Influence of Dietary Polyunsaturated Fatty Acid Intake on Potential Lipid Metabolite Diagnostic Markers in Renal Cell Carcinoma: A Case-Control Study.

Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.

Survival pattern of metastatic renal cell carcinoma patients according to WHO/ISUP grade: a long-term multi-institutional study.

The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1-4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1-2) or a high-grade group (WHO/ISUP grade 3-4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5-18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6-17.4) in the high-grade group and 28.0 months (21.1-34.9) in the low-grade group (p < 0.001). However, there was no difference in progression-free survival (PFS) rates with 9.0 months (8.0-10.0) for the high-grade group and 10.0 months (6.8-13.2) for the low-grade group (p = 0.377) in first-line treatment. In multivariable analysis, WHO/ISUP grade was a risk factor (HR = 1.511[1.135-2.013], p = 0.005) that influenced the OS. In conclusion, WHO/ISUP grade is a major data source that can be used as a ubiquitous marker of metastatic RCC in pre-IO era. Depending on whether the RCC is high or low grade, the follow-up schedule will need to be tailored according to grade, with higher-grade patients needing more active treatment as it can not only affect the OS in the previously known localized/locoregional recurrence but also the metastatic RCC patient.

Deciphering the Role of ERBB3 Isoforms in Renal Cell Carcinoma: A Comprehensive Genomic and Transcriptomic Analysis.

ERBB3, a key member of the receptor tyrosine kinase family, is implicated in the progression and development of various human cancers, affecting cellular proliferation and survival. This study investigated the expression of ERBB3 isoforms in renal clear cell carcinoma (RCC), utilizing data from 538 patients from The Cancer Genome Atlas (TCGA) Firehose Legacy dataset. Employing the SUPPA2 tool, the activity of 10 ERBB3 isoforms was examined, revealing distinct expression patterns in RCC. Isoforms uc001sjg.3 and uc001sjh.3 were found to have reduced activity in tumor tissues, while uc010sqb.2 and uc001sjl.3 demonstrated increased activity. These variations in isoform expression correlate with patient survival and tumor aggressiveness, indicating their complex role in RCC. The study, further, utilizes CIBERSORTx to analyze the association between ERBB3 isoforms and immune cell profiles in the tumor microenvironment. Concurrently, Gene Set Enrichment Analysis (GSEA) was applied, establishing a strong link between elevated levels of ERBB3 isoforms and critical oncogenic pathways, including DNA repair and androgen response. RT-PCR analysis targeting the exon 21-23 and exon 23 regions of ERBB3 confirmed its heightened expression in tumor tissues, underscoring the significance of alternative splicing and exon utilization in cancer development. These findings elucidate the diverse impacts of ERBB3 isoforms on RCC, suggesting their potential as diagnostic markers and therapeutic targets. This study emphasizes the need for further exploration into the specific roles of these isoforms, which could inform more personalized and effective treatment modalities for renal clear cell carcinoma.

Inhibition mechanism of testis-expressed gene 14 (TEX14) in cytokinetic abscission: Well-tempered metadynamics simulation studies.

Cytokinesis requires a apoptosis-linked gene 2 interacting protein X (ALIX) and a 55 kDa midbody centrosomal protein (CEP55) to activate the cell abscission in somatic cells. However, in germ cells, CEP55 forms intercellular bridges with testis-expressed gene 14 (TEX14), which blocks the cell abscission. These intercellular bridges play important roles in the synchronization of the germ cells and facilitate the coordinated passage of organelles and molecules between germ cells. If TEX14 is intentionally removed, intercellular bridges are disrupted, leading to sterility. Hence, a deeper understanding regarding the roles of TEX14 can provide significant insights into the inactivation of abscission and the inhibition of proliferation in cancer cells. Previous experimental studies have shown that the high affinity and low dissociation rate of TEX14 for CEP55 prevent ALIX from binding CEP55 and inactivate the germ cell abscission. However, detailed information about how TEX14 interacts with CEP55 to prevent the cell abscission is still lacking. To gain more specific insights into the interactions between CEP55 and TEX14 and the difference in reactivity between TEX14 and ALIX, we performed well-tempered metadynamics simulations of these protein complexes using atomistic models of CEP55, TEX14, and ALIX. We identified the major binding residues of TEX14 and ALIX with CEP55 by using 2D Gibbs free energy evaluations, the results of which are consistent with previous experimental studies. Our results may help design synthetic TEX14 mimicking peptides, which can bind CEP55 and facilitate the inactivation of abscission in abnormal cells, including cancer cells.

Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study.

PURPOSE: Intravesical mitomycin-C is recommended immediately after transurethral resection of bladder tumor for nonmuscle-invasive bladder cancer. However, a lack of compliance occurs due to the associated complications. Here, we aimed to assess the efficacy and safety of intravesical mitomycin-C before transurethral resection of bladder tumor in patients with nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This was a single-center, open-label, parallel-arm, randomized phase II clinical trial in patients with suspected nonmuscle-invasive bladder cancer before transurethral resection of bladder tumor. Participants were randomly assigned (1:1) to receive 2 doses of intravesical mitomycin-C (40 mg/20 mL) 1 day and 4 hours before transurethral resection of bladder tumor (n = 49) or no treatment (n = 50) with block randomization (size 2 and 4), stratified by bacillus Calmette-Guérin/intravesical mitomycin-C. The primary endpoint was recurrence-free survival and secondary endpoints were progression-free survival and adverse events in the per-protocol analysis. RESULTS: Seventy-one patients (33, intervention; 38, control) were well matched for baseline characteristics. Sixty-one had been followed without recurrence for at least 10.4 months; 3 and 8 patients showed recurrence in the intervention and control groups, respectively. The 1-year recurrence-free survival rate was 97% and 89% for the intervention and control groups, respectively. Neoadjuvant intravesical mitomycin-C resulted in a reduction (63%) in the relative recurrence risk (hazard ratio, 0.37; 80% 1-sided confidence interval, -∞-0.65, P = .11). Disease progression occurred in 3 patients in the control group (P = .051) but not in the intervention group. Neoadjuvant intravesical mitomycin-C was well tolerated, and adverse events were local and of grade 1/2. CONCLUSIONS: Two doses of neoadjuvant intravesical mitomycin-C are safe and effective in reducing nonmuscle-invasive bladder cancer recurrence and progression after transurethral resection of bladder tumor.

Surgical outcomes of ureteral reconstruction during cytoreductive surgery for ovarian cancer: a retrospective cohort study.

BACKGROUND: Ureteral reconstruction is required after surgical resection of the tumor invading the urinary tract in ovarian cancer with low incidence. There are no currently reported surgical outcomes of ureteral reconstruction during cytoreductive surgery. The aim of the study is to investigate the clinical features and surgical outcomes of ureteral reconstruction during primary, interval and secondary cytoreductive surgery for ovarian cancer.  METHODS: A total of 3226 patients who underwent primary, interval or secondary cytoreductive surgery for ovarian cancer between January 2000 and May 2021 were reviewed. Fifty-six patients who underwent ureteral reconstruction during cytoreductive surgery were included in the analysis.  RESULTS: Ureteral reconstruction was required in 1.7% (56/3226) of ovarian cancer patients. Of the 56 patients who underwent ureteral reconstruction during cytoreductive surgery, 35 (62.5%) had primary ovarian cancer, and 21 (37.5%) had recurrent ovarian cancer. The median tumor size invading the lower urinary tract was 2.0 cm (range, 0.4-9.5 cm). Ureteroneocystostomy with direct implantation (51.8%) and psoas hitch (8.9%), transureteroureterostomy (7.1%), and ureteroureterostomy (32.1%) were required as part of cytoreductive surgery. Complete cytoreduction with ureteral reconstruction was achieved in 83.9% (47/56) and the rest of the patient population (16.1%) achieved a gross residual tumor size of less than 1 cm. All complications, including hydronephrosis (33.9%), were managed, none resulting in long-term sequelae. In primary ovarian cancer, the 5-year disease-free survival and overall survival were 50.0% and 89.5%, respectively. In patients with recurrent ovarian cancer, the 5-year disease-free survival and overall survival were 23.6% and 64.0%, respectively. CONCLUSIONS: Ureteral reconstruction as a part of cytoreductive surgery for ovarian cancer could be performed with acceptable morbidities. Complete cytoreduction by a multidisciplinary surgical team, including urologic oncologists, should be pursued for the surgical management of ovarian cancer. TRIAL REGISTRATION: Retrospectively registered.

FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations.

