Predictive and prognostic value of preoperative pan-immune-inflammation value in patients with locally advanced rectal cancer.

This study aimed to investigate the prognostic value of the pan-immune-inflammation value (PIV) in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision. We retrospectively collected and analyzed the clinicopathological data of 215 resected LARC patients. X-tile software was used to determine the optimal threshold value for PIV in predicting overall survival (OS). The predictive ability of PIV for pathological complete regression (pCR), OS, and disease-free survival (DFS) was evaluated and compared with other inflammation markers. Univariate and multivariate logistic regression analyses for pCR and Cox regression analyses for OS and DFS were conducted. The optimal threshold value for PIV was determined to be 454.7 based on the X-tile software. Patients were then categorized into low (≤ 454.7) and high (> 454.7) PIV groups comprising 153 and 62 patients, respectively. PIV demonstrated superior predictive ability for pCR, OS, and DFS compared to other inflammation markers. LARC patients with low PIV had significantly higher pCR (P = 0.029), OS (P = 0.002), and DFS (P = 0.001) rates compared to those with high PIV. Multivariate regression analysis identified PIV as an independent prognostic factor for pCR (odds ratio = 0.32; 95% confidence interval [CI], 0.10-0.80; P = 0.014), OS (hazard ratio = 3.08; 95% CI, 1.77-5.35; P = 0.001), and DFS (hazard ratio = 2.53; 95% CI, 1.58-4.06; P = 0.002). This study confirmed that preoperative PIV could serve as a useful independent prognostic factor in LARC patients treated with nCRT.

Optimized Adipogenic Differentiation and Delivery of Bovine Umbilical Cord Stem Cells for Cultivated Meat.

Cultivated meat, also known as cell-based or clean meat, utilizes mesenchymal stem cells to cultivate mature cell types like adipocytes, which are pivotal for imparting the desired taste and texture. The delivery of differentiated cells, crucial in cultivated meat production, is facilitated through extensive exploration of 3D culturing techniques mimicking physiological environments. In this study, we investigated the adipogenic differentiation potential of bovine umbilical cord stem cells (BUSCs), sourced from discarded birth tissue, and assessed the feasibility of delivering differentiated cells for cultivated meat using gelatin methacrylate (GelMA) as a carrier for adipose tissue. Various adipogenic inducers, previously reported to be effective for human mesenchymal stem cells (hMSCs), were evaluated individually or in combination for their efficacy in promoting the adipogenesis of BUSCs. Surprisingly, while the traditional adipogenic inducers, including insulin, dexamethasone, isobutylmethylxantine (IBMX), indomethacin, and rosiglitazone, showed no significant effect on the adipogenic differentiation of BUSCs, efficient differentiation was achieved in the presence of a fatty acid cocktail. Furthermore, we explored methods for the delivery of BUSCs. Differentiated cells were delivered either encapsulated in GelMA hydrogel or populated on the surface of GelMA microparticles (MPs) as the adipose component of cultivated meat. Our findings reveal that after adipogenic induction, the lipid production per cell was comparable when cultured either within hydrogel or on MPs. However, GelMA-MPs supported better cell growth compared to hydrogel encapsulation. Consequently, the overall lipid production is higher when BUSCs are delivered via GelMA-MPs rather than encapsulation. This study not only systematically evaluated the impact of common adipogenic inducers on BUSCs, but also identified GelMA-MPs as a promising carrier for delivering bovine adipocytes for cultivated meat production.

Alginate oligosaccharides exert protective effects on hydrogen peroxide-induced senescence in H9C2 cardiomyocytes by regulating the redox state of cells.

Aging is a known independent risk factor for several cardiovascular diseases. Here, we evaluated potential effects and possible mechanisms through which alginate oligosaccharides (AOS) affect hydrogen peroxide (H2O2)-induced senescence in H9C2 cardiomyocytes. A series of AOS molecules, including oligoM, oligoG, M-5, and G-5, were investigated. AOS significantly decreased SA-ß-gal and DAPI-stained positive cells, downregulated p53 and p21 (aging-related markers) expression, and eventually protected H9C2 cells from H2O2-induced senescence. AOS decreased reactive oxygen species and malondialdehyde production, recovered mitochondrial function, and alleviated the oxidative stress state by regulating PGC-1α and NADPH oxidase subunit expression. Furthermore, AOS treatment restored the expression of antioxidant enzymes in senescent H9C2 cells. Thus, our results show in vitro evidence that AOS alleviate senescence in H9C2 cells by regulating the redox state; thus, AOS may be an effective therapeutic agent that could protect against cardiomyocyte senescence.

