Hippo-signaling-controlled MHC class I antigen processing and presentation pathway potentiates antitumor immunity.

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody-drug conjugates.

Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss via a reverse Michael reaction, leading to premature drug release in vivo. Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC. However, we discovered through previous work that hydrolysed succinimide rings can close again in a liquid formulation during storage and under thermal stress conditions. In this work, a set of maleimide linkers with hydrolysis-prone groups were designed. The corresponding ADCs were prepared and subjected to thermal stress conditions. The extent of succinimide hydrolysis and drug release was measured, and ADC properties such as SEC, DAR, pI and clog P of linkers were calculated. Our results demonstrated that even though all these groups increased the hydrolysis rate, they have different impacts on maintaining the hydrolysed succinimide ring in an open conformation and ADC stability in a liquid formulation.

Identification of the hub genes linked to zearalenone-induced hepatotoxicity in broiler chickens.

Zearalenone (ZEN) is a mycotoxin found in food and feed that impairs the function of multiple organs, especially the liver. However, the specific mechanisms through which ZEN induces liver damage in broiler chickens are not well understood. Therefore, this study aimed to identify the key genes linked to the hepatotoxicity induced by ZEN exposure in broiler chickens. Gene expression data from ZEN-treated and control chicken embryo primary hepatocytes (CEPHs) were used to implement differential expression analysis. Totally, 436 differentially expressed genes (DEGs) were detected, in which 223 and 213 genes were up- and down-regulated in ZEN-treated CEPHs, respectively. Gene ontology analysis suggested that these DEGs were involved in various biological processes, including chromosome segregation, mitotic cytokinesis, mitotic cell cycle, cell division, and mitotic spindle organization. Pathway analysis showed that the DEGs were associated with p53, FoxO, ubiquitin-mediated proteolysis, cell cycle, and mismatch repair signaling pathways. Furthermore, the hub genes, including BRCA1, CDC45, CDCA3, CDKN3, CENPE, CENPF, CENPI, CENPM, CENPU, and CEP55, potentially contributed to ZEN-induced hepatotoxicity. In conclusion, our study provides the valuable insight into the mechanism underlying ZEN-induced hepatotoxicity in broiler chickens.

Impact of dipeptide on ADC physicochemical properties and efficacy identifies Ala-Ala as the optimal dipeptide.

Side chains of natural occurring amino acids vary greatly in terms of charge state, polarity, size and hydrophobicity. Using a linear synthetic route, two amino acids were sequentially coupled to a potent glucocorticoid receptor modulator (GRM) to afford a library of dipeptide-GRM linker payloads with a range of in silico properties. The linker payloads were conjugated to a mouse anti-TNF antibody through interchain disulfide Cys. Impact of various dipeptide linkers on ADC physical properties, including solubility, hydrophobicity, and aggregation were evaluated and the in silico properties pI, Log P and tPSA of the linker drugs used to correlate with these properties. ADCs were screened in a GRE luciferase reporter assay to compare their in vitro efficacy. Data identified Ala-Ala as a superior dipeptide linker that allowed a maximum drug load of 10 while affording ADCs with low aggregation.

Ant may well destroy a whole dam: glycans of colonic mucus barrier disintegrated by gut bacteria.

The colonic mucus layer plays a critical role in maintaining the integrity of the colonic mucosal barrier, serving as the primary defense against colonic microorganisms. Predominantly composed of mucin 2 (MUC2), a glycosylation-rich protein, the mucus layer forms a gel-like coating that covers the colonic epithelium surface. This layer provides a habitat for intestinal microorganisms, which can utilize mucin glycans present in the mucus layer as a sustainable source of nutrients. Additionally, metabolites produced by the microbiota during the metabolism of mucus glycans have a profound impact on host health. Under normal conditions, the production and consumption of mucus maintain a dynamic balance. However, several studies have demonstrated that certain factors, such as dietary fiber deficiency, can enhance the metabolism of mucus glycans by gut bacteria, thereby disturbing this balance and weakening the mucus barrier function of the mucus layer. To better understand the occurrence and development of colon-related diseases, it is crucial to investigate the complex metabolic patterns of mucus glycosylation by intestinal microorganisms. Our objective was to comprehensively review these patterns in order to clarify the effects of mucus layer glycan metabolism by intestinal microorganisms on the host.

