ctDNA predicts clinical T1a to pathological T3a upstaging after partial nephrectomy.

Most patients diagnosed with clear cell renal cell carcinoma (ccRCC) are also detected with small and organ-confined tumors, and the majority of these are classified as clinical tumor stage 1a (cT1a). A considerable proportion of patients with cT1 RCC shows tumor upstaging to pathological stage 3a (pT3a), and these patients have worse oncological outcomes. The role of circulating tumor DNA (ctDNA) in RCC has been limited to monitoring treatment response and resistance. Therefore, the present study aimed to evaluate the potential of ctDNA in predicting pT3a upstaging in cT1a ccRCC. We sequenced plasma samples preoperatively collected from 48 patients who had undergone partial nephrectomy for cT1a ccRCC using data from a prospective cohort RCC. The ctDNA were profiled and compared with clinicopathological ccRCC features to predict pT3a upstaging. Associations between ctDNA, tumor complexity, and pT3a upstaging were evaluated. Tumor complexity was assessed using the anatomical classification system. Univariate analysis used chi-squared and Student's t-tests; multivariate analysis considered significant factors from univariate analyses. Of the 48 patients with cT1a ccRCC, 12 (25%) were upstaged to pT3a, with ctDNA detected in 10 (20.8%), predominantly in patients with renal sinus fat invasion (SFI; n = 8). Among the pT3a group, ctDNA was detected in 75%, contrasting with only 2.8% in patients with pT1a (1/36). Detection of ctDNA was the only significant preoperative predictor of pT3a upstaging, especially in SFI. This study is the first to suggest ctDNA as a preoperative predictor of pT3a RCC upstaging from cT1a based on preoperative radiological images.

Role of Maximal Transurethral Resection Preceding Partial Cystectomy for Muscle-Invasive Bladder Cancer.

PURPOSE: We aimed to evaluate whether maximal transurethral resection (TUR) affects the oncological outcome of partial cystectomy (PC) performed in patients with muscle-invasive bladder cancer (MIBC), although radical cystectomy (RC) and trimodal therapy (TMT) are regarded as standard treatments for MIBC. METHODS: In this retrospective study, we evaluated the data of 98 patients who underwent PC due to MIBC between January 2006 and December 2018. Of the 98 patients, 71 underwent maximal TUR. We evaluated the recurrence-free survival (PFS), pelvic recurrence-free survival (pPFS), cancer-specific survival (CSS), and overall survival (OS) using the Kaplan-Meier method according to the maximal TUR status. Variables associated with survival were analyzed using Cox regression analyses. RESULTS: The 5-year PFS (42.5% vs. 20.3%, p = 0.008), pPFS (50.7% vs. 24.1%, p = 0.003), and CSS (74.0% vs. 51.0%, p = 0.016) were also higher in patients who underwent maximal TUR. The multivariable Cox regression analysis showed that maximal TUR was associated with PFS (hazard ratio [HR] = 0.500, p = 0.029), pPFS (HR = 0.353, p = 0.004), and CSS (HR = 0.416, p = 0.027). However, maximal TUR did not affect the OS (HR = 0.618, p = 0.132). CONCLUSION: PC resulted in acceptable oncological outcomes in patients with MIBC, while maximal TUR played an important role in improving the oncological outcomes. PC after maximal TUR can be suggested as a treatment option for MIBC patients who are unable to undergo RC and TMT.

PD-1 inhibitor plus oncolytic vaccinia virus is a safe and effective treatment option for metastatic renal cell carcinoma.

BACKGROUND: Although a combination of immune checkpoint inhibitors (ICIs) is recommended as the first line treatment option for metastatic renal cell carcinoma (mRCC), several immune-related adverse events (irAEs) occur, especially hepatitis. We explored the therapeutic benefits and safety profile of combining oncolytic vaccinia virus, JX-594, with a programmed cell death protein-1 (PD-1) inhibitor. METHODS: We used early-stage and advanced-stage orthotopic murine mRCC models developed by our group. PD-1 inhibitor monotherapy or a PD-1 inhibitor combined with either JX-594 or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor were systemically injected through the peritoneum. An immunofluorescence analysis was performed to analyze the tumor immune microenvironment (TIME). irAEs were assessed in terms of hepatitis. RESULTS: In the early-stage mRCC model mice, the combination of JX-594 and a PD-1 inhibitor significantly decreased the primary tumor size and number of lung nodules, compared with the ICI combination, but the JX-594 and PD-1 inhibitor combination and ICI combination did not differ significantly in the advanced-stage mRCC model mice. The JX-594 and PD-1 inhibitor combination induced tumor-suppressing TIME changes in both the early- and advanced-stage mRCC models. Furthermore, mice treated with the ICI combination had significantly greater hepatic injuries than those treated with the JX-594 and PD-1 inhibitor combination which was evaluated in early-stage mRCC model. CONCLUSIONS: The JX-594 and PD-1 inhibitor combination effectively reduced primary tumors and the metastatic burden, similar to ICI combination therapy, through dynamic remodeling of the TIME. Furthermore, hepatitis was significantly decreased in the JX-594 and PD-1 inhibitor combination group, suggesting the potential benefit of that combination for reducing ICI-induced toxicity.

