Identification and Validation of Cuproptosis-Related LncRNA Signatures in the Prognosis and Immunotherapy of Clear Cell Renal Cell Carcinoma Using Machine Learning.

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA and ICGC cohorts related to renal clear cell carcinoma were included. GO and KEGG analyses were conducted to determine the biological significance of differentially expressed cuproptosis-related LncRNAs (CRLRs). Machine learning (LASSO), Kaplan-Meier, and Cox analyses were conducted to determine the prognostic genes. The tumor microenvironment and tumor mutation load were further studied. TIDE and IC50 were used to evaluate the response to immunotherapy, a risk model of LncRNAs related to the cuproptosis genes was established, and the ability of this model was verified in an external independent ICGC cohort. LncRNAs were identified in normal HK-2 cells and verified in four renal cell lines via qPCR. (3) Results: We obtained 280 CRLRs and identified 66 LncRNAs included in the TCGA-KIRC cohort. Then, three hub LncRNAs (AC026401.3, FOXD2-AS1, and LASTR), which were over-expressed in the four ccRCC cell lines compared with the human renal cortex proximal tubule epithelial cell line HK-2, were identified. In the ICGC database, the expression of FOXD2-AS1 and LASTR was consistent with the qPCR and TCGA-KIRC. The results also indicated that patients with low-risk ccRCC-stratified by tumor-node metastasis stage, sex, and tumor grade-had significantly better overall survival than those with high-risk ccRCC. The predictive algorithm showed that, according to the three CRLR models, the low-risk group was more sensitive to nine target drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706, ATRA, AP.24534, axitinib, and AZ628), based on the estimated half-maximal inhibitory concentrations. In contrast, the high-risk group was more sensitive to ABT.263 and AKT inhibitors VIII and AS601245. Using the CRLR models, the correlation between the tumor immune microenvironment and cancer immunotherapy response revealed that high-risk patients are more likely to respond to immunotherapy than low-risk patients. In terms of immune marker levels, there were significant differences between the high- and low-risk groups. A high TMB score in the high-risk CRLR group was associated with worse survival, which could be a prognostic factor for KIRC. (4) Conclusions: This study elucidates the core cuproptosis-related LncRNAs, FOXD2-AS1, AC026401.3, and LASTR, in terms of potential predictive value, immunotherapeutic strategy, and outcome of ccRCC.

Effect of Hyperbaric Oxygen on Tissue Damage and Expression of Adhesion Molecules and C3 in a Rat Model of Renal Ischemia-Reperfusion Injury After Kidney Transplantation.

BACKGROUND The aim of this study was to investigate the protective effect and mechanism of hyperbaric oxygen (HBO) in a rat model of renal ischemia-reperfusion injury following kidney transplantation. MATERIAL AND METHODS Sprague Dawley rats were randomly divided into 3 groups (n=18): sham group, kidney transplantation group, and HBO treatment group. Six rats in each group were sacrificed at 1, 3, and 5 hours after reperfusion, and serum and renal tissue were then collected. The serum creatinine levels and histopathological changes of the renal tissue were detected. ICAM-1, VCAM-1, and C3 expression levels were also detected by immunohistochemical staining or real-time polymerase chain reaction. RESULTS Renal function was damaged in the kidney transplantation group and the HBO treatment group compared with sham group (P<0.05). Renal histopathological changes, including tubular cell swelling, tubular dilatation, and hyaline casts, were remarkably reduced in the HBO treatment group compared to the kidney transplantation group. In the immunohistochemical examination, the expression levels of ICAM-1, VCAM-1, and C3 were obviously increased in the kidney transplantation group and the HBO treatment group; moreover, the levels in the HBO treatment group were significantly lower than in the kidney transplantation group (P<0.05). In addition, the ICAM-1 and C3 mRNA levels were increased in the kidney transplantation group and HBO treatment group, but the levels of in the HBO treatment group them were significantly decreased compared to the kidney transplantation group that at 3 and 5 hours after reperfusion (P<0.05). CONCLUSIONS HBO treatment exerted a protective effect on renal function through inhibition of adhesion molecule overexpression and complement system activation in a rat model of renal ischemia-reperfusion injury after kidney transplantation.

Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases.

