Shuanglongjiegu pill promoted bone marrow mesenchymal stem cell osteogenic differentiation by regulating the miR-217/RUNX2 axis to activate Wnt/ß-catenin pathway.

This study aimed to investigate the effects of Shuanglongjiegu pill (SLJGP) on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explore its mechanism based on miR-217/RUNX2 axis. Results found that drug-containing serum of SLJGP promoted BMSCs viability with a dose-dependent effect. Under osteogenic differentiation conditions, SLJGP promoted the expression of ALP, OPN, BMP2, RUNX2, and the osteogenic differentiation ability of BMSCs. In addition, SLJGP significantly reduced miR-217 expression, and miR-217 directly targeted RUNX2. After treatment with miR-217 mimic, the promoting effects of SLJGP on proliferation and osteogenic differentiation of BMSCs were significantly inhibited. MiR-217 mimic co-treated with pcDNA-RUNX2 further confirmed that the miR-217/RUNX2 axis was involved in SLJGP to promote osteogenic differentiation of BMSCs. In addition, analysis of Wnt/ß-catenin pathway protein expression showed that SLJGP activated the Wnt/ß-catenin pathway through miR-217/RUNX2. In conclusion, SLJGP promoted osteogenic differentiation of BMSCs by regulating miR-217/RUNX2 axis and activating Wnt/ß-catenin pathway.

Oleogels loaded with lycopene structured using Zein/EGCG/Ca2+ complexes: Preparation, characterization and potential application.

Oleogels have attracted considerable attention due to their excellent viscoelasticity and high content of polyunsaturated fatty acid. This study explored the potential of Zein/(-)-epigallocatechin-3-gallate/Ca2+ complexes oleogels loaded with lycopene as potential substitute for solid fats in biscuit formulations. Utilizing an emulsion-templated method, oleogels were prepared and characterized for visual appearance, droplet size, microstructure, and rheological properties. The incorporation of lycopene indicated a dose-dependent effect on these characteristics, achieving optimal properties at a concentration of 0.3 mg/mL. At this concentration, oleogels exhibited higher encapsulation efficiency (> 90 %), lower oil loss (< 2 %), and denser network structures. Rheological analysis highlighted the shear-thinning behavior, gel-like structure, and thixotropic recovery of oleogels. Substituting of margarine with lycopene-loaded oleogels in biscuits yielded products with regular appearance, uniform color, and potential health benefits, demonstrating the viability of these oleogels as a healthier alternative to traditional solid fats in baking.

Platelet-Derived Growth Factor C Facilitates Malignant Behavior of Pancreatic Ductal Adenocarcinoma by Regulating SREBP1 Mediated Lipid Metabolism.

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance.

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

The assembly mechanism of Zein/EGCG/PEG nanoparticles in a water system and their adsorption behavior at the oil-water interface.

In this study, the self-assembly mechanism of Zein/(-)-epigallocatechin-3-gallate/polyethylene glycol (Zein/EGCG/PEG) composite nanoparticles and their interface adsorption behavior at the oil-water interface were investigated by coarse-grained molecular dynamics simulation. Fourier transform infrared spectroscopy and conformation analysis demonstrated that there were electrostatic and hydrogen bond interactions between Zein and EGCG, physical entanglement between PEG and Zein, and hydrogen bond interaction between EGCG and PEG. The nanoparticles accumulated at the oil-water interface, and there was an obvious interface layer between oil phase and water phase, as indicated by confocal laser scanning microscope and scanning electron microscope. The adsorbing of Zein/EGCG/PEG nanoparticles at the oil-water interface was confirmed by coarse-grained molecular dynamics simulation. Further findings confirmed that Zein/EGCG/PEG nanoparticles could serve as stabilizers for oleogels with self-supporting structure, viscoelastic solid behavior and temperature response characteristics. The current research offered a novel approach to enhance protein interface characteristics and create food-grade emulsifiers and oleogelators.

Recent advances in dietary polyphenols (DPs): antioxidant activities, nutrient interactions, delivery systems, and potential applications.

Dietary polyphenols (DPs) have garnered growing interest because of their potent functional properties and health benefits. Nevertheless, the antioxidant capabilities of these substances are compromised by their multifarious structural compositions. Furthermore, most DPs are hydrophobic and unstable when subjected to light, heat, and varying pH conditions, restricting their practical application. Delivery systems based on the interactions of DPs with food constituents such as proteins, polypeptides, polysaccharides, and metal ions are being created as a viable option to improve the functional activities and bioavailability of DPs. In this review, the latest discoveries on the dietary sources, structure-antioxidant activity relationships, and interactions with nutrients of DPs are discussed. It also innovatively highlights the application progress of polyphenols and their green nutraceutical delivery systems. The conclusion drawn is that the various action sites and structures of DPs are beneficial for predicting and designing polyphenols with enhanced antioxidant attributes. The metal complexation of polyphenols and green encapsulation systems display promising outcomes for stabilizing DPs during food processing and in vivo digestion. In the future, more novel targeted delivery systems of DPs for nutrient fortification and intervention should be developed. To expand their usage in customized food products, they should meet the requirements of specific populations for personalized food and nutrition.

