Background :Further stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy. Objective :To assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). Design, setting, and participants :This was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy. Outcomes measurements and statistical analysis: Pathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. Results and limitations :We analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = -1 (p = 0.001), and 0.22 for GD = -2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001). Conclusions: Routine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression. Patient summary :We developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein.

Genetically modified organisms (GMOs) have become indispensable tools in pre-clinical research for urological cancer. Through genetic engineering techniques, researchers can modify the genetic composition of organisms, enabling the creation of appropriate experimental animal models that provide a deep insight into the mechanisms of tumorigenesis, progression, and potential therapeutic strategies for urological cancer. In this chapter, we provide a comprehensive overview of the current status of research utilizing GMOs in the investigation of prostate cancer, renal cancer, urothelial cancer, and other urological cancers. Topics covered the development of different genetically modified animal models, and the application of these models in urological cancer research. In addition, the limitations of GMOs in cancer research will be discussed.

Objective To investigate the effects and potential mechanisms of osteoblast-derived exosomes on the biological properties of prostate cancer (PC) cells. Methods Human bone marrow mesenchymal stem cells was induced to differentiate into osteoblasts, and then the exosomes were extracted from the supernatant of cell culture medium by ultracentrifugation and identified. Clone formation assay was employed to determine the effect of derived exosomes on the proliferation of PC cells, and PCR microarray was used to analyze miRNA changes after exosome treatment. Fluorescence labeling was applied to validate the transfer of miRNA between osteoblasts and tumor cells. The impact of key miRNA on the biological characteristics of PC cells was studied at the cellular and animal levels. Bioinformatics analysis was conducted to explore the target genes of key miRNA and then further validated. Results Osteoblast-derived exosomes were successfully extracted and then identified. These exosomes significantly promoted the clonogenic ability of PC cells when compared with the cells without treatment (P < 0.05). PCR microarray showed that miR-223 might be a key molecule in this process. Membrane exchange experiments demonstrated the presence of membrane exchange between osteoblasts and PC cells, and miRNA FAM labeling displayed that miR-223 was transferred within above cells. Functional experiments indicated that overexpression of miR-223 enhanced the proliferation, anti-apoptosis, and migration/invasion ability of PC cells (P < 0.05). Bioinformatics analysis indicated that APC, an inhibitor of WNT signaling pathway, may be a target gene of miR-223, which was further confirmed that overexpressing miR-223 down-regulated APC expression. Rescue experiment showed that overexpression of APC reversed the promoting effect of miR-223 on the proliferation, migration and invasion of PC cells. Conclusion Osteoblast-derived exosomes are pro-carcinogenic factors in PC, and miR-223 may be a key molecule in exosomes, which plays a oncogenic role by regulating APC in PC cells.

BACKGROUND:Dysregulation of Long Non-coding RNAs (lncRNAs) emerges to be a hallmark of cancers. Metastatic prostate cancer and localized disease that recurs after treatment are clinical challenges, it remains unclear how lncRNA plays a role in those processes. METHODS:From previous RNA-Seq data on 65 prostate cancer and adjacent normal tissues. We identified a novel lncRNA ENST00000503625 down-regulated in prostate cancer and correlated with tumor progression characteristics. Public datasets were examined for associations between ENST00000503625 expression and clinical parameters and prognoses. Subsequently, we constructed and externally validated a nomogram for predicting biochemical recurrence (BCR). Finally, in vitro experiments were carried out to determine how ENST00000503625 functions biologically in prostate cancer. RESULTS:Low ENST00000503625 in tumor was associated with poor clinical features and prognoses. TCGA pan-cancer analysis found that ENST00000503625 was deregulated in a variety of tumors and correlated with overall survival, disease-specific survival, and progression-free survival. The nomogram for predicting BCR was constructed using TCGA data, which exhibited excellent accuracy in external validation with Chinese Prostate Cancer Genome and Epigenome Atlas data. Gene Ontology and KEGG pathway analysis found that genes related to ENST00000503625 were enriched in multiple tumor progression related pathways. When ENST00000503625 was knocked down in vitro, the epithelial-mesenchymal transition was induced, by which cancer cells migrated and invaded more readily. CONCLUSION:Our data suggested that ENST00000503625 may serve as a potential prognostic marker or a therapeutic target for prostate cancer metastases.

