Tuning Crystal Phase of Palladium-Selenium Nanowires for Enhanced Ethylene Glycol Electrocatalytic Oxidation.

Alcohol electrooxidation is pivotal for a sustainable energy economy. However, designing efficient electrocatalysts for this process is still a formidable challenge. Herein, palladium-selenium nanowires featuring distinct crystal phases: monoclinic Pd7Se2 and tetragonal Pd4.5Se for ethylene glycol electrooxidation reaction (EGOR) are synthesized. Notably, the supported monoclinic Pd7Se2 nanowires (m-Pd7Se2 NWs/C) exhibit superior EGOR activity, achieving a mass activity (MA) and specific activity (SA) of 10.4 A mgPd -1 (18.7 mA cm-2), which are 8.0 (6.7) and 10.4 (8.2) times versus the tetragonal Pd4.5Se and commercial Pd/C and surpass those reported in the literature. Furthermore, m-Pd7Se2 NWs/C displays robust catalytic activity for other alcohol electrooxidation. Comprehensive characterization and density functional theory (DFT) calculations reveal that the enhanced electrocatalytic performance is attributed to the increased formation of Pd0 on the high-index facets of the m-Pd7Se2 NWs, which lowers the energy barriers for the C─C bond dissociation in CHOHCHOH* and the CO* oxidation to CO2*. This study provides palladium-based alloy electrocatalysts exhibiting the highest mass activity reported to date for the electrooxidation of ethylene glycol, achieved through the crystalline phase engineering strategy.

A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Efficacy and safety of fundoplication in treating gastroesophageal reflux related chronic cough: A meta-analysis.

Gastroesophageal reflux related chronic cough (GERC), is a common type of chronic cough. Drug treatment is the first choice. But some patients are tired of taking medicine everyday and some patients can not benefit from drugs. For these patients, fundoplication may be the most effective method. However, the importance of fundoplication in treating GERC is undervalued, and there is very few meta-analysis looking into the effect and safety of fundoplication in treating GERC. To solve this question, we performed this meta-analysis. The PRISMA strategy was used for this study. Our study was registered with PROSPERO (ID: CRD42021251072). We searched PubMed, Medline, Web of Science, and the Cochrane databases from 1990 to December of 2022. The meta-analysis was performed with Review Manager 5.4 and Stata 14. After selection and exclusion, 15 articles out of 672 were included. The meta-analysis showed that the cure rate of laparoscopic fundoplication in treating GERC was 58% (95%CI: 52%-65%), with I2 = 45%; and the effective rate was 86% (95%CI: 80%-93%), with I2 = 0%. Laparoscopic fundoplication is effective for the most of GERC patients; however, when the goal is to cure GERC completely, a relatively conservative attitude should be taken. In terms of safety, laparoscopic fundoplication is quite reliable offered by skilled surgeons.

Combined therapy of CAR-IL-15/IL-15Rα-T cells and GLIPR1 knockdown in cancer cells enhanced anti-tumor effect against gastric cancer.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown remarkable responses in hematological malignancies with several approved products, but not in solid tumors. Patients suffer from limited response and tumor relapse due to low efficacy of CAR-T cells in the complicated and immunosuppressive tumor microenvironment. This clinical challenge has called for better CAR designs and combined strategies to improve CAR-T cell therapy against tumor changes. METHODS: In this study, IL-15/IL-15Rα was inserted into the extracellular region of CAR targeting mesothelin. In-vitro cytotoxicity and cytokine production were detected by bioluminescence-based killing and ELISA respectively. In-vivo xenograft mice model was used to evaluate the anti-tumor effect of CAR-T cells. RNA-sequencing and online database analysis were used to identify new targets in residual gastric cancer cells after cytotoxicity assay. CAR-T cell functions were detected in vitro and in vivo after GLI Pathogenesis Related 1 (GLIPR1) knockdown in gastric cancer cells. Cell proliferation and migration of gastric cancer cells were detected by CCK-8 and scratch assay respectively after GLIPR1 were overexpressed or down-regulated. RESULTS: CAR-T cells constructed with IL-15/IL-15Rα (CAR-ss-T) showed significantly improved CAR-T cell expansion, cytokine production and cytotoxicity, and resulted in superior tumor control compared to conventional CAR-T cells in gastric cancer. GLIPR1 was up-regulated after CAR-T treatment and survival was decreased in gastric cancer patients with high GLIPR1 expression. Overexpression of GLIPR1 inhibited cytotoxicity of conventional CAR-T but not CAR-ss-T cells. CAR-T treatment combined with GLIPR1 knockdown increased anti-tumor efficacy in vitro and in vivo. CONCLUSIONS: Our data demonstrated for the first time that this CAR structure design combined with GLIPR1 knockdown in gastric cancer improved CAR-T cell-mediated anti-tumor response.

