Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.ope

Microbiome Analysis Using Next-Generation Sequencing in Urinary Tract Infections

In recent decades, the understanding of the genetic information of microbes and hosts has advanced considerably with the development of next-generation sequencing (NGS). For infectious diseases, genomic analysis can provide valuable information on the host disease susceptibility, microbial pathogenicity, and drug sensitivity. For urinary tract infections (UTI), NGS can reveal the pathogenic microbe and the dysbiosis of the urinary microbiome, which is a crucial factor in the pathogenesis of UTI and other urinary tract disorders. This review outlines the role of urinary microbiome dysbiosis in UTI, urinary stone disease, and cancer. Furthermore, the recent advances in NGS technologies for future applications in infectious disease research are described in detail.ope

In Vivo Feasibility Test of a New Flexible Ureteroscopic Robotic System, easyUretero, for Renal Stone Retrieval in a Porcine Model

Purpose: Using a new robotic endoscopic platform system developed for retrograde intrarenal surgery (RIRS) called easyUretero (ROEN Surgical Inc.), we evaluated the feasibility and safety of renal stone retrieval in a porcine model. Materials and methods: Six female pigs were used for our in vivo study. First, 0.3-cm-sized phantom stones were inserted into the kidneys of each pig via the ureteral access sheath. Next, renal stone retrieval was attempted using manual RIRS in three pigs and robotic RIRS in three pigs. Three surgeons performed extraction of 10 stones in each session. Results: The mean stone retrieval time by manual RIRS was significantly shorter than that by robotic RIRS (399.9±185.4 sec vs. 1127.6±374.5 sec, p=0.001). In contrast, the questionnaire regarding usability showed high satisfaction in the surgeons' fatigue category for surgeons using robotic RIRS. The radiation exposure dose was also lower in robotic RIRS than in manual RIRS (0.14 µSv vs. 45.5 µSv). Postoperative ureteral injury assessment revealed Grade 0 in manual RIRS cases and Grades 0, 1, and 2 in robotic RIRS cases. Conclusion: The easyUretero system is a new robotic RIRS system that was developed in Korea. The results of the present study suggest that using easyUretero for stone retrieval during RIRS is safe and ergonomic.ope

Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation

Tumor growth generates mechanical compression, which may trigger mechanotransduction in cancer and stromal cells and promote tumor progression. However, very little is known about how compression stimulates signal transduction and contributes to tumor progression. In the present study, we demonstrated that compression enhances a tumor progression phenotype using an in vitro compression model, and validated the results from the in vitro model with high- and low-compressed breast cancer tissues. Mechanical compression induced miR-9 downregulation by DNMT3A-dependent promoter methylation in the MDA-MB-231 and BT-474 breast cancer cell lines and in cancer-associated fibroblasts. The overexpression of miR-9 target genes (LAMC2, ITGA6, and EIF4E) was induced by miR-9 downregulation, which eventually enhanced vascular endothelial growth factors production. Demethylation and decompression could reverse compression-induced miR-9 downregulation and following overexpression of miR-9 target genes and VEGFA.ope

Clinical Assessment of Follow-Up Cystatin C-Based eGFR in Live Kidney Donors.

PURPOSE: We aimed to compare the cystatin C-based estimated glomerular filtration rate (eGFR) and the serum creatinine-based eGFR and to investigate the clinical roles of the cystatin C-based eGFR in assessing the follow-up renal function of kidney donors. MATERIALS AND METHODS: We enrolled 121 healthy kidney donors who underwent live donor nephrectomy between October 2009 and December 2010 in a prospective manner. Serum creatinine and cystatin C were measured preoperatively and were followed after the surgery (1st, 4th, and 7th postoperative day and 1st, 3rd, 6th, and 12th postoperative month). We also compared the sensitivity and specificity of each eGFR method for predicting the development of chronic kidney disease (CKD) after donor nephrectomy. RESULTS: For those who had a Modification of Diet in Renal Disease postoperative day 4 eGFR of less than 60 ml/min/1.73 m(2), the probability of developing CKD was 89.0% (Chronic Kidney Disease Epidemiology Collaboration eGFR, 66.0%; Cockcroft-Gault eGFR, 74.0%; cystatin C eGFR, 57.1%). A cystatin C eGFR of below 60 ml/min/1.73 m(2) at postoperative day 4 predicted CKD at 6 months with a specificity of 90.3%, which was the highest among the estimation methods used. Cystatin C eGFRs were generally higher than the creatinine-based eGFRs. CONCLUSIONS: We conclude that cystatin C-based estimations of the GFR are helpful for predicting the recovery of renal function in kidney donors and could be added to the follow-up protocol of kidney donors who may develop CKD, especially patients whose immediate postoperative renal function is marginal.ope