Objective To analyze the risk factors for biochemical recurrence in prostate cancer patients after radical prostatectomy (RP) and establish a risk prediction model for the recurrence. Methods A retrospective cohort study was conducted on 279 patients who underwent RP surgery in our hospital from September 2007 to March 2022. There were 21 clinical indicators collected and analyzed. After time factors were included, Lasso regression was applied to screen the indicators, Kaplan-Meier method was used to draw survival curve, univariate and multivariate Cox proportional risk regression models were employed to analyze the risk factors and establish a prediction model. Then receiver operating characteristic (ROC) curve were plotted to evaluate the discriminative performance of the model. Then a nomogram was draw based on the obtained risk factors. Calibration curve was used to evaluate the accuracy of prediction, and decision curve was employed to assess the clinical benefit. Results During a median follow-up time of 37.10 (17.60, 61.30) months, 86 cases (30.8%), at a median age of 68.00 (65.00, 72.00) years, experienced biochemical recurrence. Univariate analysis showed that 12 indicators were strongly associated with biochemical recurrence after RP (P < 0.05), and Lasso regression screening indicated 7 representative indicator sets, including nutritional risk index (NRI), clinical T-stage, pathological Gleason score, pathological T-stage, positive surgical margin, lymph node invasion, and seminal vesicle invasion. Further multifactorial analysis revealed that pathological high stage (≥pT3 stage) (HR=1.895, 95%CI: 1.045~3.435, P=0.035), positive surgical margin (HR=1.808, 95%CI: 1.006~3.25, P=0.048), lymph node invasion (HR=2.161, 95% CI: 1.118~4.175, P=0.022) and NRI ≤106.9 (HR=0.598, 95% CI: 0.378~0.946, P=0.028) were independent risk factors for biochemical recurrence. The predictive equation was established with an AUC of 0.743 (95% CI: 0.677~0.810, P < 0.001), a sensitivity of 0.826 and a specificity of 0.534. And the established nomogram has a C-index of 0.741 (95%CI: 0.677~0.805; P < 0.001), with good agreement indicated by calibration curve. Clinical decision curve displayed that there was a net benefit when the threshold probability was 15%~85%. Conclusion High pathological stage (≥pT3 stage), positive surgical margin, lymph node invasion, and NRI ≤106.9 are independent risk factors for biochemical recurrence of prostate cancer after RP. Our prediction model can make effective judgments and provide references for clinical decision making.

There is significant variability with respect to the prognosis of nonmetastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). By applying multiregion whole-exome sequencing on normal-tumor-thrombus-metastasis quadruples from 33 ccRCC patients, we showed that metastases were mainly seeded by VTT (81.8%) rather than primary tumors (PTs). A total of 706 nonmetastatic ccRCC patients with VTT from three independent cohorts were included in this study. C-index analysis revealed that pathological grading of VTT outperformed other indicators in risk assessment (OS: 0.663 versus 0.501-0.610, 0.667 versus 0.544-0.651, and 0.719 versus 0.511-0.700 for Training, China-Validation, and Poland-Validation cohorts, respectively). We constructed a risk predicting model, TT-GPS score, based on four independent variables: VTT height, VTT grading, perinephric fat invasion, and sarcomatoid differentiation in PT. The TT-GPS score displayed better discriminatory ability (OS, c-index: 0.706-0.840, AUC: 0.788-0.874; DFS, c-index: 0.691-0.717, AUC: 0.771-0.789) than previously reported models in risk assessment. In conclusion, we identified for the first-time pathological grading of VTT as an unheeded prognostic factor. By incorporating VTT grading, the TT-GPS score is a promising prognostic tool in predicting the survival of nonmetastatic ccRCC patients with VTT.