A Color-Tunable Alternating Current Organic Light Emitting Capacitor.

We demonstrate an alternating current (AC) driven light emitting capacitor in which the color of the emission spectra can be changed via an applied AC frequency. The device has a simple metal-oxide-semiconductor (MOS) capacitor structure with an organic emissive layer, enabling facile fabrication processing. The organic emissive layer comprises a thin, submonolayer low energy dye layer underneath a thick host matrix (∼30 nm) with higher energy emitting dyes. The emission of the lower energy dyes dominates at low frequency, while the higher energy emission of the host matrix dominates at high frequency. This simple color tunable device could be used for full-color displays and lighting in the future.

Gate Controlled Excitonic Emission in Quantum Dot Thin Films.

Formation of charged trions is detrimental to the luminescence quantum efficiency of colloidal quantum dot (QD) thin films as they predominantly undergo nonradiative recombination. In this regard, control of charged trion formation is of interest for both fundamental characterization of the quasi-particles and performance optimization. Using CdSe/CdS QDs as a prototypical material system, here we demonstrate a metal-oxide-semiconductor capacitor based on QD thin films for studying the background charge effect on the luminescence efficiency and lifetime. The concentration ratio of the charged and neutral quasiparticles in the QDs is reversibly controlled by applying a gate voltage, while simultaneous steady-state and time-resolved photoluminescence measurements are performed. Notably, the photoluminescence intensity is modulated by up to 2 orders of magnitude with a corresponding change in the effective lifetime. In addition, chip-scale modulation of brightness is demonstrated, where the photoluminescence is effectively turned on and off by the gate, highlighting potential applications in voltage-controlled electrochromics.

Pharmaceutical and Immunological Evaluation of Cholera Toxin A1 Subunit as an Adjuvant of Hepatitis B Vaccine Microneedles.

PURPOSE: For successful delivery of a solid vaccine formulation into the skin using microneedles, the solubility of an adjuvant should be considered because the decrease in the dissolution rate by the addition of adjuvant decreases the delivery efficiency of the vaccine. METHODS: In this study, cholera toxin A subunit 1 (CTA1) was examined as an adjuvant to Hepatitis B vaccine (HBV) microneedles because of its good water solubility, improved safety, and positive effect as shown in intramuscular administration of a liquid vaccine. RESULTS: All solid formulations with CTA 1 dissolved in in vivo mouse skin within 30 min, and they were successfully delivered into the skin. In experiments with mice, the addition of CTA1 led to improved IgG immune response compared to the use of an aluminum hydroxide-based formulation and intramuscular administration of HBV. In addition, CTA1 induced CD8 + T cell response as much as in which the aluminum hydroxide-based formulation induced. CONCLUSIONS: CTA1 is an adjuvant that satisfies both the delivery efficiency and the immunological characteristics required for vaccine microneedles. CTA1 will be used as a potential adjuvant through vaccine microneedles.

Role of Temperature-Dependent Interfacial Tension on Shear Wave Velocity for Energy Geosystems.

Interfacial tension varies with temperature. This paper investigates the effects of temperature-dependent interfacial tension on shear wave velocity. We designed a nylon cell equipped with bender elements in a cross-hole configuration to measure the shear wave velocity of nine sand-silt mixtures with different degrees of saturation (S = 0%, 2.5%, 5%, 10%, and 100%). All specimens were subjected to a temperature change from 10 °C to 1 °C. The results demonstrate that shear wave velocity tends to be very sensitive to changes in temperature at a low degree of saturation. Particle-scale analyses overlapped with the experimental results and captured the critical role of temperature-dependent interfacial tension in small-strain skeletal stiffness. In fact, the temperature should be considered during laboratory and field shear modulus measurements of the long-term performance of energy geosystems subjected to thermally induced repetitive loads.

The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis.

Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely 'hijacked' by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA-protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.