Although both the p53 and forkhead box (FOX) family proteins are key transcription factors associated with cancer progression, their direct relationship is unknown. Here, we found that FOX family proteins bind to the non-canonical homotypic cluster of the p53 promoter region (TP53). Analysis of crystal structures of FOX proteins (FOXL2 and FOXA1) bound to the p53 homotypic cluster indicated that they interact with a 2:1 stoichiometry accommodated by FOX-induced DNA allostery. In particular, FOX proteins exhibited distinct dimerization patterns in recognition of the same p53-DNA; dimer formation of FOXA1 involved protein-protein interaction, but FOXL2 did not. Biochemical and biological functional analyses confirmed the cooperative binding of FOX proteins to the TP53 promoter for the transcriptional activation of TP53. In addition, up-regulation of TP53 was necessary for FOX proteins to exhibit anti-proliferative activity in cancer cells. These analyses reveal the presence of a discrete characteristic within FOX family proteins in which FOX proteins regulate the transcription activity of the p53 tumor suppressor via cooperative binding to the TP53 promoter in alternative dimer configurations.

Reproducibility and Step-By-Step Learning Curve of Retroperitoneal Video-Assisted Mini-Laparotomy Surgery for Living Donor Nephrectomy: A Single-Center Experience.

OBJECTIVES: Living donor transplant techniques must ensure donor safety and minimize complications. To achieve this goal, in 2003, we developed a new surgical procedure named video-assisted mini-laparotomy surgery for living donor nephrectomy. Video-assisted mini-laparotomy surgery standardizes the retroperitoneal mini-laparotomy technique as an alternative to open surgery. We have previously reported on video-assisted mini-laparotomy surgery techniques for use in kidney surgery. However, there are no reports of video-assisted mini-laparotomy surgery performed at other institutions. Therefore, we introduced video-assisted mini-laparotomy surgery at another institution, and here, we report on our experience. MATERIALS AND METHODS: We evaluated a consecutive series of 38 donors who underwent video-assisted mini-laparotomy living donor nephrectomy at National Health Insurance Service Ilsan Hospital from August 2016 to November 2019. All 38 patients were enrolled. Perioperative data and outcomes were retrospectively analyzed. We recorded perioperative and postoperative data, including operative time, estimated blood loss, and duration of hospital stay. RESULTS: The mean operative time was 144.35 ± 22.79 minutes, and the mean warm ischemia time was 184.35 ± 4.97 seconds. Mean estimated blood loss was 72.85 ± 60.81 mL. At 12 months after video-assisted mini-laparotomy surgery, the mean posttransplant serum creatinine level was 1.05 ± 0.18 mg/dL, and estimated glomerular filtration rate (according to the Modification of Diet in Renal Disease study equation) was 71.9 ± 10.34 mL/min/1.73 m2. There was no intraoperative or postoperative complication. CONCLUSIONS: Previous studies reported that video- assisted mini-laparotomy surgery has a steep learning curve and is difficult to reproduce. However, video- assisted mini-laparotomy surgery is a feasible and safe technique at our institution. Video-assisted mini- laparotomy surgery is a solo surgery that can be safely performed by any surgeon with prior kidney surgery experience.

The point mutation of the cholesterol trafficking membrane protein NPC1 may affect its proper function in more than a single step: Molecular dynamics simulation study.

The Niemann-Pick type C1 (NPC1) protein is one of the key players of cholesterol trafficking from the lysosome and its function is closely coupled with the Niemann-Pick type C2 (NPC2) protein. The dysfunction of one of these proteins can cause problems in the overall cholesterol homeostasis and leads to a disease, which is called the Niemann-Pick type C (NPC) disease. The parts of the cholesterol transport mechanism by NPC1 have begun to recently emerge, especially after the full-length NPC1 structure was determined from a cryo-EM study. However, many details about the overall cholesterol trafficking process by NPC1 still remain to be elucidated. Notably, the NPC1 could act as one of the target proteins for the control of infectious diseases due to its role as the virus entry point into the cells as well as for cancer treatment due to the inhibitory effect of tumor growth. A mutation of NPC1 can leads to dysfunctions and understanding this process can provide valuable insights into the mechanisms of the corresponding protein and the therapeutic strategies against the disease that are caused by the mutation. It has been found that patients with the point mutation R518W (or R518Q) on the NPC1 show the accumulation of lipids within the lysosomal lumen. In this paper, we report how the corresponding mutation can affect the cholesterol transport process by NPC1 in the different stages by the molecular dynamics simulations. The simulation results show that the point mutation intervenes at least at two different steps during the cholesterol transport by NPC1 and NPC2 in combination, which includes the association step of NPC2 with the NPC1, the cholesterol transfer step from NPC2 to NPC1-NTD while the cholesterol passage within the NPC1 via a channel is relatively unaffected by R518W mutation. The detailed analysis of the resulting simulation trajectories reveals the important structural features that are essential for the proper functioning of the NPC1 for the cholesterol transport, and it shows how the overall structure, which thereby includes the function, can be affected by a single mutation.

