Purpose: This study aimed to evaluate the safety and efficacy of gemcitabine and cisplatin (GP) regimen in combination with immune checkpoint inhibitor sintilimab as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC) patients and the feasibility of the following selective bladder sparing surgery. Materials and Methods: Patients with histopathologically confirmed urothelial carcinoma without distant metastases (T2-4a, N ≤ 1, M0, American Joint Committee of Cancer 8th) and with adequate organ function will be enrolled. The therapeutic regimen was sintilimab 200 mg once on day 8, gemcitabine 1,000 mg/m2 and cisplatin 35 mg/m2 once on days 1 and 8, every 21 days for four cycles. The primary endpoint was pathologic complete response (pCR, pT0N0) rate. The secondary end points were ypT < 2 rate, R0 resection rate, event-free survival, and safety. Results: From May 4, 2020, to May 20, 2023, 55 patients were enrolled. Forty-six patients were evaluated for efficacy. Among the 42 patients who underwent surgery, 16 patients (38.0%) achieved pCR. Thirty-three patients (78.6%) achieved pT < 2. With a median follow-up of 15.7 months, the 1-year event-free survival was 91.3%. Notwithstanding the poor pathological baseline characteristic of a high T3-T4a proportion (39.1%), a promising bladder preservation (including 22 patients transurethral resection of bladder tumor, 5 patients partial cystectomy, and 4 surveillances) rate was achieved (67.4%). The most common grade ≥ 3 treatment-related adverse events was neutropenia (n=15, 27.3%), which was related to chemotherapy. There were no grade 3 immune-related adverse events. Conclusion Neoadjuvant GP plus sintilimab is a promising regimen for MIBC patients, with relatively high pT < 2 rate and triggering the emerging roles for the multi-disciplinary team decision-making for bladder sparing surgery.

Objective To gain insights into the biological characteristics of different populations of Culex tritaeniorhynchus within and around the Yellow Sea wetland from the perspective of the occurrence of resistance, we investigated the levels of resistance to deltamethrin and kdr gene mutation in the wetland and its peripheral areas. Methods Specimens were collected from Cx. tritaeniorhynchus populations at two monitoring sites in the Rare Bird National Nature Reserve and Tiaozi Ni Wetland Scenic Area, and also from two populations in Yancheng City and the Liuhe District of Nanjing, and the resistance of these mosquitoes to deltamethrin was determined using the CDC biotest bottle method. For each concentration of deltamethrin assessed, a random subset of exposed specimens was selected for amplification of the kdr gene fragment, followed by Sanger sequencing to identify and analyze resistance-associated mutations. Results The LC50 levels of deltamethrin among mosquitoes from the four populations in Luhe, Yancheng, the Rare Bird National Nature Reserve and the Tiaozi Ni Wetland Scenic Area were 2.048 5, 7.798 2, 3.473 3, and 17.695 5 mg/mL, respectively, with corresponding concentrations of deltamethrin ranging from 0.005 to 5.000,0.050 to 50.000,0.050 to 25.000 and 0.050 to 50.000 mg/mL, respectively. Furthermore, the ranges of the KT50 values were 11.76-107.43, 67.05-216.30,29.77-107.43 and 28.40-329.51 min; the 1-h knockdown rates were 34.58%-99.15%, 9.52%-43.80%, 55.09%-73.01%, and 10.09%-68.07%; and the 24-h mortality rates were 12.15%-67.52%,9.52%-79.56%,13.17%-82.21%, and 11.01%-78.99%, respectively. With respect to kdr gene mutation, we assayed a total of 63,70,59, and 57 mosquitoes for the four populations, for which we detected L1014F mutation frequencies of 14.29%, 35.00%, 20.34%, and 31.58%, respectively, with a majority of these mutations being heterozygous for resistance. In addition, five adult mosquitoes were identified has having synonymous mutations at site 1011[i. e. , AAT(asparagine)mutation to AAC(asparagine)]. Conclusions Our findings revealed the clear resistance of Cx. tritaeniorhynchus to deltamethrin in the Yancheng region of the Yellow Sea wetland, and the resistance phenotype and kdr frequency of Cx. tritaeniorhynchus in the wetland environment were comparable to those of Cx. tritaeniorhynchus in the wetland environment, thereby indicating that the resistance of different populations of Cx. tritaeniorhynchus was homogeneous under the pressure of different insecticide selection within and around the wetland. However, the underlying mechanisms need to be further studied.