Bovine Placentome-Derived Extracellular Matrix: A Sustainable 3D Scaffold for Cultivated Meat.

Cultivated meat, an advancement in cellular agriculture, holds promise in addressing environmental, ethical, and health challenges associated with traditional meat production. Utilizing tissue engineering principles, cultivated meat production employs biomaterials and technologies to create cell-based structures by introducing cells into a biocompatible scaffold, mimicking tissue organization. Among the cell sources used for producing muscle-like tissue for cultivated meats, primary adult stem cells like muscle satellite cells exhibit robust capabilities for proliferation and differentiation into myocytes, presenting a promising avenue for cultivated meat production. Evolutionarily optimized for growth in a 3D microenvironment, these cells benefit from the biochemical and biophysical cues provided by the extracellular matrix (ECM), regulating cell organization, interactions, and behavior. While plant protein-based scaffolds have been explored for their utilization for cultivated meat, they lack the biological cues for animal cells unless functionalized. Conversely, a decellularized bovine placental tissue ECM, processed from discarded birth tissue, achieves the biological functionalities of animal tissue ECM without harming animals. In this study, collagen and total ECM were prepared from decellularized bovine placental tissues. The collagen content was determined to be approximately 70% and 40% in isolated collagen and ECM, respectively. The resulting porous scaffolds, crosslinked through a dehydrothermal (DHT) crosslinking method without chemical crosslinking agents, supported the growth of bovine myoblasts. ECM scaffolds exhibited superior compatibility and stability compared to collagen scaffolds. In an attempt to make cultivate meat constructs, bovine myoblasts were cultured in steak-shaped ECM scaffolds for about 50 days. The resulting construct not only resembled muscle tissues but also displayed high cellularity with indications of myogenic differentiation. Furthermore, the meat constructs were cookable and able to sustain the grilling/frying. Our study is the first to utilize a unique bovine placentome-derived ECM scaffold to create a muscle tissue-like meat construct, demonstrating a promising and sustainable option for cultivated meat production.

Impact of Dietary Variations on Kuruma Shrimp (Penaeus japonicus) Assessed through Individual-Based Rearing and Insights into Individual Differences.

This study developed an individual-rearing method to compare the effects of live feed (sandworms Perinereis aibuhitensis), formulated pellet diets, and a mixture of live feed and formula feed on the Kuruma shrimp Penaeus japonicus, aiming to minimize the influence of non-dietary factors on the growth of P. japonicus, like cannibalism. Results indicated that live feed, with its higher protein, essential amino acids, and fatty acid content, led to significantly better growth and feeding performance in P. japonicus (p < 0.05) compared to pellet diets. A mixed diet resulted in a lower average daily protein intake yet maintained a growth and feeding performance comparable to live feed. The intestinal microbiota of shrimp, dominated by Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria, showed significant shifts with diet changes. Specifically, formulated feed increased the relative abundance of Vibrio and Photobacterium while decreasing Shimia and Rhodobacterales (p < 0.05), and feeding live food resulted in a more complex and stable bacterial network. Notably, individual variances in growth and feeding were observed among shrimps, with some on formulated diets showing growth comparable to those on live feed. Each shrimp's final weight, specific growth rate, protein efficiency rate, and average daily food intake positively correlated with its initial body weight (p < 0.05), and daily intake varied cyclically with the molting cycle. These findings suggest that individual-rearing is an effective approach for detailed feed evaluation and monitoring in P. japonicus, contributing to improved feed selection, development, and feeding strategies.

Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.

A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

Development and validation of a nomogram for predicting in-hospital survival rates of patients with COVID-19.