Dynamic mechanical response of hot central plant recycling asphalt pavement considering the rutting deformation of existing structure: pollution reduction and durability promotion.

In the pavement industry, there is a pressing need for the reuse of recycled asphalt pavement (RAP) materials. However, the rutting deformation in existing pavement structures is often overlooked in the design of recycled asphalt pavement, which hinders long-term performance prediction and durability assessment. This study examined the viscoelastic properties and fatigue performance of recycled asphalt mixtures. Different combinations of surface layers with varying RAP contents and binder layers with different rutting damage levels were designed. A 3D-Move Analysis model was used to analyze the dynamic mechanical response of these structures under moving loads. Results showed that the stiffness of recycled asphalt mixture increased with the RAP content, but the fatigue performance decreased by 39.4% when the RAP content reached 50%. Incorporating 50% RAP in the surface layer can reduce the compressive stress caused by vehicle loading, thus reducing the vertical compression strain and permanent deformation of the asphalt layers and the subgrade. However, the surface layer with higher RAP content is exposed to intense alternating tensile and compressive strains, leading to poor fatigue durability. The dynamic mechanical behavior of recycled asphalt pavement structures was found to be significantly impacted by the characteristics of the binder layer. The lower dynamic modulus of the binder layer (e.g., 18 mm rutting depth) can lead to more deformation and an increased risk of fatigue cracking. Moreover, the dynamic performance of mixtures with 0% and 50% RAP in the surface layer is even more affected by changes in the binder layer properties. It is recommended to consider the design of dynamic modulus combinations of existing binder layer materials and surface materials with higher RAP, in order to increase the utilization of RAP for high-grade highways and improve the stress distribution to enhance their durability.

Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer.

ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

Multi-Omics Analysis Reveals Intricate Gene Networks Involved in Female Development in Melon.

Sexual differentiation is an important developmental phenomenon in cucurbits that directly affects fruit yield. The natural existence of multiple flower types in melon offers an inclusive structure for studying the molecular basis of sexual differentiation. The current study aimed to identify and characterize the molecular network involved in sex determination and female development in melon. Male and female pools separated by the F2 segregated generation were used for sequencing. The comparative multi-omics data revealed 551 DAPs and 594 DEGs involved in multiple pathways of melon growth and development, and based on functional annotation and enrichment analysis, we summarized four biological process modules, including ethylene biosynthesis, flower organ development, plant hormone signaling, and ubiquitinated protein metabolism, that are related to female development. Furthermore, the detailed analysis of the female developmental regulatory pathway model of ethylene biosynthesis, signal transduction, and target gene regulation identified some important candidates that might have a crucial role in female development. Two CMTs ((cytosine-5)-methyltransferase), one AdoHS (adenosylhomocysteinase), four ACSs (1-aminocyclopropane-1-carboxylic acid synthase), three ACOs (ACC oxidase), two ARFs (auxin response factor), four ARPs (auxin-responsive protein), and six ERFs (Ethylene responsive factor) were identified based on various female developmental regulatory models. Our data offer new and valuable insights into female development and hold the potential to offer a deeper comprehension of sex differentiation mechanisms in melon.

A specific phenotype of pouchitis was associated with worst prognosis in patients with ulcerative colitis according to Chicago classification.