Synthesis of α-Bromo Arylethyl Sulfonyl Fluorides and ß-Arylethenesulfonyl Fluorides via Copper-Catalyzed Meerwein Arylation.

A practical copper-catalyzed process for the synthesis of the ß-arylethenesulfonyl fluorides is described. A series of α-bromo arylethyl sulfonyl fluorides was prepared via Meerwein reaction from arenediazonium tetrafluoroborates and ethenesulfonyl fluoride (ESF) under mild conditions. The following ß-arylethenesulfonyl fluorides were further obtained through a ß-elimination reaction. This protocol features excellent regio- and stereoselectivity and broad substrate scope.

[The effect of exercise on platelet-activating factor metabolism in the livers of rats fed high-fat diet].

This paper aimed to investigate the effects of exercise on hepatic platelet-activating factor (PAF) metabolism in rats fed a high-fat diet. Thirty-two male Sprague-Dawley (SD) rats were divided into control group (C), high-fat diet group (H), exercise group (EC), and high-fat diet+exercise group (EH). Serum lipids, glucose, insulin and markers of hepatic injury after a 16-week dietary and/or exercise intervention (60 min/day, 6 times/week) were measured by biochemical analysis; liver lipidomic profiles were analyzed by liquid chromatograph-mass spectrometer (LC-MS). Gene and protein expression of enzymes related to PAF metabolism were determined by qPCR and Western blot respectively. The results showed that high-fat diet feeding significantly increased the levels of low-density lipoprotein-cholesterol (LDL-C) and liver injury markers including purine nucleoside phosphorylase (PNP) and malondialdehyde (MDA) in rats, which were decreased by exercise. Furthermore, high-fat diet feeding significantly increased the hepatic PAF content, which was also attenuated by exercise. In addition, although high-fat diet treatment resulted in an increase in the expression of both PAF synthetase (PAF-CPT and PLA2) and hydrolase (Lp-PLA2 and PAF-AH(II)), induction of PAF synthetase was much greater than that of PAF hydrolase. While exercise increased the expression of Lp-PLA2 and PAF-AH(II) and decreased the expression of PAF-CPT and PLA2, key PAF synthesizing enzymes. In conclusion, high-fat diet-induced increase in hepatic PAF content is mainly due to the increase of its pathological synthesis at the translational level. Exercise reduces hepatic PAF content in high-fat fed rats by increasing PAF hydrolysis and decreasing its synthesis.

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups.

Background: Colorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. Methods: A retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. Results: The blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. Conclusions: Our study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway.

Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.

A Photoelectrochemical Retinomorphic Synapse.

Reproducing human visual functions with artificial devices is a long-standing goal of the neuromorphic domain. However, emulating the chemical language communication of the visual system in fluids remains a grand challenge. Here, a "multi-color" hydrogel-based photoelectrochemical retinomorphic synapse is reported with unique chemical-ionic-electrical signaling in an aqueous electrolyte that enables, e.g., color perception and biomolecule-mediated synaptic plasticity. Based on the specific enzyme-catalyzed chromogenic reactions, three multifunctional colored hydrogels are developed, which can not only synergize with the Bi2S3 photogate to recognize the primary colors but also synergize with a given polymeric channel to promote the long-term memory of the system. A synaptic array is further constructed for sensing color images and biomolecule-coded information communication. Taking advantage of the versatile biochemistry, the biochemical-driven reversible photoelectric response of the cone cell is further mimicked. This work introduces rich chemical designs into retinomorphic devices, providing a perspective for replicating the human visual system in fluids.

Mulberry polyphenols restored both small and large intestinal microflora in db/db mice, potentially alleviating type 2 diabetes.

Polyphenols in mulberry fruit have potential anti-diabetic effects by targeting the gut microbiota. This study investigated how mulberry polyphenols (MPs) influence the microbiota of the small and large intestines and their effects on type 2 diabetes symptoms. The results showed lower microbiota densities in the small intestine. MP treatments improved microbiota richness and diversity in both intestines, similar to metformin. In particular, at a 400 mg kg-1 dose, mulberry polyphenols decreased Firmicutes, Lactobacillus, and Bacilli, while increasing Bacteroidetes, leading to elevated propionate and butyrate levels. Less abundant small intestinal microbiota, like Enterobacterales, Mycoplasmatales, Enterobacteriaceae, and Ureaplasma, were involved in regulating blood glucose and insulin levels. Functional analysis suggested that mulberry polyphenols reshaped the small intestinal microbiota to influence blood glucose balance via unknown pathways, while in the large intestine, they primarily affected blood glucose through carbohydrate transport and metabolism. Based on their ability to regulate the composition of intestinal flora, MPs likely improved glucose homeostasis by enhancing glucose utilization, supporting pancreatic tissue health, and increasing serum antioxidant capacity. However, the specific mechanisms underlying this potential are yet to be fully explored. This study provides new insights into the influence of MPs on remodeling the microbiota residing in both the small and large intestines, which thereby may contribute to the improvement of the pathophysiology of type 2 diabetes.