Objective: Our aim was to develop and validate a nomogram for predicting the in-hospital 14-day (14 d) and 28-day (28 d) survival rates of patients with coronavirus disease 2019 (COVID-19). Methods: Clinical data of patients with COVID-19 admitted to the Renmin Hospital of Wuhan University from December 2022 to February 2023 and the north campus of Shanghai Ninth People's Hospital from April 2022 to June 2022 were collected. A total of 408 patients from Renmin Hospital of Wuhan University were selected as the training cohort, and 151 patients from Shanghai Ninth People's Hospital were selected as the verification cohort. Independent variables were screened using Cox regression analysis, and a nomogram was constructed using R software. The prediction accuracy of the nomogram was evaluated using the receiver operating characteristic (ROC) curve, C-index, and calibration curve. Decision curve analysis was used to evaluate the clinical application value of the model. The nomogram was externally validated using a validation cohort. Result: In total, 559 patients with severe/critical COVID-19 were included in this study, of whom 179 (32.02 %) died. Multivariate Cox regression analysis showed that age >80 years [hazard ratio (HR) = 1.539, 95 % confidence interval (CI): 1.027-2.306, P = 0.037], history of diabetes (HR = 1.741, 95 % CI: 1.253-2.420, P = 0.001), high APACHE II score (HR = 1.083, 95 % CI: 1.042-1.126, P < 0.001), sepsis (HR = 2.387, 95 % CI: 1.707-3.338, P < 0.001), high neutrophil-to-lymphocyte ratio (NLR) (HR = 1.010, 95 % CI: 1.003-1.017, P = 0.007), and high D-dimer level (HR = 1.005, 95 % CI: 1.001-1.009, P = 0.028) were independent risk factors for 14 d and 28 d survival rates, whereas COVID-19 vaccination (HR = 0.625, 95 % CI: 0.440-0.886, P = 0.008) was a protective factor affecting prognosis. ROC curve analysis showed that the area under the curve (AUC) of the 14 d and 28 d hospital survival rates in the training cohort was 0.765 (95 % CI: 0.641-0.923) and 0.814 (95 % CI: 0.702-0.938), respectively, and the AUC of the 14 d and 28 d hospital survival rates in the verification cohort was 0.898 (95 % CI: 0.765-0.962) and 0.875 (95 % CI: 0.741-0.945), respectively. The calibration curves of 14 d and 28 d hospital survival showed that the predicted probability of the model agreed well with the actual probability. Decision curve analysis (DCA) showed that the nomogram has high clinical application value. Conclusion: In-hospital survival rates of patients with COVID-19 were predicted using a nomogram, which will help clinicians in make appropriate clinical decisions.

A Free Amino Acid Diet Alleviates Colorectal Tumorigenesis through Modulating Gut Microbiota and Metabolites.

Colorectal cancer (CRC), a major global health concern, may be influenced by dietary protein digestibility impacting gut microbiota and metabolites, which is crucial for cancer therapy effectiveness. This study explored the effects of a casein protein diet (CTL) versus a free amino acid (FAA)-based diet on CRC progression, gut microbiota, and metabolites using carcinogen-induced (AOM/DSS) and spontaneous genetically induced (ApcMin/+ mice) CRC mouse models. Comprehensive approaches including 16s rRNA gene sequencing, transcriptomics, metabolomics, and immunohistochemistry were utilized. We found that the FAA significantly attenuated CRC progression, evidenced by reduced colonic shortening and histopathological alterations compared to the CTL diet. Notably, the FAA enriched beneficial gut bacteria like Akkermansia and Bacteroides and reversed CRC-associated dysbiosis. Metabolomic analysis highlighted an increase in ornithine cycle metabolites and specific fatty acids, such as Docosapentaenoic acid (DPA), in FAA-fed mice. Transcriptomic analysis revealed that FAA up-regulated Egl-9 family hypoxia inducible factor 3 (Egln 3) and downregulated several cancer-associated pathways including Hippo, mTOR, and Wnt signaling. Additionally, DPA was found to significantly induce EGLN 3 expression in CRC cell lines. These results suggest that FAA modulate gut microbial composition, enhance protective metabolites, improve gut barrier functions, and inhibit carcinogenic pathways.

Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence.

Objective: This study aimed to explore the association of single nucleotide polymorphisms (SNP) in the matrix metalloproteinase 2 (MMP-2) signaling pathway and the risk of vascular senescence (VS). Methods: In this cross-sectional study, between May and November 2022, peripheral venous blood of 151 VS patients (case group) and 233 volunteers (control group) were collected. Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway, assessed through carotid-femoral pulse wave velocity (cfPWV), and analyzed using multivariate logistic regression. The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality regression (GMDR) modeling. Results: Within the multivariate logistic regression models, four SNPs were screened to have significant associations with VS: chemokine (C-C motif) ligand 2 (CCL2) rs4586, MMP2 rs14070, MMP2 rs7201, and MMP2 rs1053605. Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype, and those of the T/T genotype had a 19.375-fold increased risk. CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. Conclusion: CCL2 rs4586, MMP-2 rs14070, MMP-2 rs7201, and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

[Correlation between femoral offset, rotation center and leg length discrepancy after total hip arthroplasty based on digital analysis].

