Objective To study the antitumor activities of RRx-001 derivatives with novel covalent fragments. Methods Four targeted compounds were designed and synthesized. The structures were confirmed by ¹H NMR and HRMS. A549 and HCT116 cancer cell lines were selected for antiproliferative activity assays. Results All the compounds revealed antitumor activities and compound ZM528 showed the best antitumor activity against these two cell lines with IC₅₀ values of （5.1±4.8） μmol/L and （6.0±2.7） μmol/L, respectively. Conclusion The result indicated that bromoacetyl group of RRx-001 could be substituted with other covalent fragments.

Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Objective:To evaluate the healthcare accessibility and quality of diagnosis and treatment services of Internet hospitals in China.Methods:One hundred and eighty Internet hospitals in 60 cities were seleted based on the sampling of development levels in the eastern, central and western regions of China. From April to May 2023, standardized patients methodology was applied to evaluate the accessibility(including the number of Internet hospitals, functional settings, online doctor status, the doctor′s attending rate and consultation fees) and diagnosis and treatment service quality(including the diagnosis and treatment services quality, response speed and patient′s evaluation) of Internet hospitals.Results:The average opening rate of Internet hospitals in China was 52.9% (560/1 058), the average online rate of doctors was 64.2% (1 099/1 713), the average doctor′s attending rate was 33.6% (112/333), the average consultation fee was 4.85 yuan, the average score of consultation was 1.92 out of 9, the average score of diagnosis and treatment was 1.12 out of 4, the average score of the response speed was 1.70 out of 3, and patient satisfaction was 2.73 out of 3.Conclusions:The Internet hospital accessibility in China is unevenly developed, and the overall quality of diagnosis and treatment is low. It is recommended to accurately position and optimize the function of Internet hospital, establish the incentive mechanism for online consultation doctors, construct and improve the regulatory system of Internet hospital diagnosis and treatment, so as to improve the accessibility and quality of diagnosis and treatment of Internet hospitals.

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr⁹⁹⁰ to enhance its activity. Mutation of SERCA2-Tyr⁹⁹⁰ disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca²⁺_ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca²⁺_ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr⁹⁹⁰ in HCC.

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. The pathogenesis of OLP is still unclear. Immune abnormalities mediated by T cells and related cytokines play a crucial role in the pathogenesis of OLP. In recent years, glycolytic metabolism-related transporters, enzymes and regulators, such as glucose transporter-1 (Glut1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), mammalian target of rapamycin (mTOR) and hypoxia inducible factor-1α (HIF-1a), have attracted an increasing amount of attention in OLP by regulating the proliferation and differentiation of T cells and the secretion of inflammatory factors. It has been shown that 2-deoxy-D-glucose (2-DG) or rapamycin (RAPA) inhibits the glycolytic metabolism of T cells and then inhibits OLP. This article reviews the research progress of glycolytic metabolism-related transporters, enzymes and regulatory factors in OLP in recent years.

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2^Y64A and βarr2^Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Objective:To explore the coexisting gene mutations of FLT3-ITD mutation and its association with partial clinical parameters in acute myeloid leukemia (AML).Methods:The clinical data of 236 newly diagnosed AML outpatients and hospitalized patients of Changzhou No.2 People's Hospital and the Second People's Hospital of Wuxi between December 2012 and August 2019 were retrospectively analyzed. Genome DNA-polymerase chain reaction (PCR) combined with Sanger sequencing was used to detect FLT3-ITD mutations, and 51 tumor target gene mutations in patients with FLT3-ITD mutations were detected by using high-throughput DNA sequencing combined with Sanger sequencing.Results:Among 236 AML patients, FLT3-ITD mutations were found in 71 cases (30.1%). About 97.2% (69/71) patients with FLT3-ITD mutations were accompanied by additional mutations, of which 19 patients harbored double coexisting genes mutations, 24 patients harbored 3 coexisting genes mutations and 26 patients harbored ≥ 4 coexisting genes mutations. The most common coexisting genes mutations were NPM1 (55 cases, 77.5%), followed by DNMT3A (36 cases, 50.7%), TET2 (9 cases, 12.7%), CEBPA (5 cases, 7.0%), IDH1 (4 cases, 5.6%) and NRAS (4 cases, 5.6%). In FLT3-ITD mutation group, the hemoglobin level of patients with DNMT3A mutation type was lower than that of those with DNMT3A wild type ( t = -2.37, P = 0.020); the hemoglobin level of patients with NPM1 mutation type was higher than that of those with NPM1 wild type ( t = 2.04, P = 0.045). The platelet in patients with 3 mutations and ≥ 4 mutations was higher than that in those with double mutations ( χ2 = 7.72, P = 0.021). After chemotherapy in 71 patients, the curative effect of 66 cases was evaluable, and the white blood count of 18 patients who did not reach complete remission was higher than that of 48 patients who reached complete remission ( Z = -2.74, P = 0.006). Conclusions:Most FLT3-ITD mutated patients with AML commonly show coexisting gene mutations, and the mutation types of coexisting genes are correlated with the clinical features of patients.