Discovery of small molecule c-Maf inhibitors using molecular docking-based virtual screening, molecular dynamics simulation, and biological evaluation.

Multiple myeloma (MM) is a prevalent plasma cell malignancy in the blood system that remains incurable. Given the abnormally high expression of c-Maf in most MM patients, targeting c-Maf presents an attractive therapeutic approach for treating MM malignancies. In this study, we employed a combined strategy involving molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation on existing FDA-approved drugs. Six compounds were selected for further experimental assay: vemurafenib, sorafenib, sildenafil, fluvastatin, erlotinib, and glimepiride. Among these compounds, sorafenib and glimepiride exhibited significant inhibition of myeloma cell proliferation in the RPMI-8226 cell line. Moreover, both compounds simultaneously downregulated c-Maf protein expression to induce G1 phase arrest and apoptosis in myeloma cells. Collectively, sorafenib and glimepiride may be considered promising candidates for developing more potent c-Maf inhibitors in the future.

Compressive Strain in Platinum-Iridium-Nickel Zigzag-Like Nanowire Boosts Hydrogen Catalysis.

Strain effect in the structurally defective materials can contribute to the catalysis optimization. However, it is challenging to achieve the performance improvement by strain modulation with the help of geometrical structure because strain is spatially dependent. Here, a new class of compressively strained platinum-iridium-metal zigzag-like nanowires (PtIrM ZNWs, M = nickel (Ni), cobalt (Co), iron (Fe), zinc (Zn) and gallium (Ga)) is reported as the efficient alkaline hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) catalysts. Particularly, the optimized PtIrNi ZNWs with 3% compressive strain (cs-PtIrNi ZNWs) can achieve the highest HER/HOR performances among all the catalysts investigate. Their HOR mass and specific activities are 3.2/14.4 and 2.6/32.7 times larger than those of PtIrNi NWs and commercial Pt/C, respectively. Simultaneously, they can exhibit the superior stability and high CO resistance for HOR. Further, experimental and theoretical studies collectively reveal that the compressive strain in cs-PtIrNi ZNWs effectively weakens the adsorption of hydroxyl intermediate and modulates the electronic structure, resulting in the weakened hydrogen binding energy (HBE) and moderate hydroxide binding energy (OHBE), beneficial for the improvement of HOR performance. This work highlights the importance of strain tuning in enhancing Pt-based nanomaterials for hydrogen catalysis and beyond.

Thyroid dysfunction and risk of cutaneous malignant melanoma: a bidirectional two-sample Mendelian randomization study.

Background: Epidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work. Methods: A genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran's Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes. Results: The two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p=0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism (p>0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis. Conclusion: Although the magnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM.

Pixel Self-Attention Guided Real-Time Instance Segmentation for Group Raised Pigs.