Cost-effectiveness of Finerenone in Addition to Standard of Care for Patients with Chronic Kidney Disease and Type 2 Diabetes in China.

INTRODUCTION: Adding finerenone to current standard of care (SoC), as recommended by Chinese guidelines, has shown substantial benefit in delaying chronic kidney disease (CKD) progression and reducing cardiovascular risk in patients with CKD and type 2 diabetes (T2D) in the landmark FIDELIO-DKD trial. This study aimed to evaluate the cost-effectiveness of finerenone + SoC versus SoC alone among Chinese patients with T2D and CKD from a healthcare system perspective. METHODS: A cost-effectiveness model (FINE-CKD) has been developed and published, with health states defined for CKD stages (CKD 1/2, CKD 3, CKD 4, and CKD 5 without renal replacement therapy (RRT), dialysis, or transplant) and cardiovascular event history. Additionally, the model also considered adverse events. Transition probabilities and event risks were derived using patient-level data from Asian population analysis of FIDELIO-DKD. Since the price of finerenone after the national reimbursement drug list (NRDL) inclusion was confidential, the cost of finerenone in the model was assumed to be the same as that of SoC. Other health resource costs were gathered from literature and supplemented by physician interviews. Measured by the EQ-5D-5L questionnaire, quality of life was translated into utilities based on the Chinese EQ-5D-5L value set. RESULTS: Discounted at 5.0% annually, over a lifetime horizon, finerenone + SoC resulted in a quality-adjusted life years (QALYs) gain of 0.321 versus SoC alone (8.660 vs. 8.338 QALYs), due to a reduction in the incidence of cardiovascular events and dialysis. Total costs per patient were lower under finerenone + SoC than SoC alone (381,130 CNY vs. 392,390 CNY). As a result, finerenone + SoC was a dominant treatment strategy compared with SoC alone. Sensitivity analysis has confirmed the robustness of this study. CONCLUSION: Adding finerenone to SoC was likely to be either a dominant or cost-effective treatment option compared with SoC alone in Chinese patients with CKD and T2D.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

A systematic review on reporting quality of economic evaluations for negotiated glucose-lowering drugs in China national reimbursement drug list.

BACKGROUND: This study aimed to examine the reporting quality of existing economic evaluations for negotiated glucose-lowering drugs (GLDs) included in China National Reimbursement Drug List (NRDL) using the Consolidated Health Economic Evaluation Reporting Standards 2013 (CHEERS 2013). METHODS: We performed a systematic literature research through 7 databases to identify published economic evaluations for GLDs included in the China NRDL up to March 2021. Reporting quality of identified studies was assessed by two independent reviewers based on the CHEERS checklist. The Kruskal-Wallis test and Mann-Whitney U test were performed to examine the association between reporting quality and characteristics of the identified studies. RESULTS: We have identified 24 studies, which evaluated six GLDs types. The average score rate of the included studies was 77.41% (SD:13.23%, Range 47.62%-91.67%). Among all the required reporting items, characterizing heterogeneity (score rate = 4.17%) was the least satisfied item. Among six parts of CHEERS, results part scored least at 0.55 (score rate = 54.79%) because of the incompleteness of characterizing uncertainty. Results from the Kruskal-Wallis test and Mann-Whitney U test showed that model choice, journal type, type of economic evaluations, and study perspective were associated with the reporting quality of the studies. CONCLUSIONS: There remains room to improve the reporting quality of economic evaluations for GLDs in NRDL. Checklists such as CHEERS should be widely used to improve the reporting quality of economic researches in China.

High internal phase pickering emulsions stabilized by zein/whey protein nanofibril complexes: Preparation and lycopene loading.

High internal phase Pickering emulsions (HIPPEs) prepared from natural polymers have attracted much attention in the food manufactures. However, single zein-stabilized HIPPEs are poorly stable and prone to flocculation near the isoelectric point. To address this issue, in this study, zein and whey protein nanofibrils (WPN) complex nanoparticles (ZWNPs) were successfully prepared using a pH-driven method, and ZWNPs were further used as HIPPEs stabilizers. The results showed that zein and WPN were combined together through hydrogen bonding and hydrophobic interaction to form ZWNPs, and the HIPPEs stabilized by ZWNPs had excellent stability, which could effectively protect the internally encapsulated lycopene and improve the bioaccessibility of lycopene. In conclusion, this study provides a new strategy for the preparation of stable hydrophobic protein-based HIPPEs, represented by zein.

