grown after approval to manage overactive bladder (OAB). The present review will focus on the most current data on PTNS types (percutaneous, transcutaneous, and implant) and their mechanism of action, safety, efficacy, advantages, drawbacks, limitation, and clinical applications. Recent Findings. The present review described the recent studies that addressed the tibial nerve stimulation role in OAB management. BlueWind RENOVA system, Bioness StimRouter, and eCoin are examples of emerging technologies that have evolved from interval sessions (percutaneous PTNS and transcutaneous PTNS) to continuous stimulation (implants). These can be efficiently managed at home by patients with minimum burden on the health system and fewer visits, especially in the COVID-19 pandemic. Summary. Our review shows that the tibial nerve stimulation advancements in OAB treatment have been rapidly increasing over the recent years. It is minimally invasive and effective, similar to sacral nerve stimulation (SNM), but less aggressive. Implantable PTNS has been promised in terms of efficacy, safety, and high acceptance rate. However, evidence is still limited to short-term trials, and tolerability, method, and drawbacks remain challenges.

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, severely distressing clinical syndrome characterized by bladder pain and pressure perceptions. The origin and pathophysiology of IC/BPS are currently unclear, making it difficult to diagnose and formulate successful treatments. Our study is aimed at investigating the role of immune-related genes in the diagnosis, progression, and therapy of IC/BPS. Method: The gene expression datasets GSE11783, GSE11839, GSE28242, and GSE57560 were retrieved from the GEO database for further analysis. Immune-related IC/BPS differentially expressed genes (DEGs) were identified by limma. Three distinct machine learning approaches, least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF), were used to find the immune-related IC characteristic genes. Nomogram and receiving operator curves (ROC) were plotted to measure characteristic effectiveness. Using the CMap database and the molecular docking approach, potential small-molecule medicines were found and verified. Consensus cluster analysis was also performed to separate the IC/BPS samples into immunological subtypes. Results: A total of 24 immune-related IC/BPS-DEGs were identified. When compared to the normal control group, the IC/BPS cohort had significantly more immune cell infiltration. Integrative machine learning methods discovered 5 IC/BPS characteristic genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) that may predict IC/BPS diagnosis and immune cell infiltration. Furthermore, two immunological subgroups with substantial variations in immune cell infiltration across IC/BPS samples were identified, which were named cluster1 and cluster2, with the hallmark genes having greater expression in cluster2. Finally, bumetanide was shown to have the potential to be a medication for the treatment of IC/BPS, and it performed well in terms of its molecular binding with RASGRP1. Conclusion: We found and validated 5 immune-related IC/BPS genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) and 2 IC/BPS immune subtypes. In addition, bumetanide was discovered to be a potential drug for treating IC/BPS, which may provide new insight into the diagnosis and immune therapy of IC/BPS patients.

Deep Learning-Based Classification of Epithelial-Mesenchymal Transition for Predicting Response to Therapy in Clear Cell Renal Cell Carcinoma.

Epithelial-mesenchymal transition (EMT) profoundly impacts prognosis and immunotherapy of clear cell renal cell carcinoma (ccRCC). However, not every patient is tested for EMT status because this requires additional genetic studies. In this study, we developed an EMT gene signature to classify the H&E-stained slides from The Cancer Genome Atlas (TCGA) into epithelial and mesenchymal subtypes, then we trained a deep convolutional neural network to classify ccRCC which according to our EMT subtypes accurately and automatically and to further predict genomic data and prognosis. The clinical significance and multiomics analysis of the EMT signature was investigated. Patient cohorts from TCGA (n = 252) and whole slide images were used for training, testing, and validation using an algorithm to predict the EMT subtype. Our approach can robustly distinguish features predictive of the EMT subtype in H&E slides. Visualization techniques also detected EMT-associated histopathological features. Moreover, EMT subtypes were characterized by distinctive genomes, metabolic states, and immune components. Deep learning convolutional neural networks could be an extremely useful tool for predicting the EMT molecular classification of ccRCC tissue. The underlying multiomics information can be crucial in applying the appropriate and tailored targeted therapy to the patient.