Instance segmentation is crucial to modern agriculture and the management of pig farms. In practical farming environments, challenges arise due to the mutual adhesion, occlusion, and dynamic changes in body posture among pigs, making accurate segmentation of multiple target pigs complex. To address these challenges, we conducted experiments using video data captured from varying angles and non-fixed lenses. We selected 45 pigs aged between 20 and 105 days from eight pens as research subjects. Among these, 1917 images were meticulously labeled, with 959 images designated for the training set, 192 for validation, and 766 for testing. To enhance feature utilization and address limitations in the fusion process between bottom-up and top-down feature maps within the feature pyramid network (FPN) module of the YOLACT model, we propose a pixel self-attention (PSA) module, incorporating joint channel and spatial attention. The PSA module seamlessly integrates into multiple stages of the FPN feature extraction within the YOLACT model. We utilized ResNet50 and ResNet101 as backbone networks and compared performance metrics, including AP0.5, AP0.75, AP0.5-0.95, and AR0.5-0.95, between the YOLACT model with the PSA module and YOLACT models equipped with BAM, CBAM, and SCSE attention modules. Experimental results indicated that the PSA attention module outperforms BAM, CBAM, and SCSE, regardless of the selected backbone network. In particular, when employing ResNet101 as the backbone network, integrating the PSA module yields a 2.7% improvement over no attention, 2.3% over BAM, 2.4% over CBAM, and 2.1% over SCSE across the AP0.5-0.95 metric. We visualized prototype masks within YOLACT to elucidate the model's mechanism. Furthermore, we visualized the PSA attention to confirm its ability to capture valuable pig-related information. Additionally, we validated the transfer performance of our model on a top-down view dataset, affirming the robustness of the YOLACT model with the PSA module.

Synthesis and biological activity assay of novel camptothecin-peptidic conjugates based on PEPT1.

Camptothecin (CPT) and its derivatives are potent candidates for cancer treatment. However, the clinical applications are largely restricted by non-selectivity and severe toxicities. The peptide transporter 1 (PEPT1), which is highly expressed in human intestines, has been found to be overexpressed in several cancer cells. This discovery suggests that PEPT1 has the potential to serve as a therapeutic target for both improving bioavailability and cancer-targeting treatment. Therefore, a prodrug approach for CPT targeting at PEPT1 highly expressed cancer cells was adopted in the present study. Eighteen CPT prodrugs, its peptidic conjugates, were synthesized and the structures were confirmed by NMR and HRMS. The protein expression profiles of PEPT1 in different cell lines were performed using immunofluorescence assay and western blotting analysis. The cytotoxicity of CPT prodrugs and their uptake via competition with Gly-Sar, a typical substrate of PEPT1, were evaluated in both PEPT1-overexpressed and under expressed cells. The results demonstrated that most CPT prodrugs significantly impaired Gly-Sar uptake, suggesting a higher affinity of CPT-peptidic conjugates for PEPT1 and PEPT1 overexpression cells. In addition, these prodrugs demonstrated a higher capability for inhibiting cell growth in PEPT1 highly-expressed cancer cells compared to PEPT1 under expressed cells. These results indicated that this peptidic prodrug strategy might offer great potential for improved tumor selectivity and chemotherapeutic efficacy of CPT.

Medium-term clinical efficacy of endoscopic antireflux mucosectomy on laryngopharyngeal reflux: a retrospective multicenter cohort study.