Creatinine-to-cystatin C ratio and body composition predict response to PD-1 inhibitors-based combination treatment in metastatic gastric cancer.

Background: Creatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy. Methods: One hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023. A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates. Results: The CCR was positively correlated with SMI (r=0.43; P<0.001), but not with SATI or VATI (P>0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P<0.001). Multivariate Cox analysis showed that low CCR (HR=2.395, 95% CI: 1.234-4.648, P=0.010 for PFS rate; HR=2.528, 95% CI: 1.317-4.854, P=0.005 for OS rate) and low SATI (HR=2.188, 95% CI: 1.050-4.560, P=0.037 for PFS rate; HR=2.818, 95% CI: 1.381-5.752, P=0.004 for OS rate) were both independent prognostic factors of poor 8-month PFS rate and 16-month OS rate. A nomogram based on CCR and BC-parameters showed a good performance in predicting the 12- and 16-month OS, with a concordance index of 0.756 (95% CI, 0.722-0.789). Conclusions: Low pre-treatment CCR and SATI were independently associated with lower response rates and worse survival in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.

Mechanisms of electroacupuncture relieves uterine smooth muscle spasm in dysmenorrhea rats based on Rho/ROCK signaling pathway. / 基于Rho/ROCKä¿¡å·é€šè·¯æŽ¢è®¨ç”µé’ˆä»»è„‰ã€ç£è„‰ç»ç©´ç¼“è§£ç±»ç—›ç»æ¨¡åž‹å¤§é¼ å­å®«å¹³æ»‘è‚Œç—‰æŒ›çš„æœºåˆ¶.

OBJECTIVES: To investigate the effect of electroacupuncture (EA) on Rho/Rho-associated coiled-coil-forming kinases (ROCK) signaling pathway of uterus tissue in rats with dysmenorrhea, so as to explore the underlying mechanism of EA treating primary dysmenorrhea (PD) and uterine smooth muscle spasm, and to observe whether there is a difference in the effect of meridian acupoints in Conception Vessel (CV) and Governer Vessel (GV). METHODS: Sixty female SD rats were randomly divided into saline, model, CV, GV, and non-acupoint groups, with 12 rats in each group. The dysmenorrhea model was established by subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin (OT). EA (2 Hz) was applied to "Qihai" (CV6) and "Zhongji" (CV3) for CV group, "Mingmen" (GV4) and "Yaoshu" (GV2) for GV group, "non-acupoint 1" and "non-acupoint 3" on the left side for non-acupoint group, and manual acupuncture was applied to "Guanyuan" (CV4) for CV group, "Yaoyangguan" (GV3) for GV group, "non-acupoint 2" on the left side for non-acupoint group. The treatment was conducted for 20 min each time, once daily for 10 days. The writhing score was evaluated. The smooth myoelectric signals of rats' uterus in vivo were recorded by multi-channel physiological recorder. The uterine histopathological changes were observed by HE staining. The contents of prostaglandin F2α (PGF2α), OT and calcium ion (Ca2+) in uterine tissue of rats were detected by ELISA. The protein and mRNA expression levels of smooth muscle 22-α (SM22-α), RhoA and ROCKⅡ in uterine tissue were detected by Western blot and fluorescence quantitative PCR, respectively. RESULTS: Compared with the saline group, the writhing score of rats in the model group was increased (P<0.01), the amplitude voltage of uterine smooth muscle in vivo was elevated (P<0.01), the contents of PGF2α, OT and Ca2+, the protein and mRNA expression of SM22-α, RhoA and ROCK Ⅱ in uterine tissue were all increased (P<0.01). Compared with the model and the non-acupoint groups, the writhing scores of the CV and the GV groups were decreased (P<0.01, P<0.05), the amplitude voltage of uterine smooth muscle was decreased (P<0.01), the contents of PGF2α, OT and Ca2+ in uterine tissue were decreased (P<0.01, P<0.05), and the protein expression and mRNA expression of SM22-α, RhoA and ROCKⅡ in uterine tissue were decreased (P<0.01, P<0.05). HE staining showed extensive exfoliation of uterine intima with severe edema and increased glandular secretion in the model group, which was alleviated in the CV and GV groups. CONCLUSIONS: EA at acupoints of CV and GV can significantly reduce the writhing score, uterine smooth muscle amplitude voltage, pathological injury degree of uterus, and relieve spasm of uterine smooth muscle in dysmenorrhea rats, which may be related to its effect in regulating PGF2α and OT contents, inhibiting the Rho/ROCK signaling pathway, and reducing the SM22-α, RhoA, ROCKⅡ protein and mRNA expression, and Ca2+ content in uterine tissue.