Analysis of Clinical Characteristics, Radiological Predictors, Pathological Features, and Perioperative Outcomes Associated with Perinephric Fat Adhesion Degree.

BACKGROUND: To assess the clinical characteristics, radiological predictors, and pathological features of perinephric fat adhesion degree (PFAD) graded based on fixed criteria and to determine the impact of adherent perinephric fat (APF) on retroperitoneal laparoscopic partial nephrectomy (RLPN) outcomes. METHODS: 84 patients undergoing RLPN were included and graded into 4 groups based on PFAD. Univariate and multivariate analyses were performed for clinical characteristics and radiological predictors of PFAD. Perioperative data were compared between APF groups and non-APF groups. Masson staining determined collagen fibers. Immunohistochemistry detected CD45 immune cells and CD34 vessels. RESULTS: 20, 28, 18, and 18 patients were graded as normal perinephric fat (NPF), mild adherent perinephric fat (MiPF), moderate adherent perinephric fat (MoPF), and severe adherent perinephric fat (SPF), respectively. Multivariate analysis revealed that gender (p < 0.001), age (p = 0.003), and hypertension (p = 0.006) were significant clinical risk factors of PFAD, while radiological predictors included perinephric stranding (p = 0.001), posterior perinephric fat thickness (p = 0.009), and perinephric fat density (p = 0.02). APF was associated with drain output (p = 0.012) and accompanied by immune cells gathering in renal cortex near thickened renal capsule with many vessels. CONCLUSIONS: Clinical characteristics and radiological predictors can evaluate PFAD and may assist to guide preoperative surgical option. Pathological features of APF reflect decapsulation and bleeding during kidney mobilization at RLPN.

The safety and efficiency of retroperitoneal laparoscopic adrenalectomy via extra and intra perinephric fat approaches: a retrospective clinical study.

BACKGROUND: This retrospective clinical study is to evaluate the safety and efficiency of two different approaches in retroperitoneal laparoscopic adrenalectomy and provide experience and basis for the treatment of adrenal tumors through retroperitoneal approach. METHODS: From July 2015 to February 2018, 112 patients with adrenal lesions underwent retroperitoneal laparoscopic adrenalectomy (RLA) using a 3-port method. Among them, 56 patients underwent RLA via the extra perinephric fat approach (EPFA), 56 patients underwent RLA via the intra perinephric fat approach (IPFA). Clinical data, including preoperative, operative and postoperative management were recorded. RESULTS: All surgeries were successfully completed, and there was no single patient who died during these surgeries. There was no statistically significant difference between the two groups in blood loss, postoperative complications, vena cava injury, renal cortex injury, peripheral organ injury, and post operation hospital stay. Peritoneum injury occurred more frequently in the EPFA group when compared with the IPEA group (p = 0.042). The average surgery time of the IPEA group is significantly shorter when compared with that of the EPEA group (p < 0.001). Due to serious saponification of the perinephric fat and heavy adhesion to renal fascia, three cases in IPFA group were converted to the EPFA surgery. CONCLUSION: RLA is a safe and effective procedure both via extra perinephric fat and intra perinephric fat approaches. IPEA is superior to EPEA in terms of peritoneal injury and duration. The choice may mainly depend on the experience of the surgeon, the characteristics of the adrenal tumor and the nature of the perinephric fat.

Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death.

BACKGROUND: 5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. METHODS: 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. RESULTS: 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. CONCLUSION: Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment.

Long noncoding RNA lung cancer associated transcript 1 promotes proliferation and invasion of clear cell renal cell carcinoma cells by negatively regulating miR-495-3p.