Epidemiology of prostate cancer in South Korea

BACKGROUND: Prostate cancer (PCa) is the second most frequently diagnosed cancer in male. In South Korea, PCa incidence has increased significantly, while its mortality rate has decreased steadily. To optimize the distribution of public medical resources, it is essential to analyze the contemporary epidemiology of PCa. METHODS: National population data from the National Health Insurance Statistical Yearbook and the annual report of national cancer registration and statistics in Korea were assessed. From the data, the incidence, prevalence, and mortality rates of PCa were calculated. The data were presented with reference to other types of cancers occurring in various countries from different continents. RESULTS: From 2007 to 2013, PCa incidence doubled (from 5,516 per year to 10,855 per year), while its prevalence in Korean men tripled (from 18,830 to 51,411) during the same period. The mortality rate increased slightly, from 4.2 in 2000 to 5.9 in 2007 and 6.0 in 2013 (per 100,000, age adjusted). PCa incidence increased significantly faster in men aged < 70 years than in the older age group. CONCLUSION: PCa prevalence in South Korea has increased significantly, mainly due to the rise in its incidence. As the country is facing major changes, including westernization of dietary habits and rapid population aging, its prevalence would continue to increase in near future.ope

Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche

In estrogen receptor-positive (ER+) breast cancer, it is recognized that metastases may develop after a long period of dormancy. Bone marrow (BM) vascular niche is where the dormant tumor cells are most likely to reside. So far, it is not fully understood why the dormant tumor cells become proliferative and eventually generate tumor. We hypothesized that therapeutic or menopause-related estrogen depletion may be the switch behind dormant ER+ tumor cell awakening in BM. We utilized an existing experimental model of BM endothelial niche that can simulate ER+ tumor cell dormancy to test our hypothesis. In results, estrogen depletion paradoxically promoted ER+ tumor cell proliferation in the BM endothelial niche, and their molecular phenotype shifted from dormant to awaken. Following estrogen depletion, the BM niche cells produced angiopoietin-2 (ANGPT2), which destabilized niche endothelium by interfering ANGPT1/Tie2 signaling, and promoted ER+ tumor cell survival under estrogen deficiency via cell surface integrin &1. Knockdown of ANGPT2 completely negated ER+ tumor cell awakening in the niche. Furthermore, ANGPT2 expression in ER+ tumor human samples was associated with increased risk of distant metastasis only in those who underwent adjuvant estrogen depletion therapy, not in those who did not undergo adjuvant therapy. In conclusion, we demonstrate that ANGPT2 signaling activated after estrogen depletion paradoxically triggers ER+ tumor cell awakening from dormancy in their BM niche, partly indirectly via endothelial Tie2 receptor and partly directly via tumor cell surface integrin &1.ope

Differential diagnosis of complex renal cysts based on lesion size along with the Bosniak renal cyst classification

PURPOSE: To identify size criteria for complex cystic renal masses that can distinguish renal cell carcinoma from benign cysts supplementing the Bosniak classification. MATERIALS AND METHODS: We reviewed the records of 97 patients who underwent surgery for complex cystic renal masses from January 2001 to April 2010. The pathological results were compared with the lesion sizes measured by preoperative computed tomography and other radiological features (contrast enhancement, irregularities of cyst walls and septa, and calcification) were also obtained for categorization according to the Bosniak renal cyst classification. RESULTS: Malignancy was significantly associated with cyst size (>2 cm), male gender, and younger patient age (<50 years). According to the Bosniak classification, there was no category I cyst, and all 8 category II cysts were benign. However, 3 of 18 (17%) category IIF cysts, 21 of 39 (54%) category III cysts, and 29 of 32 (90%) category IV cysts were malignant. All category IIF cysts were benign in patients older than 50 years of age. CONCLUSION: Many complex cystic renal masses smaller than 2 cm were benign. We suggest that lesion size should be taken into account when formulating treatment plans for complex cystic renal masses.ope

Compression-induced Expression of Glycolysis Genes in CAFs Correlates With EMT and Angiogenesis Gene Expression in Breast Cancer

Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression. However, very little is known about how compressive stress contributes to tumor progression. Here, we show that compressive stress induces glycolysis in human breast cancer associated fibroblast (CAF) cells and thereby contributes to the expression of epithelial to mesenchymal (EMT)- and angiogenesis-related genes in breast cancer cells. Lactate production was increased in compressed CAF cells, in a manner dependent on the expression of metabolic genes ENO2, HK2, and PFKFB3. Conditioned medium from compressed CAFs promoted the proliferation of breast cancer cells and the expression of EMT and/or angiogenesis-related genes. In patient tissues with high compressive stress, the expression of compression-induced metabolic genes was significantly and positively correlated with EMT and/or angiogenesis-related gene expression and metastasis size. These findings illustrate a mechanotransduction pathway involving stromal glycolysis that may be relevant also for other solid tumours.ope

p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer

High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results-an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional "all or none" groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.ope