BACKGROUND: The impact of different pouch phenotypes on long-term functional outcomes and quality of life (QoL) remains unclear. Our aim is to investigate the association between endoscopic pouchitis phenotypes and patients' long-term prognosis by assessing pouch function and QoL. METHODS: Pouchitis was classified into distinct phenotypes according to the Chicago Classification. Pouch function was assessed using the Pouch Functional Score (PFS), and QoL was evaluated using the Cleveland Global Quality of Life (CGQL) score. RESULTS: A total of 252 patients were enrolled in the study, with 78 patients diagnosed with pouchitis. According to the Chicago classification, 42 of these pouchitis patients exhibited an endoscopic phenotype characterized by a combination of diffuse inflammation of the pouch body, inlet involvement, and cuffitis, referred to as the Diffuse-Inlet-Cuffitis phenotype. Patients with pouchitis of the Diffuse-Inlet-Cuffitis phenotype showed significantly higher PFS (11.5 vs 5.5, p = 0.013) and lower CGQL scores (0.67 vs 0.7, p = 0.029) compared to those with other pouch phenotypes. Independent risk factors for this severe phenotype were identified as preoperative disease duration (OR = 1.062, 95% CI: 1.006-1.122, p = 0.030) and disease extent E3 (OR = 2.836, 95% CI: 1.052-7.644, p = 0.036). CONCLUSIONS: Our study suggested that pouchitis with the Diffuse-Inlet-Cuffitis endoscopic phenotype is common and seriously impairs the long-term prognosis in patients with UC after IPAA. The finding will be beneficial to the stratified management of patients with pouchitis.

Development and validation of two nomograms for predicting overall survival and Cancer-specific survival in prostate cancer patients with bone metastases: a population-based study.

BACKGROUND: Prostate cancer with bone metastasis has significant invasiveness and markedly poorer prognosis. The purpose of this study is to establish two nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of prostate cancer patients with bone metastasis. METHODS: From January 2000 to December 2018, a total of 2683 prostate adenocarcinoma with bone metastasis patients were identified from the Surveillance, Epidemiology, and End Results Program (SEER) database. These patients were then divided into a training cohort and a validation cohort, with OS and CSS as the study endpoints. Correlation analyses were employed to assess the relationship between variables. Univariate and multivariate Cox analyses were utilized to ascertain the independent prognostic factors. Calibration curves and the area under the time-dependent receiver operating characteristic curve (time-dependent AUC) were employed to evaluate discrimination and calibration of the nomogram. DCA was applied to examine accuracy and clinical benefits. The clinical utility of the nomogram and the AJCC Stage System was compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Lastly, the risk stratifications of the nomogram and the AJCC Stage System were compared. RESULTS: There was no collinearity among the variables that were screened. The results of multivariate Cox regression analysis showed that seven variables (age, surgery, brain metastasis, liver metastasis, lung metastasis, Gleason score, marital status) and six variables (age, surgery, lung metastasis, liver metastasis, Gleason score, marital status) were identified to establish the nomogram for OS and CSS, respectively. The calibration curves, time-dependent AUC curves, and DCA revealed that both nomograms had pleasant predictive power. Furthermore, NRI and IDI confirmed that the nomogram outperformed the AJCC Stage System. CONCLUSION: Both nomograms had satisfactory accuracy and were validated to assist clinicians in evaluating the prognosis of PABM patients.

Identification of the Hub Genes Linked to Lead (IV)-Induced Spleen Toxicity Using the Rat Model.

Exposure to lead (Pb) has harmful effects on the organs of both humans and animals, particularly the spleen. However, the precise mechanisms through which Pb (IV) exposure leads to spleen toxicity remain unclear. Hence, this study aimed to identify the key genes and signaling pathways involved in spleen toxicity caused by Pb (IV) incubation. We obtained the dataset GSE59925 from the Gene Expression Omnibus, which included spleen samples treated with lead tetraacetate (PbAc4) as well as control samples on the 1st and 5th day. Through differential expression analysis, we identified 607 and 704 differentially expressed genes (DEGs) in the spleens on the 1st and 5th day following PbAc4 treatment, respectively, with 245 overlapping DEGs between the two time points. Gene ontology analysis revealed that the commonly shared DEGs were primarily involved in signal transduction, drug response, cell proliferation, adhesion, and migration. Pathway analysis indicated that the common DEGs were primarily associated with MAPK, TNF, cAMP, Hippo, and TGF-ß signaling pathways. Furthermore, we identified the hub genes such as CXCL10, PARP1, APOE, and VDR contributing to PbAc4-induced spleen toxicity. This study enhances our understanding of the molecular mechanisms underlying Pb (IV) toxicity in the spleen.

A Two-Stage Automatic System for Detection of Interictal Epileptiform Discharges from Scalp Electroencephalograms.