OBJECTIVE: CT scans combined with Mimics software were used to measure femoral offset (FO), rotation center height (RCH) and lower leg length discrepancy (LLD) following total hip arthroplasty (THA), and the relationship between FO, RCH and LLD after THA is discussed. METHODS: Retrospective analysis was performed on 40 patients with unilateral THA who met standard cases from October 2020 to June 2022. There were 21 males and 19 females, 18 patients on the left side and 22 patients on the right side, aged range from 30 to 81 years old, with an average age of (58.90 ±14.13) years old, BMI ranged from 17.3 to 31.5 kg·m-2 with an average of (25.3±3.4) kg·m-2. There were 30 cases of femoral head necrosis (Ficat type Ⅳ), 2 cases of hip osteoarthritis (Tönnis type Ⅲ), 2 cases of developmental hip dislocation combined with end-stage osteoarthritis (Crowe type Ⅲ), and 6 cases of femoral neck fracture (Garden type Ⅳ). Three-dimensional CT reconstruction of pelvis was taken preoperative and postoperative, and three-dimensional reconstruction model was established after processing by Mimics software. FO, RCH and LLD were measured on the model. The criteria for FO reconstruction were as follows:postoperative bilateral FO difference less than 5 mm;the standard for equal length of both lower limbs was as follows:postoperative LLD difference less than 5 mm. RESULTS: Bilateral FO difference was positively correlated with LLD (r=0.744, P<0.001). Chi-square test was performed between the FO reconstructed group and the non-reconstructed eccentricity group:The results showed that the isometric ratio of lower limbs in the FO reconstructed group was significantly higher than that in the FO reconstructed group (χ2=6.320, P=0.012). The bilateral RCH difference was significantly negatively correlated with LLD(r=-0.877, P<0.001). There is a linear relationship between bilateral FO difference and bilateral RCH difference and postoperative LLD, and the linear regression equation is satisfied:postoperative LLD=0.038x-0.099y+0.257(x:postoperative bilateral FO difference, y:postoperative bilateral RCH difference; Unit:cm), F=77.993, R2=0.808, P=0.009. CONCLUSION: After THA, LLD increased with the increase of FO and decreased with the increase of RCH. The effect of lower limb isometric length can be obtained more easily by reconstruction of FO. There is a linear relationship between the bilateral FO difference and the bilateral RCH difference after THA and LLD, and the regression equation can provide a theoretical reference for judging LLD.

Rainfall-runoff partitioning in small watersheds of different vegetation types in the loess area based on hydrogen and oxygen isotope tracing.

Recognizing watershed runoff process and its component sources is a prerequisite for the rational use of water resources. To elucidate the effects and quantitative contributions of various vegetation types on the components of watershed runoff, we centered on the Caijiachuan main channel watershed in Jixian, Shanxi and five sub-watersheds with distinct vegetation types. By tracking the hydrological responses to two representative rainfall events and assessing the spatiotemporal variations in hydrogen and oxygen isotope signatures, we aimed to discern disparities in the runoff processes across these sub-watersheds and pinpoint their constituent origins. The results showed that under medium rainfall condition, the contribution rates of event water to the river flow of each watershed were in an order of protected forest (94.3%) > Caijiachuan main channel (83.1%) > agro-pastoral composite (64.3%) > plantation-secondary forest (52.4%) > cropland (0.3%) > secondary forest (0.0%); under light rainfall condition, plantation-secondary forest (52.4%) > protected forest (58.5%) > cropland (40.6%) > secondary forest (15.8%) > agro-pastoral composite (12.5%) > Caijiachuan main channel (9.3%). The event water contribution rate of secondary forest and protected forest watersheds to runoff was higher than that of plantation watersheds. The secondary forests watersheds had a stronger runoff storage capacity. The event water contribution rate of protected forest and agro-pastoral composite watersheds under medium rainfall intensity condition was greater than that under light rainfall intensity condition, while the event water contribution rate of cropland, plantation-secondary forest, and secondary forest watersheds was in adverse. The event water contribution to the runoff of forested watersheds was greater than that of cropland watersheds, which may be related to the presence of silt dams at the mouth of agricultural watershed channels. This study can provide a scientific basis for the analysis of water conservation and runoff change attribution in the loess area of west Shanxi.