Structure-based inhibitor design for reshaping bacterial morphology.

The spiral shape of intestinal pathogen Campylobacter jejuni is critical for invasion of intestinal mucosa epithelial cells. Insofar as this cell morphology plays a role in the pathology of C. jejuni infection, its restructuring by pharmacological intervention could be an unexplored means to prevention of infection. We recently described that peptidoglycan hydrolase 3 (Pgp3) is involved in the spiral-shape formation of C. jejuni. We report herein the design and synthesis of the hydroxamate-based inhibitors targeting Pgp3. C. jejuni cells exposed to these inhibitors changed from the helical- to rod-shaped morphology, comparable to the case of the pgp3-deletion mutant. Evidence for the mechanism of action was provided by crystal structures of Pgp3 in complex with inhibitors, shedding light into the binding modes of inhibitors within the active site, supported by kinetics and molecular-dynamics simulations. C. jejuni exposed to these inhibitors underwent the morphological change from helical- to rod-shaped bacteria, an event that reduce the ability for invasion of the host cells. This proof of concept suggests that alteration of morphology affects the interference with the bacterial infection.

The effect of subsequent immunosuppressant use in organ-transplanted patients on prostate cancer incidence: a retrospective analysis using the Korean National Health Insurance Database.

BACKGROUNDS: Prostate cancer (PC) is the most common solid organ cancer. However, there is still no definite consensus before and after organ transplantation (TPL). We aimed to analyze whether PC incidence increased in TPL patients with subsequent use of immunosuppressants using the Korean National Health Insurance Database. METHODS: TPL patients between 2003 and 2015(N = 12,970) were age- and year-matched to non-TPL patients (N = 38,910) in a 1:3 ratio. Multivariate Cox regression analysis adjusted for significant prognostic clinicopathological parameters, including the duration of immunosuppressant agent use (0-300 or > 300 days), and Kaplan-Meier analysis with log-rank test were used to evaluate the association of TPL with PC incidence between the groups. RESULTS: Median overall survival was 4.86 years; overall mortality rate was 3.4% (n = 1761). Regardless of differences in baseline characteristics between the groups, multivariate analysis for PC incidence showed that age, immunosuppressant use, and TPL organ subtypes were significant factors for the overall population, whereas only age was significant in the TPL group (p < 0.05). After adjusting for age, underlying disease, and prescribed medication (aspirin, statin), multiple subgroup analysis models for PC incidence were evaluated. PC incidence was increased in the TPL group (hazard ratio [HR] 1.965, p < 0.001); however, PC incidence in the TPL group became insignificant after adjusting for immunosuppressant use (p = 0.194). Kaplan-Meier curves also showed that PC incidence was significantly different according to age and TPL with the use of immunosuppressants between the TPL and non-TPL groups. CONCLUSIONS: PC incidence was higher in the TPL group using immunosuppressants than in the non-TPL group. TRIAL REGISTRATION:  The study was retrospectively registered.

Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype.

BACKGROUND AND OBJECTIVES: Transcriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation. MATERIALS AND METHODS: To focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting. RESULTS: We identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy. CONCLUSION: We propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.

How Does Androgen Deprivation Therapy Affect Mental Health including Cognitive Dysfunction in Patients with Prostate Cancer?

Androgen deprivation therapy (ADT) is used to block the release of androgen in prostate cancer to promote the regression of cancer cells, and hence, disease progression. Its indication has been widened from the metastatic setting to the localized setting in prostate cancer. Long-term ADT for suppressing androgen release leads to a rapid decrease in androgen, termed as andropause, resulting in several dose and duration dependent adverse effects, including cognitive dysfunction such as dementia. Many retrospective and prospective studies, as well as meta-analyses, have attempted to confirm the crucial relationship between ADT and cognitive dysfunction, but pro and contrary opinions regarding this issue are ongoing owing to the absence of randomized controlled trials. Additionally, several recent studies have suggested the negative effects of dose- and duration-dependent ADT on cognitive dysfunction, especially in 40-65-year-old patients with prostate cancer, who are currently active workers in the society. This review article discusses several studies examining the influence of ADT on mental health based on diverse significant perspectives, especially cognitive dysfunction.

Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity.