Recently, long noncoding RNAs have emerged as new gene regulators and prognostic markers in several cancers, including renal cell carcinoma (RCC). Here, we focused on the long noncoding RNA lung cancer associated transcript 1 (LUCAT1) based on clear cell RCC (ccRCC) the cancer genome atlas (TCGA) data. However, whether aberrant expression of LUCAT1 in ccRCC is correlated with malignancy, metastasis or prognosis has not been elucidated. In the current study, we found that the expression of LUCAT1 was upregulated in ccRCC tissues and cancer cell lines. Upregulated LUCAT1 was positively correlated with larger tumor size, advanced tumor-node-metastasis (TNM) stage, higher smoking frequency, nodal metastasis and shorter overall survival in patients with ccRCC. Inhibition of LUCAT1 by small interfering RNA reduced cell proliferation and invasion of ccRCC cells in vitro. In vivo assay showed that the tumor volume and weight were lower in the group of LUCAT1 inhibition than that in the control group. We then found that LUCAT1 directly bound and inhibited the expression of micoRNA-495-3p (miR-495-3p), which subsequently regulated the expression of special adenine-thymine (AT)-rich DNA-binding protein 1 (SATB1). Collectively, LUCAT1 was critical for proliferation and invasion of ccRCC cells by regulating miR-495-3p and SATB1. Our findings indicated that LUCAT1 and miR-495-3p may offer potential novel therapeutic targets of treatment of ccRCC.

[Clinical research on the correlations between type 2 diabetes mellitus and renal clear cell carcinoma].

OBJECTIVE: To investigate the relationship between renal clear cell carcinoma and type 2 diabetes mellitus (DM). METHODS: Two hundreds and sixty-four patients with renal clear cell carcinoma and four hundred controls who suffered from non-urinary system, non-neoplastic or non-hormone-related disorders, were enrolled from January 2008 to December 2012. The incidence of diabetes between the 2 groups and the relationship between renal clear cell carcinoma and duration of diabetes were compared, moreover, renal clear cell carcinoma patients with DM were compared with patients without DM for their clinical features, laboratory examinations and histological characteristics. RESULTS: The comparison of renal clear cell carcinoma group and control group: the incidence of DM in the two groups were 19.7% and 12.8% respectively, and the difference was significant (χ(2) = 5.86, P < 0.05, OR = 1.68). In the renal clear cell carcinoma group, the proportion of patients with DM diagnosed within 2-4 years was 4.92%, which were significant higher than those in the control group 1.70% (χ(2) = 5.49, P < 0.05, OR = 2.91). And men with diabetes had high occurrence risk 86% of renal clear cell carcinoma (OR = 1.86, 95%CI: 1.09-3.15). The comparison of diabetes patients subgroup and non-diabetic patients subgroup in renal clear cell carcinoma group: in respect of clinical features, greatest tumor diameter in the two subgroups were (4.9 ± 2.3) cm and (4.2 ± 2.1) cm respectively, and the difference was significant (t = 1.96, P < 0.05). However, there was no significant difference in terms of age, gender and cancer location between the two subgroups (P > 0.05). In respect of laboratory examinations, serum creatinine in the two subgroups were (72 ± 20) µmol/L and (65 ± 17) µmol/L, and the difference was significant (t = 2.34, P < 0.05); serum urea nitrogen in the 2 subgroups were (7.1 ± 2.1) mmol/L and (6.0 ± 1.5) mmol/L respectively, and the difference was significant too (t = 1.47, P < 0.05). In respect of histological characteristics, the proportion of well differentiated clear cell carcinoma were 80.8% and 81.1% respectively, and the difference was significant (χ(2) = 4.23, P < 0.05). The proportion of stage II were 25.0% and 27.8% respectively and the difference was significant (χ(2) = 4.08, P < 0.05). CONCLUSIONS: DM is closely related with renal clear cell carcinoma and DM may be a possible risk factor for the tumor. And for elderly patients with diabetes who appear waist discomfort or hematuria, a careful examination of kidney is important to make early diagnosis, give timely treatment and improve survival prognosis.