The accumulation of uremic toxins such as urea nitrogen, blood creatinine, and uric acid of patients with renal failure in vivo would lead to aggravated kidney damage. In this study, coated aldehyde oxy-starch (CAO) was used as an adsorbent to investigate its in vitro adsorption performance on renal failure indexes for urea, indoxyl sulfate (INS), monomethylamine (MMA), dimethylamine (DMA), uric acid (UA), and creatinine (Cr). The effects of variables such as pH, temperature, concentration, dosage, and time on the adsorption capacity of CAO were systematically investigated, employing analytical techniques of high-performance liquid chromatography (HPLC) and gas chromatography (GC). The results revealed that CAO exhibited a strong adsorption capacity for urea, INS, and MMA, alongside a moderate adsorption capacity for DMA, UA, and Cr. The adsorption kinetics and thermodynamic studies indicated that the adsorption of urea and UA by CAO were fitted in pseudo-first-order kinetics, and the adsorption isotherm aligned with the Freundlich adsorption model. The enthalpy change ΔH of urea in adsorption was in the range of 40 to 60 kJ·mol^-1, which demonstrated the presence of strong adsorption force due to the interactions of coordinating groups. The ΔH of UA was greater than 80 kJ·mol^-1, indicating the generation of chemical bonds during the adsorption. Both of them, Gibbs free energy ΔG was less than 0, within the range of -20 to 0 kJ·mol^-1, suggested that the adsorption of urea and UA by CAO occurred spontaneously as physical adsorption process. The adsorption entropy ΔS of urea and UA was > 0, which indicated an increase in entropy throughout the adsorption. The infrared spectroscopygram showed the formation of a chemical bond, specifically the imine bond, following the adsorption of urea by CAO, thereby indicating a chemical reaction during the adsorption. This study elucidates the adsorption mechanism of CAO on various indexes of renal failure, providing a scientific basis for its clinical usage.

ObjectiveTo explore the potential mechanism of acupuncture with the method of soothing the liver and regulating the mind in improving depressive disorder. MethodsEighteen C57BL/6J mice were randomly divided into blank group， model group， and acupuncture group， with 6 mice in each group. The model group and the acupuncture group were subjected to depression induction by intraperitoneal injection of lipopolysaccharide （LPS）， while the blank group received an equal volume of normal saline once daily for seven consecutive days. Concurrently， the acupuncture group received "soothing the liver and regulating the mind" acupuncture intervention starting from the first day of modeling， once daily for 14 days； whereas the blank group and the model group were only restrained without acupuncture. The sucrose preference test was used to assess sucrose preference rate， the open-field test to measure center stay time and total travel distance， and the forced swim test to evaluate immobility time. Hematoxylin-eosin （HE） staining was performed to observe hippocampal morphological changes. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in hippocampal tissue. Western blot analysis was conducted to examine the protein expression levels of Toll-like receptor 4 （TLR4） and nuclear factor-κB （NF-κB） in the hippocampus. ResultsCompared to the blank group， the model group showed a significant reduction in sucrose preference rate， center stay time， and total travel distance， along with a significant increase in immobility time in the forced swim test， hippocampal IL-1β， IL-6， and TNF-α levels， as well as TLR4 and NF-κB protein expression （P＜0.01）， and the histological examination revealed blurred hippocampal neuronal boundaries， loose arrangement， and some neurons exhibiting nuclear pyknosis and deep staining. Compared to the model group， the acupuncture group demonstrated a significant increase in sucrose preference rate， center stay time， and total travel distance， along with a significant reduction in immobility time in the forced swim test， hippocampal IL-1β， IL-6， and TNF-α levels， and TLR4 and NF-κB protein expression （P＜0.01）， and the histological analysis showed that hippocampal neurons in the acupuncture group were more tightly arranged， with reduced nuclear pyknosis and deep staining. ConclusionAcupuncture with the "soothing the liver and regulating the mind" method can significantly improve depression-like behavior， potentially by inhibiting the hippocampal TLR4/NF-κB signaling pathway and alleviating inflammatory responses.