NAD(P)-dependent steroid dehydrogenase-like (NSDHL), an essential enzyme in human cholesterol synthesis and a regulator of epidermal growth factor receptor (EGFR) trafficking pathways, has attracted interest as a therapeutic target due to its crucial relevance to cholesterol-related diseases and carcinomas. However, the development of pharmacological agents for targeting NSDHL has been hindered by the absence of the atomic details of NSDHL. In this study, we reported two X-ray crystal structures of human NSDHL, which revealed a detailed description of the coenzyme-binding site and the unique conformational change upon the binding of a coenzyme. A structure-based virtual screening and biochemical evaluation were performed and identified a novel inhibitor for NSDHL harboring suppressive activity towards EGFR. In EGFR-driven human cancer cells, treatment with the potent NSDHL inhibitor enhanced the antitumor effect of an EGFR kinase inhibitor. Overall, these findings could serve as good platforms for the development of therapeutic agents against NSDHL-related diseases.

Epithelial Splicing Regulatory Protein (ESPR1) Expression in an Unfavorable Prognostic Factor in Prostate Cancer Patients.

BACKGROUND: To evaluate the role of epithelial splicing regulatory protein 1 (ESRP1) expression in survival prognoses and disease progression for prostate cancer (PC) using The Cancer Genome Atlas (TCGA) dataset and to validate it using patients' prostatectomy specimens. METHODS: A preliminary investigation into the clinical significance of ESRP1 in PC was conducted using TCGA PC PRAD dataset and then using immunohistochemistry in 514 PC patients' tissue microarrays of radical prostatectomy specimens. The interpretation of immunohistochemistry was done using its intensity (high vs. low) or the semi-quantitative expression value (H-score, 0-300). The prognostic significance of ESRP1 expression was analyzed for biochemical recurrence (BCR), recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) using the Cox proportional-hazards model (p < 0.05). RESULTS: In the publicly available prostate adenocarcinoma dataset, ESRP1 expression was significantly higher in the tumor samples compared to the normal samples (p < 0.001). Survival analysis showed that the tumor samples in the ESRP1-high group had significantly worse BCR-free survival and RFS compared to the ESRP1-low group (p < 0.05), whereas OS was not (p=0.08). These results were largely consistent with the 514 patients' clinical data during a median 91.2 months of follow-up. After adjusting for significant prognostic clinicopathological factors, the multivariable models showed that the ESRP1 was a significantly risk factor for CSS (Hazard ratio 3.37, p = 0.034) and for BCR (HR 1.34, p=0.049) without any significance for OS (p=0.464). CONCLUSIONS: The higher ESRP1 expression appeared increased risk of disease progression and cancer-specific death in PC.

Over-activation of a nonessential bacterial protease DegP as an antibiotic strategy.

Rising antibiotic resistance urgently begs for novel targets and strategies for antibiotic discovery. Here, we report that over-activation of the periplasmic DegP protease, a member of the highly conserved HtrA family, can be a viable strategy for antibiotic development. We demonstrate that tripodal peptidyl compounds that mimic DegP-activating lipoprotein variants allosterically activate DegP and inhibit the growth of an Escherichia coli strain with a permeable outer membrane in a DegP-dependent fashion. Interestingly, these compounds inhibit bacterial growth at a temperature at which DegP is not essential for cell viability, mainly by over-proteolysis of newly synthesized proteins. Co-crystal structures show that the peptidyl arms of the compounds bind to the substrate-binding sites of DegP. Overall, our results represent an intriguing example of killing bacteria by activating a non-essential enzyme, and thus expand the scope of antibiotic targets beyond the traditional essential proteins or pathways.

Robot-assisted laparoendoscopic single-site upper urinary tract surgery with da Vinci Xi surgical system: Initial experience.

Purpose: The da Vinci Xi robot surgical system was newly released with several upgrades and modifications made to its previous Si platform; to further enhance the capabilities to carry out minimally invasive surgery. This study aimed to evaluate the intraoperative and postoperative outcomes of robot laparoendoscopic single-site surgery performed with the da Vinci Xi system. Materials and Methods: Retrospective chart review of patients undergoing of robot laparoendoscopic single-site by a single surgeon using the Xi single-site platform from November 2016 and May 2019. For the da Vinci Xi system, multichannel port and "Lap Single Vision" port access platform were placed through a single periumbilical incision. Results: Fourteen patients underwent single-site surgery with benign cases (n=9) and partial nephrectomy cases (n=5). Among surgeries for the partial nephrectomy patients, one case of conversion to multiport robotic surgery occurred due to difficulty of tumor resection. Other major intraoperative complication, renal vein injury, was occurred in a patient who underwent a pyelolithotomy. The patient required a blood transfusion however, we were able to repair the vascular injury using prolene suture without additional port placement and open conversion. In our series, there were no conversions to open. The postoperative course was uneventful in all patients; only Clavien-Dindo III complications occurred. Conclusions: Our preliminary experience with robot laparoendoscopic single-site surgery using the da Vinci Xi system demonstrated feasibility and safety in selected patients. Further studies with a greater number of patients in multiple settings will help to fully elucidate the role of da Vinci Xi surgical system in single-site surgery.

