Elucidating the need for prostate cancer risk calculators in conjunction with mpMRI in initial risk assessment before prostate biopsy at a tertiary prostate cancer center.

OBJECTIVE: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection. METHODS: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality. RESULTS: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60-0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82-0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups. CONCLUSION: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation.

Otoferlin is a prognostic biomarker in patients with clear cell renal cell carcinoma: A systematic expression analysis.

OBJECTIVES: To comprehensively investigate the role of otoferlin as a prognostic and diagnostic biomarker in clear cell renal cell carcinoma. METHODS: Three independent cohorts were used to study otoferlin in clear cell renal cell carcinoma: The Cancer Genome Atlas cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 514, normal renal tissue n = 81); study validation cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 79, normal renal tissue n = 44); and immunohistochemistry cohort (protein expression; clear cell renal cell carcinoma n = 142, normal renal tissue n = 30). Otoferlin gene expressions were extracted from The Cancer Genome Atlas database or determined using quantitative real-time polymerase chain reaction, respectively. Protein expression was assessed using immunohistochemistry staining against otoferlin on tissue microarrays. Correlations between otoferlin messenger ribonucleic acid/protein expression and clinicopathological data/patient survival were statistically tested. RESULTS: Otoferlin messenger ribonucleic acid expression was significantly upregulated in clear cell renal cell carcinoma compared with normal renal tissue. High expression levels correlated with advanced stage, higher grade and metastatic tumors, accompanied by independent prognostic significance for overall and cancer-specific survival. In contrast, otoferlin protein expression was downregulated in tumor tissue. Although, high otoferlin expression in clear cell renal cell carcinoma was positively correlated with histological grading and independently predictive of a shortened progression-free survival. CONCLUSION: Our data suggest otoferlin as an indicator of tumor aggressiveness and as a prognostic biomarker for patients with clear cell renal cell carcinoma, leading to the conclusion that otoferlin could promote the malignancy of clear cell renal cell carcinoma.

Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplantation.

Late allocation of organs for transplant impairs post-liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow-up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child-Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child-Pugh C, was an independent predictor of reduced transplant-free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post-LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post-LT mortality. Liver Transplantation 24 15-25 2018 AASLD.

Urology consultants versus large language models: Potentials and hazards for medical advice in urology.

Background: Current interest surrounding large language models (LLMs) will lead to an increase in their use for medical advice. Although LLMs offer huge potential, they also pose potential misinformation hazards. Objective: This study evaluates three LLMs answering urology-themed clinical case-based questions by comparing the quality of answers to those provided by urology consultants. Methods: Forty-five case-based questions were answered by consultants and LLMs (ChatGPT 3.5, ChatGPT 4, Bard). Answers were blindly rated using a six-step Likert scale by four consultants in the categories: 'medical adequacy', 'conciseness', 'coherence' and 'comprehensibility'. Possible misinformation hazards were identified; a modified Turing test was included, and the character count was matched. Results: Higher ratings in every category were recorded for the consultants. LLMs' overall performance in language-focused categories (coherence and comprehensibility) was relatively high. Medical adequacy was significantly poorer compared with the consultants. Possible misinformation hazards were identified in 2.8% to 18.9% of answers generated by LLMs compared with <1% of consultant's answers. Poorer conciseness rates and a higher character count were provided by LLMs. Among individual LLMs, ChatGPT 4 performed best in medical accuracy (p < 0.0001) and coherence (p = 0.001), whereas Bard received the lowest scores. Generated responses were accurately associated with their source with 98% accuracy in LLMs and 99% with consultants. Conclusions: The quality of consultant answers was superior to LLMs in all categories. High semantic scores for LLM answers were found; however, the lack of medical accuracy led to potential misinformation hazards from LLM 'consultations'. Further investigations are necessary for new generations.

Delayed symptomatic renal arteriovenous fistula in a 24 years old male following renal biopsy.