BACKGROUND AND AIMS: Studies on the effect of antireflux mucosectomy (ARMS) on laryngopharyngeal reflux disease (LPRD) are lacking. We conducted a multicenter retrospective study to explore the clinical efficacy of ARMS on LPRD. METHODS: We retrospectively analyzed the data of patients diagnosed with LPRD by oropharyngeal 24-hour Dx-pH monitoring who underwent ARMS. The effects of ARMS on LPRD were evaluated by comparing the 36-Item Short-Form Survey (SF-36), reflux symptom index (RSI), and 24-hour Dx-pH monitoring scores before and 1 year after surgery. Patients were divided into groups according to gastroesophageal flap valve (GEFV) grade to explore the effect of GEFV on prognosis. RESULTS: One hundred eighty-three patients were included in the study. The oropharyngeal pH monitoring results showed that the effective rate of ARMS was 72.1% (132/183). After surgery, the SF-36 score was higher (P = .000), RSI score was lower (P = .000), and the symptoms of constant throat clearing; difficulty swallowing food, liquids, and pills; coughing after eating or after lying down; troublesome or annoying cough; and breathing difficulties or choking episodes were significantly improved (P < .05). Upright reflux was dominant in GEFV grade I to III patients, and the SF-36, RSI, and upright Ryan index scores were significantly improved after surgery (P < .05). In GEFV grade IV patients, regurgitation was dominant in the supine position, and the above evaluation indexes were worse after surgery (P < .05). CONCLUSIONS: ARMS is effective for LPRD. The GEFV grade can predict the prognosis of surgery. ARMS is effective in GEFV grade I to III patients, but the effect is not exact in GEFV grade IV patients and may even be aggravated.

Laparoscopic fundoplication in treating refractory gastroesophageal reflux-related chronic cough: A meta-analysis.

BACKGROUND: Gastroesophageal reflux-related chronic cough (GERC), is one common type of chronic cough. Drug treatment is effective for some GERC patients. But, there is refractory GERC (rGERC). For rGERC, fundoplication may be the only effective method. However, there were very few studies about laparoscopic fundoplication in treating rGERC, and the cure rate of fundoplication in treating rGERC was unknown. So there is a question, what is the cure rate of fundoplication in treating rGERC? To solve this question, we performed this meta-analysis. METHODS: The PRISMA strategy and Cochrane collaboration method were used for this study. Our study was registered with PROSPERO (ID: CRD42021251072). We searched PubMed, Medline, Web of Science, and the Cochrane databases from 1990 to December 2022. The meta-analysis was performed with Review Manager 5.4 and Stata 14. RESULTS: After selection and exclusion, 8 articles out of 672 were included. The meta-analysis showed the cure rate of laparoscopic fundoplication in treating rGERC was 62% (95% confidence interval: 53-71%), with no deaths in 503 patients. There was no significant heterogeneity or bias in the meta-analysis. CONCLUSIONS: In terms of safety, laparoscopic fundoplication is quite reliable offered by skilled surgeons. In terms of cure rate, laparoscopic fundoplication could completely heal two-thirds of rGERC patients; however, there are still some patients who can not be completely cured by fundoplication.

The 'double­track sign': A novel CT finding suggestive of the diagnosis of T1a gastric cancer.

Effective identification of T1a stage cancer is crucial for planning endoscopic resection for early gastric cancers. The present study aimed to determine the diagnostic value of the double-track sign in patients with T1a gastric cancer using computed tomography (CT) imaging. A total of 152 patients diagnosed with pathologically proven T1a gastric cancer at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between July 2011 and August 2021 were retrospectively reviewed. The control group consisted of 2,926 patients with gastritis. Clinical data, including patient characteristics and preoperative CT imaging findings with gastric morphological features, were reviewed and analyzed. Out of 51 patients with T1a gastric cancer finally included, 31 (60.8%) exhibited local double-track enhancement changes of the stomach, referred to as the 'double-track sign', on CT images. In addition, four patients (7.8%) had well-enhanced mucosal thickening of the gastric wall. Of the 2,926 control subjects, none had any double-track sign and six patients (0.2%) had local gastric wall thickening with abnormally strengthened enhancement. In conclusion, a double-track sign on CT images is beneficial in the diagnostic differentiation of T1a gastric cancer.

Preoperative prediction of vessel invasion in locally advanced gastric cancer based on computed tomography radiomics and machine learning.