Desulfovibrio desulfuricans and its derived metabolites confer resistance to FOLFOX through METTL3.

BACKGROUND: Chemoresistance is a critical factor contributing to poor prognosis in clinical patients with cancer undergoing postoperative adjuvant chemotherapy. The role of gut microbiota in mediating resistance to tumour chemotherapy remains to be investigated. METHODS: Patients with CRC were categorised into clinical benefit responders (CBR) and no clinical benefit responders (NCB) based on chemotherapy efficacy. Differential bacterial analysis using 16S rRNA sequencing revealed Desulfovibrio as a distinct microbe between the two groups. Employing a syngeneic transplantation model, we assessed the effect of Desulfovibrio on chemotherapy by measuring tumour burden, weight, and Ki-67 expression. We further explored the mechanisms underlying the compromised chemotherapeutic efficacy of Desulfovibrio using metabolomics, western blotting, colony formation, and cell apoptosis assays. FINDINGS: In comparison, Desulfovibrio was more abundant in the NCB group. In vivo experiments revealed that Desulfovibrio colonisation in the gut weakened the efficacy of FOLFOX. Treatment with Desulfovibrio desulfuricans elevates serum S-adenosylmethionine (SAM) levels. Interestingly, SAM reduced the sensitivity of CRC cells to FOLFOX, thereby promoting the growth of CRC tumours. These experiments suggest that SAM promotes the growth and metastasis of CRC by driving the expression of methyltransferase-like 3 (METTL3). INTERPRETATION: A high abundance of Desulfovibrio in the intestines indicates poor therapeutic outcomes for postoperative neoadjuvant FOLFOX chemotherapy in CRC. Desulfovibrio drives the manifestation of METTL3 in CRC, promoting resistance to FOLFOX chemotherapy by increasing the concentration of SAM. FUNDING: This study is supported by Wuxi City Social Development Science and Technology Demonstration Project (N20201005).

ASIC1 promotes migration and invasion of hepatocellular carcinoma via the PRKACA/AP-1 signaling pathway.

Hepatocellular carcinoma (HCC) exhibits a high mortality rate due to its high invasion and metastatic nature, and the acidic microenvironment plays a pivotal role. Acid-sensing ion channel 1 (ASIC1) is upregulated in HCC tissues and facilitates tumor progression in a pH-dependent manner, while the specific mechanisms therein remain currently unclear. Herein, we aimed to investigate the underlying mechanisms by which ASIC1 contributes to the development of HCC. Using bioinformatics analysis, we found a significant association between ASIC1 expression and malignant transformation of HCC, such as poor prognosis, metastasis and recurrence. Specifically, ASIC1 enhanced the migration and invasion capabilities of Li-7 cells in the in vivo experiment using an HCC lung metastasis mouse model, as well as in the in vitro experiments such as wound healing assay and Transwell assay. Furthermore, our comprehensive gene chip and molecular biology experiments revealed that ASIC1 promoted HCC migration and invasion by activating the PRKACA/AP-1 signaling pathway. Our findings indicate that targeting ASIC1 could have therapeutic potential for inhibiting HCC progression.

Human Mesenchymal Stem Cells on Size-Sorted Gelatin Hydrogel Microparticles Show Enhanced In Vitro Wound Healing Activities.

The demand for innovative therapeutic interventions to expedite wound healing, particularly in vulnerable populations such as aging and diabetic patients, has prompted the exploration of novel strategies. Mesenchymal stem cell (MSC)-based therapy emerges as a promising avenue for treating acute and chronic wounds. However, its clinical application faces persistent challenges, notably the low survivability and limited retention time of engraftment in wound environments. Addressing this, a strategy to sustain the viability and functionality of human MSCs (hMSCs) in a graft-able format has been identified as crucial for advanced wound care. Hydrogel microparticles (HMPs) emerge as promising entities in the field of wound healing, showcasing versatile capabilities in delivering both cells and bioactive molecules/drugs. In this study, gelatin HMPs (GelMPs) were synthesized via an optimized mild processing method. GelMPs with distinct diameter sizes were sorted and characterized. The growth of hMSCs on GelMPs with various sizes was evaluated. The release of wound healing promoting factors from hMSCs cultured on different GelMPs were assessed using scratch wound assays and gene expression analysis. GelMPs with a size smaller than 100 microns supported better cell growth and cell migration compared to larger sizes (100 microns or 200 microns). While encapsulation of hMSCs in hydrogels has been a common route for delivering viable hMSCs, we hypothesized that hMSCs cultured on GelMPs are more robust than those encapsulated in hydrogels. To test this hypothesis, hMSCs were cultured on GelMPs or in the cross-linked methacrylated gelatin hydrogel (GelMA). Comparative analysis of growth and wound healing effects revealed that hMSCs cultured on GelMPs exhibited higher viability and released more wound healing activities in vitro. This observation highlights the potential of GelMPs, especially those with a size smaller than 100 microns, as a promising carrier for delivering hMSCs in wound healing applications, providing valuable insights for the optimization of advanced therapeutic strategies.