In silico analysis of differentially expressed genesets in metastatic breast cancer identifies potential prognostic biomarkers.

BACKGROUND: Identification of specific biological functions, pathways, and appropriate prognostic biomarkers is essential to accurately predict the clinical outcomes of and apply efficient treatment for breast cancer patients. METHODS: To search for metastatic breast cancer-specific biological functions, pathways, and novel biomarkers in breast cancer, gene expression datasets of metastatic breast cancer were obtained from Oncomine, an online data mining platform. Over- and under-expressed genesets were collected and the differentially expressed genes were screened from four datasets with large sample sizes (N > 200). They were analyzed for gene ontology (GO), KEGG pathway, protein-protein interaction, and hub gene analyses using online bioinformatic tools (Enrichr, STRING, and Cytoscape) to find enriched functions and pathways in metastatic breast cancer. To identify novel prognostic biomarkers in breast cancer, differentially expressed genes were screened from the entire twelve datasets with any sample sizes and tested for expression correlation and survival analyses using online tools such as KM plotter and bc-GenExMiner. RESULTS: Compared to non-metastatic breast cancer, 193 and 144 genes were differentially over- and under-expressed in metastatic breast cancer, respectively, and they were significantly enriched in regulating cell death, epidermal growth factor receptor signaling, and membrane and cytoskeletal structures according to the GO analyses. In addition, genes involved in progesterone- and estrogen-related signalings were enriched according to KEGG pathway analyses. Hub genes were identified via protein-protein interaction network analysis. Moreover, four differentially over-expressed (CCNA2, CENPN, DEPDC1, and TTK) and three differentially under-expressed genes (ABAT, LRIG1, and PGR) were further identified as novel biomarker candidate genes from the entire twelve datasets. Over- and under-expressed biomarker candidate genes were positively and negatively correlated with the aggressive and metastatic nature of breast cancer and were associated with poor and good prognosis of breast cancer patients, respectively. CONCLUSIONS: Transcriptome datasets of metastatic breast cancer obtained from Oncomine allow the identification of metastatic breast cancer-specific biological functions, pathways, and novel biomarkers to predict clinical outcomes of breast cancer patients. Further functional studies are needed to warrant validation of their roles as functional tumor-promoting or tumor-suppressing genes.

Evaluation of Thawing and Stress Restoration Method for Artificial Frozen Sandy Soils Using Sensors.

Undisturbed frozen samples can be efficiently obtained using the artificial ground freezing method. Thereafter, the restoration of in situ conditions, such as stress and density after thawing, is critical for laboratory testing. This study aims to experimentally explore the effects of thawing and the in situ stress restoration process on the geomechanical properties of sandy soils. Specimens were prepared at a relative density of 60% and frozen at -20 °C under the vertical stress of 100 kPa. After freezing, the specimens placed in the triaxial cell underwent thawing and consolidation phases with various drainage and confining stress conditions, followed by the shear phase. The elastic wave signals and axial deformation were measured during the entire protocol; the shear strength was evaluated from the triaxial compression test. Monotonic and cyclic simple shear tests were conducted to determine the packing density effect on liquefaction resistance. The results show that axial deformation, stiffness, and strength are minimized for a specimen undergoing drained thawing, restoring the initial stress during the consolidation phase, and that denser specimens are less susceptible to liquefaction. Results highlight that the thawing and stress restoration process should be considered to prevent the overestimation of stiffness, strength, and liquefaction resistance of sandy soils.

Evolution of Small Strain Soil Stiffness during Freeze-Thaw Cycle: Transition from Capillarity to Cementation Examined Using Magnetic and Piezo Crystal Sensors.

Freeze-thaw cycles caused by seasonal temperature fluctuations significantly affect the geotechnical engineering properties. This study investigated the crucial role of water distribution patterns in the characterization of elastic wave properties for the fine F-110 sand during a freeze-thaw cycle. Sand specimens with four different water distribution patterns were prepared, namely homogeneously-mixed, evaporation-driven, vertically-, and horizontally-layered specimens. The P- and S-wave signatures of the specimens were monitored using piezo crystal sensors. Results indicated the criticality of water distribution patterns in the determination of small-strain soil properties even though the specimens had identical global water saturation. The nuclear magnetic resonance-based water volume depth profiles indicated that the evaporation-driven specimens had more heterogeneous pore-invasive ice-bonding layers at a high water saturation region; by contrast, the drying process facilitated uniform meniscuses around the particle contacts near the air percolation threshold. Elastic wave measurements for laboratory-prepared specimens might over/underestimate the small-strain soil stiffness of sediments in nature, wherein the drying processes prevailed to control the water saturation. This study highlighted a clear transition from capillary-controlled to cementation-controlled elastic wave properties during temperature oscillations.