Objective To preliminarily investigate the safety and effectiveness of robot-assisted kidney transplantation (RAKT) in the perioperative period. Methods Clinical data of 14 patients undergoing renal transplantation in our department from June 2018 to March 2022 were collected and retrospectively analyzed. They were 8 males and 6 females, and at an age of 22 to 45 years. There were 4 patients receiving robotic-assisted laparoscopic living-donor kidney transplantation (RAKT group), and 10 cases receiving open kidney transplantation (OKT group) with deceased donor kidney. Arterio-venous anastomoses (AVAs) time, length of post-operative stay, pre- and post-operative serum creatinine levels, intraoperative blood loss, and incidence of post-operative complications were retrospectively analyzed between the patients of the 2 groups. Results The surgeries went well in the 14 patients. The amount of intraoperative blood loss was 162.5±47.8 mL in the RAKT group and 245.1±68.5 mL in the OKT group(P < 0.05). The arterial anastomosis time was 32.5±6.5 min in the RAKT group and 24.3±5.3 min in the OKT group. The venous anastomosis time was 16.5±3.8 min in the RAKT group and 14.6±1.5 min in the OKT group. The blood creatinine level was 98.1±33.2 μmol/L in the RAKT group and 142.8±42.1 μmol/L in the OKT group in 7 d after surgery. The retention time of drainage tube was 10.0±1.2 d in the OKT group and 6.5±0.5 d in the RAKT group(P < 0.01). The length of stay after surgery was 13.0±2.5 d in the RAKT group and 16.3±2.1 d in the OKT group(P=0.01). Conclusion RAKT is safer than OKT in the perioperative period and causes fewer postoperative complications.

Unilateral adrenalectomy is the standard treatment for patients with aldosterone-producing adenoma (APA), but it lacks an option for patients with APA who refuse or are not suitable for surgery. In this study, we studied whether catheter-based adrenal ablation for APA is comparable to adrenalectomy. A total of 2185 hypertensive patients were screened, and 112 patients with APA were recruited and counselled on the treatment options. Fifty-two patients opted for catheter-based adrenal ablation, and 60 opted for adrenalectomy. Clinical and biochemical outcomes were assessed at 6 months after treatment. Factors associated with hypertension remission and the advantages and limitations of this approach were evaluated. According to the primary aldosteronism surgical outcome (PASO) criteria, complete and partial clinical success was achieved in 21 (40.4%) and 23 (44.2%) patients in the ablation group vs. 33 (55.0%) and 23 (38.3%) patients in the adrenalectomy group, respectively. Complete and partial biochemical success was achieved in 30 (57.7%) and 17 (32.7%) patients in the ablation group vs. 51 (85.0%) and 5 (8.3%) patients in the adrenalectomy group, respectively. The complete clinical success rate was not (P > 0.05), but the complete biochemical success rate was significantly different between the two groups (P < 0.01). Factors associated with adrenal ablation-mediated hypertension remission were hypertension duration and serum potassium level at baseline. Compared with surgery, adrenal ablation requires a shorter operating time and time to resume physical activity. Catheter-based adrenal ablation may be an alternative and feasible option for APA patients unwilling to receive surgical treatment.

Background: The prediction of new baseline renal function after partial nephrecunny (PN) has important clinical implications. This study aimed to establish a precise personalized nomogram integrating pre-, intraand post-operative variables to predict new baseline function after PN. Methods: This nomogram was constructed based on 213 consecutive PN cases at a large-volume institution from 2014 to 2017 and externally validated by a prospective cohort from January to December 2018 at the same institution. Multivariate cox regression and logistic least absolute shrinkage and selection operator (LASSO) regression were used to select predictors. The performance of the nomogram was assessed by the concordance index (C-index), calibration plot, decision curve analysis and Kaplan-Meier plot. Results: The average drop percent of the estimated glomerular filtration rate (eGFR) was -8.6% (-12.3%, -7.2%). Multivariate Cox regression analysis and LASSO regression revealed that age, baseline eGFR, RENAL nephrometry score, ischemia time, and AKI were independent predictive factors. These five factors were subsequently incorporated to establish an integrated nomogram, with a C-index of 0.910, excellent calibration plot and net clinical benefit. An external validation of 67 patients showed a C-index of 0.801, excellent calibration and clinical net benefit. Conclusions: Our proposed nomogram based on pre-, intra- and post-operative outcomes accurately predicts personalized new baseline eGFR after PN. The successful personalized prediction of at-risk individuals at an early stage can provide multi-professional consideration and timely management.