Vessel invasion (VI) is an important factor affecting the prognosis of gastric cancer (GC), and the accurate determination of preoperative VI for locally advanced GC is of great clinical significance. Traditional methods for the evaluation of VI require postoperative pathological examination. Noninvasive preoperative evaluation of VI is therefore crucial to determine the best treatment strategy. To determine the value of preoperative prediction of gastric VI based on portal venous phase computed tomography (CT) radiomic features and machine-learning models, a retrospective analysis of 296 patients with locally advanced GC confirmed through pathological examination was performed. They were divided into two groups, VI+ (n=213) and VI- (n=83), based on pathological results. Using pyradiomics to extract two-dimensional radiomic features of the portal venous stage of locally advanced GC, data were divided into training (n=207) and validation sets (n=89), with a ratio of 7:3, and three feature selection methods were cascaded and merged. Finally, least absolute shrinkage and selection operator (LASSO) regression was used for feature screening to obtain the optimal feature subset. Four current representative machine-learning algorithms were used to construct the prediction model, the receiver operating characteristic curve was constructed to evaluate the predictive performance of the model, and the area under the curve (AUC), accuracy, sensitivity, and specificity were calculated. The differentiation degree, and the Lauren's and CA199 classifications were independent risk factors for locally advanced GC VI. Pyradiomics extracted 864 quantitative features of portal vein images of locally advanced GC. After filtering out low variance features using R, 236 features remained. Next, 18 features were screened using the LASSO algorithm. Extreme gradient boosting (XGBoost), logistic regression, Gaussian naive Bayes, and support vector machine models were constructed based on the 18 best features screened out of the portal venous CT images of advanced GC and three independent risk factors of GC VI in clinical features predicted the training set AUC values of 0.914, 0.897, 0.880, and 0.814, respectively. The predicted validation set AUC values were 0.870, 0.877, 0.859, and 0.773, respectively. The DeLong test results indicated no statistically significant difference in AUC values between the XGBoost and logistic regression models in the training and validation sets. The four machine-learning models showed high predictive performance. The logistic regression model had the highest AUC value in the validation set (0.877), and the accuracy and F1 score were 77 and 87.6%, respectively. CT radiomic features and machine-learning models based on the portal venous phase can be used as a noninvasive imaging method for the preoperative prediction of VI in locally advanced GC. The logistic regression model exhibited the highest diagnostic performance.

Phosphorylation of IWS1 by AKT maintains liposarcoma tumor heterogeneity through preservation of cancer stem cell phenotypes and mesenchymal-epithelial plasticity.

Chemotherapy remains the mainstay of treatment for patients with advanced liposarcoma (LPS), but response rates are only 25% and the overall survival at 5 years is dismal at 20-34%. Translation of other therapies have not been successful and there has been no significant improvement in prognosis for nearly 20 years. The aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the aggressive clinical behavior LPS and in resistance to chemotherapy, but the precise mechanism remains elusive and efforts to target AKT clinically have failed. Here we show that the AKT-mediated phosphorylation of the transcription elongation factor IWS1, promotes the maintenance of cancer stem cells in both cell and xenograft models of LPS. In addition, phosphorylation of IWS1 by AKT contributes to a "metastable" cell phenotype, characterized by mesenchymal/epithelial plasticity. The expression of phosphorylated IWS1 also promotes anchorage-dependent and independent growth, cell migration, invasion, and tumor metastasis. In patients with LPS, IWS1 expression is associated with reduced overall survival, increased frequency of recurrence, and shorter time to relapse after resection. These findings indicate that IWS1-mediated transcription elongation is an important regulator of human LPS pathobiology in an AKT-dependent manner and implicate IWS1 as an important molecular target to treat LPS.

Interleukin-18-primed human umbilical cord-mesenchymal stem cells achieve superior therapeutic efficacy for severe viral pneumonia via enhancing T-cell immunosuppression.