We report a case of a 24-year-old male with a history of kidney biopsy at young age due to chronic renal dysfunction and challenging hypertension, who presented with flank pain and hematuria. Initial imaging suggested renal pelvis enlargement, but MRI revealed a massive renal arteriovenous malformation (AVM). Angiographic embolization was abandoned due to extensive effluent flow, followed by successful surgical resection preserving healthy kidney tissue. This case underscores the importance of considering renal AVMs in the differential diagnosis of young patients with gross hematuria or refractory hypertension to prevent complications and improve patient outcomes.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer.

PURPOSE: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. MATERIAL AND METHODS: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. RESULTS: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). CONCLUSION: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

High serum sodium predicts immunotherapy response in metastatic renal cell and urothelial carcinoma.

OBJECTIVES: The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. METHODS: We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. RESULTS: We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. CONCLUSIONS: Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities.

Ring Finger Protein 34 (RNF34) as a Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ring finger proteins play pivotal roles in diverse cellular processes and are implicated in contribution to cancer. Ring finger protein 34 (RNF34) has antiapoptotic and oncogenic properties. RNF34 is upregulated during carcinogenesis and tumor progression in the colorectal adenoma-carcinoma sequence and was already described to mediate chemoresistance. In clear cell renal cell carcinoma (ccRCC), however, the role and expression patterns of RNF34 are unknown. METHODS: First, we investigated the association of RNF34 mRNA expression with clinicopathological parameters and survival using data obtained from The Cancer Genome Atlas (TCGA) ccRCC cohort (N = 533). To assess RNA34 protein expression, we performed immunohistochemical (IHC) staining of an established ccRCC cohort (University of Bonn) in a tissue microarray (TMA) format. This validation cohort contains 109 primary ccRCC samples. IHC data were associated with clinicopathological parameters and overall survival (Kaplan-Meier analysis). Adjustment for covariables was done using the Cox regression model. RESULTS: RNF34 expression is correlated with adverse clinicopathological parameters. Survival analysis revealed an association between RNF34 expression and shortened survival. Cox regression analysis confirmed RNF34 expression as an independent prognostic parameter. CONCLUSION: Our study provides evidence for RNF34 as a prognostic biomarker in ccRCC and points toward a major role of this protein in renal cell carcinoma carcinogenesis.

Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution.

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology-driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88-97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23-69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of "stroma-rich tumors" is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. PATIENT SUMMARY: Urothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.

First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

A Bayesian inversion for emissions and export productivity across the end-Cretaceous boundary.

The end-Cretaceous mass extinction was marked by both the Chicxulub impact and the ongoing emplacement of the Deccan Traps flood basalt province. To understand the mechanism of extinction, we must disentangle the timing, duration, and intensity of volcanic and meteoritic environmental forcings. In this study, we used a parallel Markov chain Monte Carlo approach to invert for carbon dioxide (CO2) and sulfur dioxide (SO2) emissions, export productivity, and remineralization from 67 to 65 million years ago using the LOSCAR (Long-term Ocean-atmosphere-Sediment CArbon cycle Reservoir) model. Our results closely match observed and proxy data and suggest decoupled CO2 and SO2 emissions, a two-step decline in export productivity with a protracted recovery, and no clear volatile impulse at the boundary. More broadly, our methods provide a potential path forward for efficient parallel inversion of complex Earth system models.

Identification of F-Box/SPRY Domain-Containing Protein 1 (FBXO45) as a Prognostic Biomarker for TMPRSS2-ERG-Positive Primary Prostate Cancers.