Retroperitoneal single-site robot-assisted partial nephrectomy using Lapsingle Vision advanced access platform: initial three case reports.

Robot-assisted partial nephrectomy is currently the standard for treatment of small renal mass. Recently, robot-assisted single site surgery has been introduced. However, there have been few reports of retroperitoneal approaches. Herein, we report initial case series of retroperitoneal single-site robot-assisted partial nephrectomy using the da Vinci Xi surgical system using the Lapsingle Vision advanced access platform. Three patients have undergone retroperitoneal single-site robot-assisted partial nephrectomy due to incidental finding of renal mass. Operation duration, estimated blood loss, warm ischemia time, estimated glomerular filtration rate (eGFR) change, and complication were evaluated. Renal cell carcinoma of the two clear cell type and one chromophobe was diagnosed based on the pathological examination. Initial two cases were successfully completed with minimal bleeding and warm ischemic time within 25 minutes. The last 3rd case has been converted to multiport operation due to limited retroperitoneal space and difficulty in managing upper pole renal mass. Retroperitoneal single-site robot-assisted partial nephrectomy is a feasible treatment modality for treatment of posterior or lateral renal masses. Additional cases are needed to confirm the safety and efficacy of this technique.

FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku.

The balance between major DNA double-strand break (DSB) repair pathways is influenced by binding of the Ku complex, a XRCC5/6 heterodimer, to DSB ends, initiating non-homologous end joining (NHEJ) but preventing additional DSB end resection and homologous recombination (HR). However, the key molecular cue for Ku recruitment to DSB sites is unknown. Here, we report that FOXL2, a forkhead family transcriptional factor, directs DSB repair pathway choice by acetylation-dependent binding to Ku. Upon DSB induction, SIRT1 translocates to the nucleus and deacetylates FOXL2 at lysine 124, leading to liberation of XRCC5 and XRCC6 from FOXL2 and formation of the Ku complex. FOXL2 ablation enhances Ku recruitment to DSB sites, imbalances DSB repair kinetics by accelerating NHEJ and inhibiting HR, and thus leads to catastrophic genomic events. Our study unveils the SIRT1-(de)acetylated FOXL2-Ku axis that governs the balance of DSB repair pathways to maintain genome integrity.

Establishment of patient-derived three-dimensional organoid culture in renal cell carcinoma.

Purpose: Renal cell carcinoma is a heterogeneous kidney cancer, and over 403,000 cases were reported worldwide in 2018. Current methods for studying renal cell carcinoma are limited to two-dimensional (2D) culture of primary cell lines and patient-derived xenograft models. Numerous studies have suggested that 2D culture poorly represents the diversity, heterogeneity, and drug-resistance of primary tumors. The time and cost associated with patient-derived xenograft models poses a realistic barrier to their clinical utility. As a biomimetic model, patient-derived three-dimensional (3D) organoid culture can overcome these disadvantages and bridge the gap between in vitro cell culture and in vivo patient-derived xenograft models. Here, we establish a patient-derived 3D organoid culture system for clear cell renal cell carcinoma and demonstrate the biomimetic characteristics of our model with respect to both primary kidney cancer and conventional 2D culture. Materials and Methods: Normal renal tissues and tumor tissues were collected from patients with clear cell renal cell carcinoma. The dissociated cells were cultured as conventional 2D culture and 3D organoid culture. The biomimetic characteristic of the two cultures were compared. Results: Compared with 2D culture, the 3D organoid cultures retained the characteristic lipid-rich, clear cell morphology of clear cell renal cell carcinoma. Carbonic anhydrase 9 and vimentin were validated as biomarkers of renal cell carcinoma. Expression of the two validated biomarkers was more enhanced in 3D organoid culture. Conclusions: Patient-derived 3D organoid culture retains the characteristics of renal cell carcinoma with respect to morphology and biomarker expression.