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Long noncoding RNAs (lncRNAs) promote cell proliferation, migration, invasion and castration resistance in prostate cancer (PCa). Understanding the inherited molecular mechanisms by which lncRNAs contribute to the progression of PCa to a lethal disease could have an important impact on cancer detection, diagnosis and prognosis. In our study, PCa‐associated lncRNA transcripts from RNA‐seq data were identified and screened via bioinformatics analysis, NCBI annotations and literature review. We identified a novel lncRNA, lncAPP (lncRNA activated in PCa progression), which activates in PCa progression and is expressed in primary tumor tissues and urine samples of patients with localized or advanced PCa. Urinary‐based lncAPP is a promising biomarker for predicting PCa progression. In vitro and in vivo studies demonstrated that lncAPP enhanced cell proliferation and promoted migration and invasion. The underlying mechanism of lncRNA was investigated by RNA immunoprecipitation, dual‐luciferase reporter system assay, etc. Upregulation of lncAPP promoted cell migration and invasion via competitively binding miR218 to facilitate ZEB2/CDH2 expression. In addition, in vivo subcutaneous tumor xenograft models and tail intravenously injection metastatic models were constructed to evaluate lncRNA function. Targeting lncAPP/miR218 axis in cell lines and tumor xenografts restrained tumor progression properties both in vitro and in vivo. These results establish that lncAPP/miR218 axis plays a critical role in PCa progression, and they also suggest new strategies to prevent tumor progression for therapeutic purposes.

Background: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c.517C > T, p.Arg173*) alone rather than a two-hit mutation. Case presentation: A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C > T, p.Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related. Conclusions: A novel germline ARMC5 mutation (c. 517C > T, p.Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease.

BACKGROUND:Long non-coding RNAs (lncRNAs) can be used as prognostic biomarkers in many types of cancer.OBJECTIVE:We sought to establish an lncRNA signature to improve postoperative risk stratification for patients with localized clear cell renal cell carcinoma (ccRCC).DESIGN, SETTING, AND PARTICIPANTS:Based on the RNA-seq data of 444 stage I-III ccRCC tumours from The Cancer Genome Atlas project, we built a four-lncRNA-based classifier using the least absolute shrinkage and selection operation (LASSO) Cox regression model in 222 randomly selected samples (training set) and validated the classifier in the remaining 222 samples (internal validation set). We confirmed this classifier in an external validation set of 88 patients with stage I-III ccRCC from a Japan cohort and using quantitative reverse transcription polymerase chain reaction (RT-PCR) in another three independent sets that included 1869 patients from China with stage I-III ccRCC.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Univariable and multivariable Cox regression, Harrell's concordance index (c-index), and time-dependent receiver operating characteristic curves were used to evaluate the association of the classifier with overall survival, disease-specific survival, and disease-free survival.RESULTS AND LIMITATIONS:Using the LASSO Cox regression model, we built a classifier named RCClnc4 based on four lncRNAs: ENSG00000255774, ENSG00000248323, ENSG00000260911, and ENSG00000231666. In the RNA-seq and RT-PCR data sets, the RCClnc4 signature significantly stratified patients into high-risk versus low-risk groups in terms of clinical outcome across and within subpopulations and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.34 [95% confidence interval {CI}: 1.03-1.75; p=0.028] to 1.89 [95% CI, 1.55-2.31; p<0.001]) after adjusting for clinical and pathologic factors. The RCClnc4 signature achieved a higher accuracy (mean c-index, 0.72) than clinical staging systems such as TNM (mean c-index, 0.62) and the stage, size, grade, and necrosis (SSIGN) score (mean c-index, 0.64), currently reported prognostic signatures and biomarkers for the estimation of survival. When integrated with clinical characteristics, the composite clinical and lncRNA signature showed improved prognostic accuracy in all data sets (TNM + RCClnc4 mean c-index, 0.75; SSIGN + RCClnc4 score mean c-index, 0.75). The RCClnc4 classifier was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients.CONCLUSIONS:The RCClnc4 classifier is a promising and potential prognostic tool in predicting the survival of patients with stage I-III ccRCC. Combining the lncRNA classifier with clinical and pathological parameters allows for accurate risk assessment in guiding clinical management.PATIENT SUMMARY:The RCClnc4 classifier could facilitate patient management and treatment decisions.

Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4–6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-β1, we propose that metformin exerts its effects by targeting the TGF-β1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.

In this study, we report here a rare case of polycythemia and cRCC in the same patient, which may be helpful in understanding clinical features and molecular mechanisms underlying VHL-mutation-associated cRCC and polycythemia induced by germline mutation of HIF2A. Firstly, we identified a rare but well studied germline mutation resulting in polycythemia in HIF2A (c.1609G>A, p.Gly537Trp) in the blood of the patient and his daughter. Meanwhile, we identified an inactivating VHL mutation (c.391A>T, p.N131Y), as well as TP53 mutation(c.977A>T, p.E326V) and mTOR mutation(c.7498A>T, p.I2500F) in renal cancer tissue. Moreover, protein levels of VHL, HIF1A, HIF2A, EPO, and VEGF estimated by immunohistochemical staining substantiated hyperactivation of the oxygen-sensing pathway. In addition, we identified 158 somatic SNP/indel mutations, including 90 missense/nonsense/splice/stop-loss mutations by whole-exome sequencing (WES) of the tumor specimen and matched normal DNA.

Carney complex (CNC) is a multiple neoplasia syndrome with autosomal dominant inheritance. CNC is characterized by the presence of myxomas, spotty skin pigmentation, and endocrine overactivity. No direct correlation has been established between disease-causing mutations and phenotype.A 16-year-old boy was admitted because of excessive weight gain over 3 years and purple striae for 1 year. Physical examination revealed Cushingoid features and spotty skin pigmentation on his face, lip, and sclera.The patient was diagnosed as Carney complex.the patient underwent right adrenalectomy and partial adrenalectomy of the left adrenal gland.Results of imaging showed bilateral adrenal nodular hyperplasia, multiple microcalcifications of the bilateral testes, and compression fracture of the thoracolumbar spine. Histopathological results confirmed multiple pigmented nodules in the adrenal glands. DNA sequencing revealed a nonsense mutation in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A; c.205C > T). After the second adrenalectomy, the Cushingoid features disappeared, and cortisol levels returned to normal.Carney complex is a rare disease that lacks consistent genotype-phenotype correlations. Our patient, who carried a germline PRKAR1A nonsense mutation (c.205C > T), clinical features included spotty skin pigmentation, osteoporosis, and primary pigmented nodular adrenal disease. Adrenalectomy is the preferred treatment for Cushing syndrome due to primary pigmented nodular adrenal disease.

We previously reported that PlncRNA-1, a long non-coding RNA that is up-regulated in prostate cancer (PCa), affects the proliferation and apoptosis of PCa cells. However, the molecular mechanisms underlying these effects remain largely unknown. In this study, we demonstrated that long non-coding RNA PlncRNA-1, whose expression is promoted by Androgen Receptor (AR), protects AR from microRNA-mediated suppression in PCa cells. PlncRNA-1 knockdown resulted in the up-regulation of a series of AR-targeting microRNAs, among which miR-34c and miR-297 were found to regulate both AR and PlncRNA-1 expression at the post-transcriptional level. Functional analysis revealed that miR-34c and miR-297 overexpression down-regulated AR expression and inhibited the expression of downstream AR targets and that PlncRNA-1 overexpression rescued these effects. The association of PlncRNA-1 with tumor progression was also evaluated in mouse xenograft models, PCa tissues (16 paired samples), and blood samples (35 biopsy-negative and 37 biopsy-positive). Together, the data generated in this study indicate that PlncRNA-1 sponges AR-targeting microRNAs to protect AR from microRNA-mediated down-regulation and that these events form a regulatory feed-forward loop in the development of PCa. These findings suggest that PlncRNA-1 might potentially serve as a novel biomarker in PCa and that PlncRNA-1 might warrant further investigation to determine its potential role as a promising therapeutic target in PCa.

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.