The objective of this work was to develop a deep learning-based automatic system with reliable performance in detecting interictal epileptiform discharges (IEDs) from scalp electroencephalograms (EEGs). For the present study, 484 raw scalp EEG recordings were included, standardized, and split into 406 for training and 78 for testing. Two neurophysiologists individually annotated the recordings for training in channel-wise manner. Annotations were divided into segments, on which nine deep neural networks (DNNs) were trained for the multiclassification of IED, artifact, and background. The fitted IED detectors were then evaluated on 78 EEG recordings with IED events fully annotated by three experts independently (majority agreement). A two montage-based decision mechanism (TMDM) was designed to determine whether an IED event occurred at a single time instant. Area under the precision-recall curve (AUPRC), as well as false-positive rates, F1 scores, and kappa agreement scores for sensitivity = 0.8 were estimated. In multitype classification, five DNNs provided one-versus-rest AUPRC mean value >0.993 using fivefold cross-validation. In IED detection, the system that had integrated the temporal convolutional network (TCN)-based IED detector and the TMDM rule achieved an AUPRC of 0.811. The false positive was 0.194/min (11.64/h), and the F1 score was 0.745. The agreement score between the system and the experts was 0.905. The proposed framework provides a TCN-based IED detector and a novel two montage-based determining mechanism that combined to make an automatic IED detection system. The system would be useful in aiding clinic EEG interpretation.

Investigations of Single-Subunit tRNA Methyltransferases from Yeast.

tRNA methylations, including base modification and 2'-O-methylation of ribose moiety, play critical roles in the structural stabilization of tRNAs and the fidelity and efficiency of protein translation. These modifications are catalyzed by tRNA methyltransferases (TRMs). Some of the TRMs from yeast can fully function only by a single subunit. In this study, after performing the primary bioinformatic analyses, the progress of the studies of yeast single-subunit TRMs, as well as the studies of their homologues from yeast and other types of eukaryotes and the corresponding TRMs from other types of organisms was systematically reviewed, which will facilitate the understanding of the evolutionary origin of functional diversity of eukaryotic single-subunit TRM.

The impact of previous conservative treatment of atypical hyperplasia on pregnancy outcomes after IVF/ICSI-embryo transfer: a propensity score-matched retrospective cohort study.

STUDY QUESTION: Do women have worse pregnancy and neonatal outcomes of IVF/ICSI-fresh embryo transfer (ET) after conservative treatment of atypical hyperplasia (AH)? SUMMARY ANSWER: AH has no impact on live birth but is associated with increased risks of pregnancy loss and preterm delivery (PTD). WHAT IS KNOWN ALREADY: AH is a precancerous lesion of endometrial cancer. Several recognized AH risk factors include nulliparity, increased body mass index, ovulation disorders, diabetes mellitus, and others. As such, patients are suggested to attempt conception upon achieving AH regression. Recently, successful pregnancies with IVF/ICSI have been increasingly reported. STUDY DESIGN, SIZE, DURATION: Forty-two patients with AH regression and 18 700 women with no evidence of endometrial abnormality, who underwent their first autologous oocytes' retrieval and fresh ET cycles of IVF/ICSI in the Center for Reproductive Medicine, Shandong University, from May 2008 to July 2021, were retrospectively enrolled. PARTICIPANTS/MATERIALS, SETTING, METHODS: First, 42 AH patients were propensity score matched with control women (n = 168) at a 1:4 ratio. Reproductive outcomes and maternal/neonatal complications were compared between the matched pairs. Binary logistic regression analyses were conducted to assess odds ratios (ORs) of AH for live birth, pregnancy loss, and PTD from AH women and all 18 700 eligible controls. MAIN RESULT AND THE ROLE OF CHANCE: Patients with AH achieved a numerically lower live birth rate (LBR) as compared to the matched controls, but without significant difference (26% versus 37%, P = 0.192). However, compared with the matched controls, AH patients showed significantly higher rates of pregnancy loss (52% versus 21%, P = 0.003) and PTD (45% versus 16%, P = 0.041). Further analyses revealed a statistically significantly increased rate of late pregnancy loss (17% versus 3%, P = 0.023), but not early miscarriage (35% versus 18%, P = 0.086), in the AH group. Furthermore, after correcting for potential confounders, the likelihood of a live birth in AH patients narrowly failed to be statistically significantly different from controls (adjusted OR [aOR]: 0.51, 95% CI: 0.25-1.04, P = 0.064). Nonetheless, the logistic regression reconfirmed that AH was an independent risk factor for pregnancy loss (aOR: 3.62, 95% CI: 1.55-8.46, P = 0.003), late pregnancy loss (aOR: 9.33, 95% CI: 3.00-29.02, P < 0.001), and PTD (aOR: 5.70, 95% CI: 1.45-22.38, P = 0.013). LIMITATIONS, REASONS FOR CAUTION: Selection bias was an inherent drawback of this study. First, because of the low AH prevalence among women receiving IVF/ICSI treatment, and consequently, limited sample size, the relationship between AH with LBR and adverse complications might be concealed and underestimated. Hence, the results should be interpreted cautiously. Similarly, the impacts of diverse clinical features of AH patients on the pregnancy outcomes need further studies in a larger population. Second, although most data used in this study were obtained by reviewing the medical records, missing data did exist and so did the recall bias. Third, although the propensity score matching and multivariable logistic models were performed collectively in order to minimize potential confounders between AH and controls, the intrinsic disadvantages of the retrospective nature of this study could not be avoided completely, and additional confirmation bias might be induced with reduplication of statistical analyses. WIDER IMPLICATION OF THE FINDINGS: Our results highlight the necessity of adequate counseling and intensive pregnancy monitoring for AH individuals and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Key Research & Developmental Program of China (2022YFC2703800), the Natural Science Foundation of Shandong Province (ZR2022MH009), and Projects of Medical and Health Technology Development Program in Shandong Province (202005010520, 202005010523). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Causes of death after testicular cancer diagnosis: a US population-based analysis.

BACKGROUND: After the introduction of cisplatin-based chemotherapy, the survival time of testicular cancer (TC) patients has improved dramatically. However, the overall risk of death in patients with TC remains significantly higher than in the general population. The aim of this study was to assess and quantify the causes of death after TC diagnosis. METHOD: In total, 44,975 men with TC in the United States diagnosed and registered by the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2018 were studied. In this study, standardized mortality rates (SMRs) were calculated for each cause of death in TC individuals and further analyzed in strata according to age and race. RESULT: Of the included participants, 3,573 (7.94%) died during the follow-up period. The greatest proportion of deaths (38.20%) occurred within 1 to 5 years after diagnosis. Most deaths occurred from TC itself and other cancers. For non-malignant conditions, the most common causes of death within 1 years after diagnosis were accidents and adverse effects (53, 4.75%) followed by diseases of heart (45, 4.04%). However, > 1 years after diagnosis, the most common noncancer causes of death were heart diseases. Results of stratified analysis show that non-Hispanic White TC participants have a lower SMR (0.68, 95% CI, 33.39-38.67) from Cerebrovascular Diseases than the general U.S. CONCLUSIONS: Although TC remains the most common cause of death after TC diagnosis, other non-TC causes of death represent a significant number of deaths among TC men. These findings help TC survivors understand the various health risks that may occur at different follow-up periods.

WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia.

WDR54 has been recently identified as a novel oncogene in colorectal and bladder cancers. However, the expression and function of WDR54 in T-cell acute lymphoblastic leukemia (T-ALL) were not reported. In this study, we investigated the expression of WDR54 in T-ALL, as well as its function in T-ALL pathogenesis using cell lines and T-ALL xenograft. Bioinformatics analysis indicated high mRNA expression of WDR54 in T-ALL. We further confirmed that the expression of WDR54 was significantly elevated in T-ALL. Depletion of WDR54 dramatically inhibited cell viability and induced apoptosis and cell cycle arrest at S phase in T-ALL cells in vitro. Moreover, knockdown of WDR54 impeded the process of leukemogenesis in a Jurkat xenograft model in vivo. Mechanistically, the expression of PDPK1, phospho-AKT (p-AKT), total AKT, phospho-ERK (p-ERK), Bcl-2 and Bcl-xL were downregulated, while cleaved caspase-3 and cleaved caspase-9 were upregulated in T-ALL cells with WDR54 knockdown. Additionally, RNA-seq analysis indicated that WDR54 might regulate the expression of some oncogenic genes involved in multiple signaling pathways. Taken together, these findings suggest that WDR54 may be involved in the pathogenesis of T-ALL and serve as a potential therapeutic target for the treatment of T-ALL.

Scanning-based compressive hyperspectral imaging via spectral-coded illumination.

In this Letter, we present a novel, to the best of our knowledge, scanning-based compressive hyperspectral imaging method via spectral-coded illumination. We achieve efficient and flexible spectral modulation by spectral coding of a dispersive light source while spatial information is obtained by point-wise scanning, which can be applied to optical scanning imaging systems such as lidar. In addition, we propose a new tensor-based joint hyperspectral image reconstruction algorithm that considers spectral correlation and spatial self-similarity to recover three-dimensional hyperspectral data from compressive sampled data. Both simulated and real experiments show that our method has superior performance in visual quality and quantitative analysis.

YBX1 as an oncogenic factor in T-cell acute lymphoblastic leukemia.

Y-box-binding protein 1 (YBX1), a member of the RNA-binding protein family, is a critical regulator of cell survival in various solid tumors and acute myeloid leukemia. However, the function of YBX1 in T-cell acute lymphoblastic leukemia (T-ALL) remains elusive. Here, we found that YBX1 was upregulated in patients with T-ALL, T-ALL cell lines, and NOTCH1-induced T-ALL mice. Furthermore, depletion of YBX1 dramatically reduced cell proliferation, induced cell apoptosis, and induced G0/G1 phase arrest in vitro. Moreover, YBX1 depletion significantly decreased the leukemia burden in the human T-ALL xenograft and NOTCH1-induced T-ALL mice model in vivo. Mechanistically, downregulation of YBX1 markedly inhibited the expression of total AKT serine/threonine kinase (AKT), p-AKT, total extracellular signal-regulated kinase (ERK), and p-ERK in T-ALL cells. Taken together, our results uncovered a critical role of YBX1 in the leukemogenesis of T-ALL, which may have great potential as a biomarker and therapeutic target in T-ALL.

Incremental value of radiomics with machine learning to the existing prognostic models for predicting outcome in renal cell carcinoma.

Purpose: To systematically evaluate the potential of radiomics coupled with machine-learning algorithms to improve the predictive power for overall survival (OS) of renal cell carcinoma (RCC). Methods: A total of 689 RCC patients (281 in the training cohort, 225 in the validation cohort 1 and 183 in the validation cohort 2) who underwent preoperative contrast-enhanced CT and surgical treatment were recruited from three independent databases and one institution. 851 radiomics features were screened using machine-learning algorithm, including Random Forest and Lasso-COX Regression, to establish radiomics signature. The clinical and radiomics nomogram were built by multivariate COX regression. The models were further assessed by Time-dependent receiver operator characteristic, concordance index, calibration curve, clinical impact curve and decision curve analysis. Result: The radiomics signature comprised 11 prognosis-related features and was significantly correlated with OS in the training and two validation cohorts (Hazard Ratios: 2.718 (2.246,3.291)). Based on radiomics signature, WHOISUP, SSIGN, TNM Stage and clinical score, the radiomics nomogram has been developed. Compared with the existing prognostic models, the AUCs of 5 years OS prediction of the radiomics nomogram were superior to the TNM, WHOISUP and SSIGN model in the training cohort (0.841 vs 0.734, 0.707, 0.644) and validation cohort2 (0.917 vs 0.707, 0.773, 0.771). Stratification analysis suggested that the sensitivity of some drugs and pathways in cancer were observed different for RCC patients with high-and low-radiomics scores. Conclusion: This study showed the application of contrast-enhanced CT-based radiomics in RCC patients, creating novel radiomics nomogram that could be used to predict OS. Radiomics provided incremental prognostic value to the existing models and significantly improved the predictive power. The radiomics nomogram might be helpful for clinicians to evaluate the benefit of surgery or adjuvant therapy and make individualized therapeutic regimens for patients with renal cell carcinoma.