The objective of the present study was to systematically investigate the clinical features, diagnosis and therapeutic treatment of Von Hippel-Lindau (VHL) syndrome in order to improve understanding of this disease. A total of 3 cases of VHL syndrome treated at the Affiliated Hospital of Zunyi Medical College (Zunyi, China) between September 2014 and October 2015 were retrospectively analyzed. The associated literature was reviewed, and the diagnostic and therapeutic features were discussed. Case 1 was diagnosed as VHL syndrome accompanied by a renal tumor on the right side, and radical tumor resection in the right kidney was performed. Postoperative pathological examination indicated clear cell carcinoma. Case 2 was diagnosed as VHL syndrome accompanied by bilateral adrenal pheochromocytoma. The left-side adrenal tumor was removed, and postoperative pathological analysis was suggestive of adrenal pheochromocytoma. Case 3 visited the hospital due to the presence of masses on the left and right sides of the kidney, but did not undergo surgery for personal reasons. Follow-ups were scheduled subsequent to surgery at another hospital. The diagnosis in all 3 cases was confirmed by genetic testing, where VHL mutations were detected in all patients. Following surgery, pedigree and genetic analysis was performed in all 3 pedigrees and VHL mutations were identified in 7 family members. The diagnosis of VHL syndrome should be based on the clinical manifestation of the patients and the results of genetic tests. DNA analysis of mutations is the main method for diagnosis. An appropriate surgical plan should be formulated based on the site, size and number of tumors, and the condition of the patient. Since VHL syndrome is an inheritable genetic disorder and relapse following surgery is common, pedigree analysis of the patient and lifelong follow-ups are essential. Additionally, physicians should pay attention to VHL syndrome in order to avoid missing diagnosis or misdiagnosis.

Scrotal Paragonimiasis in adults: Two case reports and review of literature.

RATIONALE: Paragonimiasis is a parasitic disease caused by Paragonimus in the lungs; it can be divided into intrapulmonary type and extrapulmonary type. Adult patients with scrotal paragnonimus are rarely seen clinically and not widely reported in the literature. Here, we report 2 cases of scrotal paragonimiasis in adults and their treatment process. PATIENT CONCERNS: Two young males sought medical advice because of scrotal masses. Both patients had the previous history of eating uncooked river crabs and presented with palpable quasicircular nodules of about 1.5 × 1.0 cm in testicles, which were well-defined, resilient in tenderness. The bilateral inguinal lymph nodes were not enlarged. DIAGNOSIS AND INTERVENTIONS: The 2 patients underwent scrotal mass resection; postoperative pathology examination confirmed scrotum paragonimiasis. Both the patients were administered praziquantel after operation. OUTCOMES: They were followed up for 1 year and 4 years, respectively; both recovered well, free from recurrence. Scrotum color Doppler ultrasound examination found no obvious abnormality. LESSONS: Adult patients with scrotum paragonimiasis are rarely seen clinically. Moreover, its clinical manifestations are not typical that leads to missed diagnosis and misdiagnosis. Diagnosis of the disease needs to combine with disease histories, manifestations, and relevant auxiliary examinations. But the diagnosis can be confirmed only by histopathological examination. The main method for treatment of scrotal paragonimiasis is antiparasitic treatment. However, health education is crucial to prevent this disease and relapse.

Impact of immunosuppressive agents on the expression of indoleamine 2,3-dioxygenase, heme oxygenase-1 and interleukin-7 in mesangial cells.

Chronic allograft nephropathy (CAN) is a major cause of graft loss following kidney transplantation and may result from the interactions of various immune and non-immune factors. The aim of the present study was to establish an in vitro model of glomerular mesangial cell injury in order to examine the gene expression levels of indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1) and interleukin-7 (IL-7) in mesangial cells during the healing process as well as to investigate the effects of various immunosuppressants on the expression of these genes. The HBZY-1 glomerular mesangial cell line was pre-treated in vitro with cytochalasin B for 2 h to induce reversible damage. Following the pre-treatment, the HBZY-1 cells were divided into five groups: Blank control group, cyclosporine A (CsA) group, tacrolimus (Tac) group, mycophenolate mofetil (MMF) group and rapamycin (RAPA) group. After treating the mesangial cells with each immunosuppressive drug for 6, 12 or 24 h, the mRNA and protein expression levels of IDO, HO-1 and IL-7 were examined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemical analyses. The results showed that expression levels of HO-1 were significantly upregulated in response to treatment with CsA, FK506, RAPA and MMF, whereas the expression levels of IL-7 were markedly downregulated by treatment with the above immunosuppressants. CsA, FK506 and MMF significantly enhanced the expression levels of IDO, whereas RAPA exhibited no apparent effect on IDO. The present study may contribute to the understanding of the pathogenesis of CAN and provide novel strategies for the prevention and treatment of CAN.