Objective:To analyse the impact of diagnosis-related groups (DRG) payment reform on the length of stay and hospitalisation expenses of patients in pilot medical institutions of Beijing, for references for the formulation and optimisation of DRG payment related policies.Methods:The home page data of inpatient medical records from 56 medical institutions that implemented DRG payment in Beijing from April to October 2021 (before DRG payment reform) and April to October 2022 (after DRG payment reform). Patients participating in the basic medical insurance for urban employees in Beijing were selected as the reform group, and others served as the control group. The difference-in-differences model (DID) were used to analyse the related indicators, to evaluate the effectiveness of the reform.Results:This study comprised a total of 3 294 003 inpatients. Of them, 1 714 134 cases were in the control group (911 100 cases before the reform and 803 034 cases after) and 1 579 869 cases were in the study group (802 899 cases before the reform and 776 970 cases after). The gender, age composition and treatment methods of patients changed little before and after the reform. But the proportion of patients with severe comorbidities or complications rose from 11.11% before the reform to 13.19% after the reform. Through the analysis of the DID model, the DRG payment reform could reduce the length of stay ( P=0.001) and hospitalization expenses of patients ( P<0.001), and played a certain optimising role in the cost structure. Among them, the proportion of medical service expenses did not change significantly ( P=0.977), the proportion of inspection and testing expenses, as well as drug expenses decreased slightly ( P=0.001, P=0.004), and the proportion in consumable expenditures increased slightly ( P=0.001). Conclusions:DRG payment reform played a positive role in shortening the length of stay and hospitalization expenses. It was suggested that medical institutions in Beijing should further optimize the structure of patient hospitalization expenses, with a focus on exploring effective ways to increase the medical service revenue and reasonably control the consumables costs.

Objective To explore the effect of SGLT2 inhibitor(SGLT2i)Dagaglipzin(Dap)on mitochondrial autophagy in cardiomyocytes in diabetic cardiomyopathy(DCM)by regulating mitochondrial membrane transporter TOM20.Methods H9C2 cardiomyocytes cultured in vitro were divided into normal control(Con)group,HG+PA group,knockout TOM20(HG+PA+siTOM20)group,knockout control(HG+PA+siNC)group,Dap intervention(HG+PA+Dap)group,and solvent control(HG+PA+DMSO)group.The expression of TOM20 was predicted by RNA-seq second-generation sequencing in HG+PA group.The expression of TOM20 and mitochondrial autophagy related proteins was detected by Western blot,the mitochondrial membrane potential was measured by immunofluorescence staining,and the mitochondrial autophagy level was evaluated by transmission electron microscopy.Results Compared with Con group,protein expressions of TOM20 and P62 were increased(P<0.05),while protein expressions of ULK1,Parkin,Beclin1 and LC3-B were decreased(P<0.05),mitochondrial membrane potential was destroyed,the number of mitochondrial autophagosomes was reduced,and autophagy activity was inhibited in HG+PA group.Compared with HG+PA+siNC group and HG+PA+DMSO group,the protein expressions of TOM20 and P62 were decreased(P<0.05),while the protein expressions of ULK1,Parkin,Beclin1 and LC3-B were increased(P<0.05),the damage of mitochondrial membrane potential decreased,the number of mitochondrial autophagosomes increased,and the inhibition of autophagy activity reversed in HG+PA+siTOM20 and HG+PA+DAPA groups.Conclusions SGLT2 inhibitors appear to partially restore mitochondrial function in diabetic cardiomyopathy by suppressing TOM20 expression,potentially through activation of mitochondrial autophagy.

Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it's imperative to elucidate the impact of CAFs on SCs in PNI⁺ OSCCs. We describe a disease progression-driven shift of PNI^- towards PNI⁺ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Schwann Cells/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Cancer-Associated Fibroblasts/metabolism* ; Animals ; Carcinoma, Squamous Cell/metabolism* ; Neoplasm Invasiveness/pathology* ; Male ; Female ; Mice ; Cell Movement/physiology* ; Cell Proliferation/physiology* ; Cell Line, Tumor ; Leukemia Inhibitory Factor/metabolism* ; Middle Aged

In China, the regulatory framework for medical device procurement and sales, particularly concerning anti-commercial bribery, relies heavily on punitive mechanisms applied after violations occur. Consequently, there is an urgent need to establish a scientific risk regulation framework as a complementary approach. Effective risk-oriented regulatory models require precise identification of risk areas in commercial bribery. Focusing on several major procurement scenarios such as centralized bulk-buying, tendering and bidding processes, in-hospital procurement, and online purchasing, this article analyzes the structural factors contributing to these risks, represented by the absence of certification mechanisms, lack of transparency in information disclosure, and inadequate checks and balances. Based on official risk assessment results, this study applies the theory of power and responsibility to propose a preventive regulatory framework that combines industry self-discipline and administrative oversight. By combining these approaches, the framework aims to develop regulatory measures that can effectively reduce commercial bribery risks and prevent illegal and non-compliant conduct.
China ; Equipment and Supplies/economics* ; Commerce/legislation & jurisprudence* ; Humans ; Risk Assessment

Objective:To investigate the protective effect of quercetin against 5-fluorouracil(5-FU)-induced damage in the human immortalized keratinocytes(HACAT),and to elucidate its possible mechanism.Methods:The HACAT cells were divided into control group(normal cultured cells),5-FU group(treated with 7.5 mg·L-1 5-FU for 24 h),and low,medium,and high doses of quercetin groups(HACAT cells treated with 25,50,and 75 μmol·L-1 quercetin combined with 7.5 mg·L-15-FU for 24 h).Cell counting kit-8(CCK-8)assay was used to detect the survival rates of HACAT cells treated with different doses(0,10,25,50,75 and 100 μmol·L-1)of quercetin in various groups.The fluorescent probe of reactive oxygen species(ROS)was used to detect ROS levels in the HACAT cells in various groups.Annexin Ⅴ-FITC/PI double staining was used to detect the apoptosis of HACAT cells in various groups.Western blotting method was used to detect the expression levels of B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),Cleaved Caspase-3,cyclooxygenase-2(COX-2),interleukin-1 β(IL-1β),and interleukin-6(IL-6)in the HACAT cells in various groups.Results:The CCK-8 assay results showed that compared with 0 μmol·L-1 quercetin group,the survival rates of HACAT cells in 10,25,50 and 75 μmol·L-1quercetin groups showed no significant differences(P＞0.05),while the survival rates of HACAT cells in 100 μmol·L-1 quercetin group was significantly decreased(P＜0.05).Compared with 5-FU group,the survival rates of the HACAT cells in low,medium and high doses of quercetin group were significantly increased(P＜0.05).Compared with 5-FU group,the ROS levels in low,medium,and high doses of quercetin groups were significantly decreased(P＜0.05).Annexin Ⅴ-FITC/PI double staining assay showed that compared with 5-FU group,the apoptotic rates in low,medium and high doses of quercetin groups were significantly decreased(P＜0.05).The Western blotting results showed that compared with 5-FU group,the expression levels of Bcl-2 protein in medium and high doses of quercetin groups were significantly increased(P＜0.05),the expression levels of Bax and Cleaved Caspase-3 proteins in low,medium and high doses of quercetin groups were significantly decreased(P＜0.05),the expression levels of COX-2 protein in medium and high doses of quercetin groups were significantly decreased(P＜0.05),and the expression levels of IL-1β and IL-6 proteins in medium dose of quercetin group were significantly decreasd(P＜0.05).Conclusion:Quercetin has protective effect on 5-FU-induced damage in the HACAT cells,and its mechanism may be related to the reduction of the expression of ROS and inflammatory factor COX-2 which attenuate the apoptosis.

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis