A Nomogram Including Sarcopenia for Predicting Progression-Free Survival in Patients with Localized Papillary Renal Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Because of to the removal of subclassification of papillary renal cell carcinoma (pRCC), the survival prognostification of localized pRCC after surgical treatment became inadequate. Sarcopenia was widely evaluated and proved to be a predictive factor for prognosis in RCC patients. Therefore, we comprehensively investigated the survival prediction of the body composition parameters for localized pRCC. METHODS: Patients pathologically diagnosed with pRCC between February 2012 and February 2022 in our center were enrolled. The body composition parameters, including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and perirenal adipose tissue (PRAT), were measured by the images of preoperative computed tomography (CT). The primary outcome was set as progression-free survival (PFS), and the cutoff values of body composition parameters were calculated by using the Youden from receiver operating characteristic curve (ROC) curves. Univariate and multivariate Cox proportional regression analyses were performed to explore independent risk factors for survival prediction. Then, significant factors were used to construct a prognostic nomogram. The performance of the nomogram was evaluated by Harrell's C-index, calibration curves and time-dependent ROC curves. RESULTS: A total of 105 patients were enrolled for analysis. With a median follow-up time of 30.48 months, 25 (23.81%) patients experienced cancer progression. The percentage of sarcopenia was 74.29%. Univariate Cox analysis identified that gender, PRAT, SAT, skeletal muscle (SM), sarcopenia, surgical technique, and tumor diameter were associated with progression. Further multivariate analysis showed that sarcopenia (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.03-0.66), SAT (HR 6.36, 95% CI 2.39-16.93), PRAT (HR 4.66, 95% CI 1.77-12.27), tumor diameter (HR 0.35, 95% CI 0.14-0.86), and surgical technique (HR 2.85, 95% CI 1.06-7.64) were independent risk factors for cancer progression. Then, a prognostic nomogram based on independent risk factors was constructed and the C-index for progression prediction was 0.831 (95% CI 0.761-0.901), representing a reasonable discrimination, the calibration curves, and the time-dependent ROC curves verified the good performance of the nomogram. CONCLUSIONS: A prognostic nomogram, including sarcopenia, SAT, PRAT, tumor diameter, and surgical technique, was constructed to calculate the probability of progression for localized pRCC patients and needs further external validation for clinical use in the future.

Diagnostic performance of machine learning in systemic infection following percutaneous nephrolithotomy and identification of associated risk factors.

Objective: This study aims to investigate the predictive performance of machine learning in predicting the occurrence of systemic inflammatory response syndrome (SIRS) and urosepsis after percutaneous nephrolithotomy (PCNL). Methods: A retrospective analysis was conducted on patients who underwent PCNL treatment between January 2016 and July 2022. Machine learning techniques were employed to establish and select the best predictive model for postoperative systemic infection. The feasibility of using relevant risk factors as predictive markers was explored through interpretability with Machine Learning. Results: A total of 1067 PCNL patients were included in this study, with 111 (10.4 %) patients developing SIRS and 49 (4.5 %) patients developing urosepsis. In the validation set, the risk model based on the GBM protocol demonstrated a predictive power of 0.871 for SIRS and 0.854 for urosepsis. Preoperative and postoperative platelet changes were identified as the most significant predictors. Both thrombocytopenia and thrombocytosis were found to be risk factors for SIRS or urosepsis after PCNL. Furthermore, it was observed that when the change in platelet count before and after PCNL surgery exceeded 30*109/L (whether an increase or decrease), the risk of developing SIRS or urosepsis significantly increased. Conclusion: Machine learning can be effectively utilized for predicting the occurrence of SIRS or urosepsis after PCNL. The changes in platelet count before and after PCNL surgery serve as important predictors.

Preparation and evaluation of the PD0721­DOX antibody­drug conjugate targeting EGFRvIII to inhibit glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is prominently expressed in various epithelial tumors. PD0721, a single-chain antibody (scFv), has been developed to specifically target EGFRvIII. Although doxorubicin (DOX) is an essential treatment approach for glioblastoma (GBM), its toxic effects and limited targeting capabilities are a challenge. To overcome the above limitations, antibody-drug conjugates (ADCs) have been developed to exploit the specificity of monoclonal antibodies in directing potent cytotoxic drugs to tumor cells expressing the target antigens. The present study aimed to conjugate DOX with PD0721 scFv to construct a PD0721-DOX ADC targeting EGFRvIII and examine its targeting effect and in vitro anti-GBM activity. PD0721-DOX ADC was generated by combining PD0721 scFv with DOX, using dextran T-10 as a linker. The drug-to-antibody ratio (DAR) was measured by ultraviolet and visible spectrophotometry (UV-Vis). A series of techniques, including cytotoxicity assays, immunofluorescence, cell internalization and flow cytometry assays were employed to evaluate the targeting efficacy and anti-GBM activity of the PD0721-DOX ADC. Following the conjugation of PD0721 scFv with DOX, the UV-Vis results showed a noticeable red shift in the maximum absorbance. The DAR of PD0721 scFv and DOX was 9.23:1. Cytotoxicity assays demonstrated that DK-MG cells treatment with PD0721-DOX ADC at 10 and 20 µg/ml significantly increased cytotoxicity compared with U-87MG ATCC cells (all P<0.01). Confocal microscopy revealed distinct green and red fluorescence in EGFRvIII-expressing DK-MG cells, while no fluorescence was observed in EGFRvIII negative U-87MG ATCC cells. Furthermore, compared with U-87MG ATCC cells, DK-MG cells showed effective internalization of the PD0721-DOX ADC (P<0.001). Finally, flow cytometric analyses indicated that the PD0721-DOX ADC significantly promoted the apoptosis of DK-MG cells compared with U-87MG ATCC cells (P<0.01). In summary, the current study suggested that the PD0721-DOX ADC could exhibit a notable targeting efficacy and potent anti-GBM activity.

Discovery of an OTUD3 inhibitor for the treatment of non-small cell lung cancer.

The ubiquitin-proteasome system (UPS) controls protein turnover, and its dysfunction contributes to human diseases including cancer. Deubiquitinating enzymes (DUBs) remove ubiquitin from proteins to maintain their stability. Inhibition of DUBs could induce the degradation of selected oncoproteins and has therefore become a potential therapeutic strategy for cancer. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. Here, we report a small-molecule inhibitor of OTUD3 (named OTUDin3) by computer-aided virtual screening and biological experimental verification. OTUDin3 exhibited pronounced antiproliferative and proapoptotic effects by inhibiting deubiquitinating activity of OTUD3 in non-small-cell lung cancer (NSCLC) cell lines. Moreover, OTUDin3 efficaciously inhibited growth of lung cancer xenografts in mice. In summary, our results support OTUDin3 as a potent inhibitor of OTUD3, the inhibition of which may be a promising therapeutic strategy for NSCLC.

In situ synthesis of two-dimensional graphene-like nickel-molybdenum nitride as efficient electrocatalyst towards water-splitting under large-current density.

Transition metal nitride (TMNs) electrocatalysts have attracted tremendous attentions for their unique electron structure, high activity, and excellent stability. Herein, a two-dimensional (2D) graphene-like structured nickel-molybdenum nitride (Ni-MoN) on nickel foam (NF), is prepared via facile hydrothermal and following nitridation process. The as-prepared Ni-MoN-450 (pyrolysis at 450 °C) displays good hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances in alkaline media. Only 22 mV and 117 mV are needed to achieve current densities of 10 mA cm-2 and 500 mA cm-2 in 1.0 M KOH, respectively, toward HER. The assembled two-electrode system, with the synthesized Ni-MoN-450 as the anode and cathode, exhibits good performance to achieve 1000 mA cm-2 in 1.0 M KOH + 25 °C and 6.0 M KOH + 80 °C. Moreover, it also presents long-term stability under large-current density, which verified its robust property.

Single enrichment systems possibly underestimate both exposures and biological effects of organic pollutants from drinking water.

Comprehensive enrichment of contaminants in drinking water is an essential step for accurately determining exposure levels of contaminants and testing their biological effects. Traditional methods using a single absorbent for enriching contaminants in water might not be adequate for complicated matrices with different physical-chemical profiles. To examine this hypothesis, we used an integrated enrichment system that had three sequential stages-XAD-2 resin, poly (styrene-divinylbenzene) and activated charcoal to capture organic pollutants and disinfection by-products (DBPs) from drinking water in Shanghai. Un-adsorbed Organic Compounds in Eluates (UOCEs) named UOCEs-A, -B, and-C following each adsorption stage were determined by gas chromatography-mass spectrometry to evaluate adsorption efficiency of the enrichment system. Meanwhile, biological effects such as cytotoxicity, effects on reactive oxygen species (ROS) generation and glutathione (GSH) depletion were determined in human LO2 cells to identify potential adverse effects on exposure to low dose contaminants. We found that poly-styrene-divinylbenzene (PS-DVB) and activated charcoal (AC) could still partly collect UOCEs-A and-B that the upper adsorption column incompletely captured, and that potential carcinogens like 2-naphthamine were present in all eluates. UOCEs-A at (1-4000), UOCEs-B at (1000-4000), and UOCEs-C at (2400-4000) folds of the actual concentrations had significant cytotoxicity to LO2 cells. Additionally, ROS and GSH change in cells treated with UOCEs indicated the potential for long-term effects of exposure to some mixtures of contaminants such as DBPs at low doses. These results suggested that an enriching system with a single adsorbent would underestimate the exposure level of pollutants and the biological effects of organic pollutants from drinking water. Effective methods for pollutants' enrichment and capture of drinking water should be given priority in future studies on accurate evaluation of biological effects exposed to mixed pollutants via drinking water.

The gut microbiota and its products: Establishing causal relationships with obesity related outcomes.

Gut microorganisms not only participate in the metabolism of carbohydrate, lipids, protein, and polypeptides in the intestine but also directly affect the metabolic phenotypes of the host. Although many studies have described the apparent effects of gut microbiota on human health, the development of metagenomics and culturomics in the past decade has generated a large amount of evidence suggesting a causal relationship between gut microbiota and obesity. The interaction between the gut microbiota and host is realized by microbial metabolites with multiple biological functions. We concentrated here on several representative beneficial species connected with obesity as well as the mechanisms, with particular emphasis on microbiota-dependent metabolites. Finally, we consider the potential clinical significance of these relationships to fuel the conception and realization of novel therapeutic and preventive strategies.

SNHG1/miR-556-5p/TCF12 feedback loop enhances the tumorigenesis of meningioma through Wnt signaling pathway.

Meningioma, as a sort of the malignantly intracranial tumors, has captured public attention for its second-highest morbidity all over the world. Long noncoding RNAs (lncRNAs), including lncRNA SNHG1, have been well known as essential players in the development of diverse cancers. However, the biological effect and regulatory mechanism of SNHG1 have not been mentioned in meningioma. In this work, it was discovered that SNHG1 was overexpressed in meningioma cell lines. SNHG1 deficiency restrained cell growth as well as accelerated apoptosis. Then mechanism experiments demonstrated that SNHG1 functioned as the role of sponging miR-556-5p and negatively regulated miR-556-5p expression. Moreover, it was verified that TCF12 is the direct downstream target of miR-556-5p. Furthermore, SNHG1/miR-556-5p/TCF12 axis promoted cell proliferation and suppressed cell apoptosis in meningioma via activating the Wnt signaling pathway. In the end, it was confirmed that TCF12 expression was positively regulated by SNHG1, and TCF12 could promote transcription of SNHG1 through binding with the promoter region of SNHG1. In conclusion, the SNHG1/miR-556-5p/TCF12 feedback loop promotes the tumorigenesis of meningioma through the Wnt signaling pathway.

Green and Orange Fluorescent Carbon Dots for Detecting Oral Cancer by Staining Tissue Sections.

By using ethylenediamine (ED) with nitric acid (NA) and formic acid (FA) as raw materials, two types of new carbon dots (CDs) were prepared using microwave method. The as-prepared CDs showed excellent water solubility and photoluminescence properties. The optimum excitation wavelength and emission wavelength of new CDs were at 430 nm and 500 nm (for CDs fabricated with ED and NA) and at 480 nm and 570 nm (for CDs synthesized with ED and FA), respectively. Dyeing the oral tissue with these new CDs was found to be an effective means to stain oral tissue sections. The cell morphology and distribution of the oral tissues can be clearly observed under a fluorescence microscopy. Compared with the hematoxylin-eosin (HE) staining method, a common staining method in biopsy, the dyeing operation of the new CDs is simpler with clearer imaging effect. The difference in cell morphology and distribution between normal oral tissues and pathological oral tissues was observed under a fluorescence microscope by CDs staining to distinguish normal tissues from pathological tissues. Thus, a novel method for detecting oral cancer was developed.

Gut microbiome interventions in human health and diseases.

Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome-based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.