Coronavirus disease 2019 (COVID-19) treatments are still urgently needed for critically and severely ill patients. Human umbilical cord-mesenchymal stem cells (hUC-MSCs) infusion has therapeutic benefits in COVID-19 patients; however, uncertain therapeutic efficacy has been reported in severe patients. In this study, we selected an appropriate cytokine, IL-18, based on the special cytokine expression profile in severe pneumonia of mice induced by H1N1virus to prime hUC-MSCs in vitro and improve the therapeutic effect of hUC-MSCs in vivo. In vitro, we demonstrated that IL-18-primed hUC-MSCs (IL18-hUCMSC) have higher proliferative ability than non-primed hUC-MSCs (hUCMSCcon). In addition, VCAM-1, MMP-1, TGF-ß1, and some chemokines (CCL2 and CXCL12 cytokines) are more highly expressed in IL18-hUCMSCs. We found that IL18-hUCMSC significantly enhanced the immunosuppressive effect on CD3+ T-cells. In vivo, we demonstrated that IL18-hUCMSC infusion could reduce the body weight loss caused by a viral infection and significantly improve the survival rate. Of note, IL18-hUCMSC can also significantly attenuate certain clinical symptoms, including reduced activity, ruffled fur, hunched backs, and lung injuries. Pathologically, IL18-hUCMSC transplantation significantly enhanced the inhibition of inflammation, viral load, fibrosis, and cell apoptosis in acute lung injuries. Notably, IL18-hUCMSC treatment has a superior inhibitory effect on T-cell exudation and proinflammatory cytokine secretion in bronchoalveolar lavage fluid (BALF). Altogether, IL-18 is a promising cytokine that can prime hUC-MSCs to improve the efficacy of precision therapy against viral-induced pneumonia, such as COVID-19.

Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma.

The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.

Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration.

Transplantation of mesenchymal stem cells (MSCs) holds promise to repair severe traumatic injuries. However, current transplantation practices limit the potential of this technique, either by losing the viable MSCs or reducing the performance of resident MSCs. Herein, we design a "bead-jet" printer, specialized for high-throughput intra-operative formulation and printing of MSCs-laden Matrigel beads. We show that high-density encapsulation of MSCs in Matrigel beads is able to augment MSC function, increasing MSC proliferation, migration, and extracellular vesicle production, compared with low-density bead or high-density bulk encapsulation of the equivalent number of MSCs. We find that the high-density MSCs-laden beads in sparse patterns demonstrate significantly improved therapeutic performance, by regenerating skeletal muscles approaching native-like cell density with reduced fibrosis, and regenerating skin with hair follicle growth and increased dermis thickness. MSC proliferation within 1-week post-transplantation and differentiation at 3 - 4 weeks post-transplantation are suggested to contribute therapy augmentation. We expect this "bead-jet" printing system to strengthen the potential of MSC transplantation.

Silencing TRPM2 enhanced erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins.

Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. Cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival. Our bioinformatic analysis revealed that TRPM2 is associated with cellular responses to chemical stimulus and oxidative stress, implying the potential role of TRPM2 in ferroptosis. Gastric cancer cells were treated with the ferroptosis-inducer, Erastin and RSL3. siRNA transfection was used to silence TRPM2. The levels of GSH, Fe2+, ROS and lipid peroxidation, and the activity of GPx activity were evaluated by flow cytometry and spectrophotometer. The effect of TRPM2 on ubiquitination of HIF-1α and Nrf2 were evaluated by co-immunoprecipitation. Erastin and RSL3 induced the up-regulation of TRPM2 in gastric cancer cell lines, especially in SGC7901 and MGC803. These two cells also showed stronger resistance to Erastin and RSL3 than the other cell lines. TRPM2 knockdown reduced the concentration of GSH and GPx activity, but enhanced the concentration of Fe2+, ROS and lipid peroxidation, which are significant indicators of ferroptosis. Importantly, silencing TRPM2 enhanced the inhibitory effects of Erastin and RSL3 on gastric cancer cell viability, migration, and invasion. TRPM2 stabilized and finally elevated the abundance of HIF-1α and Nrf2 in SGC7901 and MGC803 cells upon Erastin and RSL3. Activation of HIF-1α impaired Erastin- and RSL3-induced ferroptosis after TRPM2 knockdown. Collectively, silencing TRPM2 enhanced Erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-022-00545-z.