Nanoscale Mapping of Morphology of Organic Thin Films.

We determine precise nanoscale information about the morphologies of several organic thin film structures using Fourier plane imaging microscopy (FIM). We used FIM microscopy to detect the orientation of molecular transition dipole moments from an extremely low density of luminescent dye molecules, which we call "morphology sensors". The orientation of the sensor molecules is driven by the local film structure and thus can be used to determine details of the host morphology without influencing it. We use symmetric planar phosphorescent dye molecules as the sensors that are deposited into the bulk of organic film hosts during the growth. We demonstrate morphological mapping with a depth resolution to a few Ångstroms that is limited by the ability to determine thickness during deposition, along with an in-plane resolution limited by optical diffraction. Furthermore, we monitor morphological changes arising from thermal annealing of metastable organic films that are commonly employed in photonic devices.

Complementary Hybrid Semiconducting Superlattices with Multiple Channels and Mutual Stabilization.

An organic-inorganic hybrid superlattice with near perfect synergistic integration of organic and inorganic constituents was developed to produce properties vastly superior to those of either moiety alone. The complementary hybrid superlattice is composed of multiple quantum wells of 4-mercaptophenol organic monolayers and amorphous ZnO nanolayers. Within the superlattice, multichannel formation was demonstrated at the organic-inorganic interfaces to produce an excellent-performance field effect transistor exhibiting outstanding field-effect mobility with band-like transport and steep subthreshold swing. Furthermore, mutual stabilizations between organic monolayers and ZnO effectively reduced the performance degradation notorious in exclusively organic and ZnO transistors.

OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase.

Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene CKS2 encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.

Tumor suppressive function of Matrin 3 in the basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

MicroRNAs and metastasis: small RNAs play big roles.

MicroRNAs (miRNAs) are small non-coding RNAs regulating post-transcriptional gene expression. They play important roles in many biological processes under physiological or pathological conditions, including development, metabolism, tumorigenesis, metastasis, and immune response. Over the past 15 years, significant insights have been gained into the roles of miRNAs in cancer. Depending on the cancer type, miRNAs can act as oncogenes, tumor suppressors, or metastasis regulators. In this review, we focus on the role of miRNAs as components of molecular networks regulating metastasis. These miRNAs, termed metastamiRs, promote or inhibit metastasis through various mechanisms, including regulation of migration, invasion, colonization, cancer stem cell properties, epithelial-mesenchymal transition, and microenvironment. Some of these metastamiRs represent attractive therapeutic targets for cancer treatment.

The prognostic impact of downgrading and upgrading from biopsy to radical prostatectomy among men with Gleason score 7 prostate cancer.

BACKGROUND: Recently, a new prostate cancer (PC) grading system was introduced, where Gleason score (GS) 7 was divided into 3 + 4 = 7 and 4 + 3 = 7 due to the different prognoses associated with each tumor type. However, whether downgrading or upgrading from needle biopsy (NB) to radical prostatectomy (RP) affects oncologic outcomes is currently unknown. Herein, we investigated the prognostic impact of downgrading and upgrading from NB to RP among men with GS 7 PC. METHODS: We retrospectively reviewed the medical records of 3003 patients with localized PC who underwent RP between 2005 and 2014. We included 692 patients with GS 7 PC on both NB and RP specimens. We analyzed the data using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Of the 692 patients enrolled in this study, 389 (56.2%) and 303 (43.8%) patients had RP GS 3 + 4 = 7 and RP GS 4 + 3 = 7 PC, respectively. On the basis of NB and RP GS, 264 (38.1%), 125 (18.1%), 142 (20.5%), and 161 (23.3%) patients were classified as 3 + 4/3 + 4, 4 + 3/3 + 4, 3 + 4/4 + 3, and 4 + 3/4 + 3, respectively. Kaplan-Meier curves showed significant differences in biochemical recurrence (BCR)-free survival across the groups (P < .001). In the multivariate analyses, these groups were significantly associated with BCR (4 + 3/3 + 4: hazard ratio [HR], 1.675; 3 + 4/4 + 3: HR, 1.908; and 4 + 3/4 + 3: HR, 2.699). CONCLUSIONS: Downgrading and upgrading from NB to RP was an independent predictor of BCR in men with GS 7 PC, which could be due to the amount of Gleason pattern 4.