Engineering metal-carbide hydrogen traps in steels.

Hydrogen embrittlement reduces the durability of the structural steels required for the hydrogen economy. Understanding how hydrogen interacts with the materials plays a crucial role in managing the embrittlement problems. Theoretical models have indicated that carbon vacancies in metal carbide precipitates are effective hydrogen traps in steels. Increasing the number of carbon vacancies in individual metal carbides is important since the overall hydrogen trapping capacity can be leveraged by introducing abundant metal carbides in steels. To verify this concept, we compare a reference steel containing titanium carbides (TiCs), which lack carbon vacancies, with an experimental steel added with molybdenum (Mo), which form Ti-Mo carbides comprising more carbon vacancies than TiCs. We employ theoretical and experimental techniques to examine the hydrogen trapping behavior of the carbides, demonstrating adding Mo alters the hydrogen trapping mechanism, enabling hydrogen to access carbon vacancy traps within the carbides, leading to an increase in trapping capacity.

Imaging diagnosis and efficacy monitoring by [89Zr]Zr-DFO-KN035 immunoPET in patients with PD-L1-positive solid malignancies.

Rationale: Although programmed death-ligand 1 (PD-L1) inhibitors have achieved efficacy in cancer therapy, their response rate is low. Differences in the prognosis of patients with cancer under anti-PD-L1 treatment are related to the PD-L1 level in tumors. Accurate PD-L1 detection can optimize the accuracy of tumor immunotherapy and avoid ineffective clinical diagnosis and treatments. Methods: We investigated the imaging efficiency and therapy monitoring capacity of [89Zr]Zr-DFO-KN035 immunoPET for tumors. We labeled the monodomain anti-PD-L1 antibody KN035 with the radionuclide zirconium-89 and used this tracer for PET imaging. [89Zr]Zr-DFO-KN035 uptakes in patients with PD-L1-positive tumors, including primary and metastatic tumors, as well as in normal tissues, were comparatively assessed by using positron emission tomography/computed tomography imaging. Results: In PD-L1-positive patients, [89Zr]Zr-DFO-KN035 was sensitive in tumor-targeting imaging and could detect multiple metastatic foci, including multiple bone metastases (tumor-to-muscle ratios of 7.102 and 6.118 at 55 and 120 h, respectively) and lymph-node metastases (tumor-to-muscle ratios of 11.346 and 6.542 at 55 and 120 h, respectively). The needed radioactive dose of [89Zr]Zr-DFO-KN035 (55.5-92.5 MBq) used in this study was considerably lower than that of [18F]FDG (370-555 MBq). [89Zr]Zr-DFO-KN035 monitored and predicted the site of adverse reactions in antitumor immunotherapy. Moreover, after antitumor treatment, [89Zr]Zr-DFO-KN035 enabled observational imaging for therapeutic efficacy evaluation, which can help predict patient prognosis. Conclusion: [89Zr]Zr-DFO-KN035 can be used for the diagnosis and therapy monitoring of PD-L1-positive tumors and provide noninvasive and comprehensive observations for tumor diagnostic imaging, prognosis prediction, and efficacy evaluation.

A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy.

BACKGROUND: The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non-small-cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. METHODS: This study evaluated the combination of IBI310 (an anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibody) and sintilimab (an anti-programmed death 1 [PD-1]) antibody) in NSCLC patients who have previously been treated with anti-PD-1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7-40.5) in cohort B. DCR were 46.7% (95% CI, 21.3-73.4) and 66.7% (95% CI, 38.4-88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow-up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35-2.73) versus 2.73 (95% CI, 1.41-4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09-not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13-NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment-related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. CONCLUSION: IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti-PD-1/L1-resistant NSCLC patients.

Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy.

Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced ferroptosis. The glutathione peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.