BACKGROUND: F-box/SPRY domain-containing protein 1 (FBXO45) plays a crucial role in the regulation of apoptosis via the ubiquitylation and degradation of specific targets. Recent studies indicate the prognostic potential of FBXO45 in several cancers. However, its specific role in prostate carcinoma remains unclear. METHODS: A systematic analysis of FBXO45 mRNA expression in PCA was performed using The Cancer Genome Atlas database and a publicly available Gene Expression Omnibus progression PCA cohort. Subsequently, FBXO45 protein expression was assessed via immunohistochemical analysis of a comprehensive tissue microarray cohort. The expression data were correlated with the clinicopathological parameters and biochemical-free survival. The immunohistochemical analyses were stratified according to the TMPRSS2-ERG rearrangement status. To assess the impact of FBXO45 knockdown on the tumour proliferation capacity of cells and metastatic potential, transfection with antisense-oligonucleotides was conducted within a cell culture model. RESULTS: FBXO45 mRNA expression was associated with adverse clinicopathological parameters in the TCGA cohort and was enhanced throughout progression to distant metastasis. FBXO45 was associated with shortened biochemical-free survival, which was pronounced for the TMPRSS2-ERG-positive tumours. In vitro, FBXO45 knockdown led to a significant reduction in migration capacity in the PC3, DU145 and LNCaP cell cultures. CONCLUSIONS: Comprehensive expression analysis and functional data suggest FBXO45 as a prognostic biomarker in PCA.

Early CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: an updated multicentre real-world experience applying different CRP kinetics definitions.

Objectives: Although biomarkers predicting therapy response in first-line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world first-line mRCC cohort. Methods: Metastatic renal carcinoma patients treated with IO-based first-line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as 'CRP flare-responder', 'CRP responder' and 'non-CRP responder'; according to Ishihara et al., patients were defined as 'normal', 'normalised' and 'non-normalised' based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non-normalised group. Conclusion: Different early CRP kinetics may predict therapy response in first-line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Is Vesicostomy Still a Contemporary Method of Managing Posterior Urethral Valves?

In boys with posterior urethral valves (PUVs) the main treatment aim is to preserve long-term bladder and renal function. To determine the effectiveness of secondary vesicostomy in boys with PUVs, the medical records of 21 patients with PUV (2010-2019), divided into two groups (group I: valve ablation; group II: secondary vesicostomy), were reviewed regarding the course of serum creatinine, renal ultrasound, voiding cystourethrogram, urodynamics, postoperative complications, need of further surgery, and long-term solution. The median age of all patients at first follow-up was 11 (9-13) months and at last follow-up 64.5 (39.5-102.5) months. Despite a significant difference of the SWDR score (shape, wall, reflux, and diverticula) (p = 0.014), both groups showed no significant differences preoperatively. Postoperatively, serum creatinine (p = 0.024), grade of vesicoureteral reflux (p = 0.003), side of upper tract dilatation (p = 0.006), side of megaureter (p = 0.004), and SWDR score (p = 0.002) were significantly decreased in group II. Postoperative urodynamic measurements showed comparable results in both groups. Stoma complications were found in three (20%) patients (group II). Eight (53.3%) patients already received a closure of the vesicostomy. Seven out of eight (87.5%) patients were able to micturate spontaneously. Vesicostomy remains a reliable treatment option for boys with PUV to improve bladder function and avoid further damage to the urinary tract.

[Trampolining-induced gross hematuria : Unmasking the nutcracker syndrome]. / Trampolinspringen-induzierte Makrohämaturie : Das demaskierte Nussknackersyndrom.

The case of a 12-year-old boy with sports-induced recurrent macrohematuria and left-sided flank pain is reported. After extensive laboratory and imaging diagnostics, the diagnosis of nutcracker syndrome is made based on the characteristic clinical manifestation. Under a conservative approach and abstention from the triggering sport, a clinical as well as image-morphologically confirmed maturation occurred.

Evolution of AquablationVR-From innovation to establishment.

Technological progress is continuously improving medical care. The urological profession is well-known for further development of technical innovations and quick transfer into daily practice. Robot-assisted surgery, for example, has been part of the clinical routine in modern urological clinics for many years. In the endourological field, the implementation and further evolution of laser-based procedures have dominated research in the last decade. Recently, in 2015, the presentation of a new robot-assisted technique of waterjet-based ablation of prostate tissue raised attention in the society-the AquablationVR therapy. Aquablation therapy has been investigated within several randomized and controlled clinical trials, and-with growing experience- the technique has been modified over recent years to improve the safety of the procedure. Due to the clinical outcome, the number of hospitals performing Aquablation therapy is increasing continuously. This article provides an overview of the technique, its modifications, and the current status of evidence.

Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells.

Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib's ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-triggered apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients.

The geometry of multi-marginal Skorokhod Embedding.

The Skorokhod Embedding Problem is one of the classical problems in the theory of stochastic processes, with applications in many different fields [cf.  the surveys (Hobson in: Paris-Princeton lectures on mathematical finance 2010, Volume 2003 of Lecture Notes in Mathematics, Springer, Berlin, 2011; Oblój in: Probab Surv 1:321-390, 2004)]. Many of these applications have natural multi-marginal extensions leading to the (optimal) multi-marginal Skorokhod problem. Some of the first papers to consider this problem are Brown et al. (Probab Theory Relat Fields 119(4):558-578, 2001), Hobson (Séminaire de Probabilités, XXXII, Volume 1686 of Lecture Notes in Mathematics, Springer, Berlin, 1998), Madan and Yor (Bernoulli 8(4):509-536, 2002). However, this turns out to be difficult using existing techniques: only recently a complete solution was be obtained in Cox et al. (Probab Theory Relat Fields 173:211-259, 2018) establishing an extension of the Root construction, while other instances are only partially answered or remain wide open. In this paper, we extend the theory developed in Beiglböck et al. (Invent Math 208(2):327-400, 2017) to the multi-marginal setup which is comparable to the extension of the optimal transport problem to the multi-marginal optimal transport problem. As for the one-marginal case, this viewpoint turns out to be very powerful. In particular, we are able to show that all classical optimal embeddings have natural multi-marginal counterparts. Notably these different constructions are linked through a joint geometric structure and the classical solutions are recovered as particular cases. Moreover, our results also have consequences for the study of the martingale transport problem as well as the peacock problem.

Foundations for a Realism-Based Ontology of Protein Aggregates.

The objective of this paper is to propose formal definitions for the terms 'protein aggregate' and 'protein-containing complex' such that the descriptions and usages of these terms in biomedical literature are unified and that those portions of reality are correctly represented. To this end, we surveyed the literature to assess the need for a distinction between these entities, then compared the features of usages and definitions found in the literature to the definitions for those terms found in Bioportal ontologies. Based on the results of this comparison, we propose updated definitions for the terms 'protein aggregate' and 'protein-containing complex'. Thus far, we propose the following distinguishing factors: first, that one important difference lies in whether an entity is disposed to change type in response to certain structural alterations, such as dissociation of a continuant part, and second that an important difference lies in the ability of the entity to realize its function after such an event occurs. These distinctions are reflected in the proposed definitions.

Knockdown of Myoferlin Suppresses Migration and Invasion in Clear-Cell Renal-Cell Carcinoma.

BACKGROUND/AIM: Myoferlin (MYOF) has emerged as an oncogenic protein in various human cancer types. This study was conducted to investigate comprehensively the expression and functional properties of MYOF in clear-cell renal-cell carcinoma (ccRCC) with respect to its value as diagnostic biomarker and therapeutic target. MATERIALS AND METHODS: mRNA and protein expression of MYOF were assessed by quantitative polymerase chain reaction and immunohistochemistry. siRNA-mediated knockdown of MYOF was performed in the RCC cell line ACHN followed by proliferation, migration and invasion assays. RESULTS: MYOF mRNA and protein expression were significantly up-regulated in ccRCC. Higher mRNA levels were measured in advanced tumors. MYOF protein expression was increased in tumors with higher histological grades, and those with positive lymph node and surgical margin status. MYOF knockdown led to reduction of migration and invasion in ACHN cells, whereas expression of angiogenesis-associated genes tyrosine-protein kinase receptor-2 (TIE2), angiopoietin 2 (ANG2) and caveolin-1 (CAV1) was up-regulated following knockdown. CONCLUSION: MYOF may serve as a diagnostic biomarker of tumor progression and a potential therapeutic target in ccRCC.