Assessing the anatomical characteristics of renal masses has a limited effect on the prediction of pathological outcomes in solid, enhancing, small renal masses: results using the PADUA classification system.

OBJECTIVE: To evaluate whether assessing the anatomical characteristics of renal masses increases the accuracy of prediction of tumour pathology in small renal masses (SRMs). PATIENTS AND METHODS: We retrospectively reviewed 1129 consecutive patients who underwent extirpative surgeries for a clinical T1 renal mass, for which the preoperative aspects and dimensions used for an anatomical (PADUA) classification were available. Multivariate logistic regression analyses of demographic and anatomical characteristics were performed. Nomograms to predict malignancy and high grade pathology were constructed using a basic model (age, sex and tumour size), and an extended model (anatomical characteristics incorporated into the basic model), and the area under the curve (AUC) between models was compared. RESULTS: Age, sex and tumour size were significantly associated with malignancy and high grade pathology in the T1 and T1a category (except sex for high grade pathology in T1a tumours). Exophytic rate (T1 and T1a) and renal sinus or urinary collecting system involvement (only T1a) were also significant predictors of high grade pathology. Nomograms using the extended model for malignancy showed an insignificant AUC increase compared with those using the basic model (T1, from 0.771 to 0.780, P = 0.149, and T1a, from 0.803 to 0.819, P = 0.055). For high grade pathology, the extended model achieved a significant AUC increase (from 0.595 to 0.643, P = 0.014) in the T1a category, but the AUC for both T1 and T1a tumours showed merely modest competence (0.654 and 0.643, respectively). CONCLUSION: Age, sex and tumour size are the primary predictors of tumour pathology of SRMs, and incorporating other anatomical characteristics has only a limited positive effect on the accuracy of prediction of pathological outcomes.

External validation of the RENAL nephrometry score nomogram for predicting high-grade renal cell carcinoma in solid, enhancing, and small renal masses.

PURPOSE: To confirm predictive accuracies of the RENAL nephrometry score (RNS) nomogram for identifying malignancy and high-grade renal cell carcinoma (RCC) in an external cohort of small renal masses (SRMs). METHODS: A total of 1,129 patients who underwent extirpative renal surgery for solid and enhancing cT1 renal tumors between 2005 and 2012 at a single institution were included in the validation cohort. A single uro-radiologist utilized computed tomography image reconstruction to classify tumors according to the RNS. The area under the curve (AUC) and calibration plots were used to determine predictive accuracies of malignancy and high-grade models of the RNS nomogram. RESULTS: Malignant and high-grade tumors were identified in 1,012 (89.6%) and 389 (38.4%) patients with cT1 tumors, and in 658 (87.3%) and 215 (32.6%) patients with cT1a tumors, respectively. Predictive performances of the nomogram for malignancy and high-grade models revealed AUCs of 0.722 and 0.574 for cT1 tumors, and 0.727 and 0.495 for cT1a tumors, respectively. The predictive value of the malignancy model was comparable to that of the model-development cohort (AUC = 0.76); however, the predictive value of the high-grade model was inferior to that of the model-development cohort (AUC = 0.73). CONCLUSIONS: Unlike previous validation studies, we report inferior predictive performance of the RNS nomogram for discriminating high-grade RCC in solid and enhancing SRMs. This suggests that the RNS nomogram may be unreliable for preoperatively predicting high-grade RCC in SRMs, in which tumor size, the key determinant of high-grade RCC, is a limiting factor.

OTUD6A orchestrates complex modulation of TEAD4-mediated transcriptional programs.

TEAD transcription factors play a central role in the Hippo signaling pathway. In this study, we focused on transcriptional enhancer factor TEF-3 (TEAD4), exploring its regulation by the deubiquitinase OTU domain-containing protein 6A (OTUD6A). We identified OTUD6A as a TEAD4-interacting deubiquitinase, positively influencing TEAD-driven transcription without altering TEAD4 stability. Structural analyses revealed specific interaction domains: the N-terminal domain of OTUD6A and the YAP-binding domain of TEAD4. Functional assays demonstrated the positive impact of OTUD6A on the transcription of YAP-TEAD target genes. Despite no impact on TEAD4 nuclear localization, OTUD6A selectively modulated nuclear interactions, enhancing YAP-TEAD4 complex formation while suppressing VGLL4 (transcription cofactor vestigial-like protein 4)-TEAD4 interaction. Critically, OTUD6A facilitated YAP-TEAD4 complex binding to target gene promoters. Our study unveils the regulatory landscape of OTUD6A on TEAD4, providing insights into diseases regulated by YAP-TEAD complexes.