Aiming at the medical practice problems of the surgical steel medical instruments, such as the crevice corrosion, the poor mechanical compatibility and the Ni, Cr plasma exudation, the laser deposition of Ti-6Al-4V alloy cladding layer at the local functional area as alternative coating was proposed and realized as a new process method. The accurate element content and good formability Ti-6Al-4V cladding powder was chosen, the low power and high duty cycle optimized laser process was adopt, the alternative coating of good fusion and low dilution was prepared. Through the elemental line scanning, the interface microstructure analysis and the experiments of basic mechanical properties, the basic properties of the cladding were characterized and verified. The experiments results showed that, the Ti, Al and V contents of the top coating were respectively about 88%, 4.9% and 3.9%, no sensitizing ions such as Cr and Ni were detected. Initial equiaxed α phase, flake β phase dist were distributed in the coating and interface, the α' martensite was precipitated at the boundary of the flake β phase, some refined granular β phase dispersion pinned to the grain boundary of basket structure. The microhardness of cladding layer was 352.08~312.76 HV_0.1. The friction coefficient of the cladding layer was about 0.22~0.65. A new technology and method reference for improving and upgrading the performance of surgical medical devices is provided by this research.
Alloys ; Corrosion ; Materials Testing ; Steel ; Titanium

Objective:To explore influence on physical development of children aged 18 months from HIV-positive mothers for prevention mother to child transmission of HIV (PMTCT) in Guangxi Zhuang autonomous region, and provide evidence for the improvement PMTCT program.Methods:This retrospective case control study was conducted in 554 HIV negative infants aged 18 months whose HIV positive mothers had received PMTCT services reported through PMTCT system database from January 1, 2010 to December 31, 2017 and 1 109 healthy infants born in 2017, whose mothers were healthy, in Lingshan, Luzhai, and Hengxian counties, ranking top three counties with high HIV infection prevalence, in Guangxi. PMTCT data and physical development data such as height, weight and head circumference of children aged 18 months were collected. The physical dysplasia in the infants was defined as at least one of the three main indicators of height, weight and head circumference below the normal range.Results:The number of HIV-positive mother and their infants in the case group were 667 and 554 respectively, and the PMTCT rates were 91.15 % (608/667) and 96.57 % (535/554) respectively. HIV positive rate, mortality rate and mother to child transmission rate of the infants aged 18 months were 1.44 % (8/554), 3.07 % (17/554) and 1.91 % (8/418) respectively, and the physical examination results of the infants aged 18 months showed that the physical dysplasia rate was 30.51 % (169/554). Among the 1 109 infants in the control group, the physical dysplasia rate was 9.83 % (109/1 109). The difference between the case group and the control group was significant ( P<0.01). Conclusion:The PMTCT rates of HIV positive mother and their children were more than 90.00 %, respectively. However, poor physical development rate of infants aged 18 months were more than 30.00 %. The possible influence of PMTCT on physical development of the infants aged 18 months of HIV positive mother’s needs to be further studied.

Objective:To understand the characteristics and associated factors of newly reported HIV/AIDS cases with non-marital or non-commercial heterosexual transmission, in Guangxi Zhuang Autonomous Region (Guangxi), 2015-2018.Methods:Information of newly reported HIV/AIDS cases aged ≥18 years in Guangxi between 2015 and 2018 was collected from the National Comprehensive HIV/AIDS Information System. Unconditional logistic regression model was used to access those factors that were associated with HIV infections through non-marital or non-commercial heterosexual contact.Results:Between 2015 and 2018, a total number of 35 497 HIV/AIDS cases, aged ≥18 years were newly reported in Guangxi. Among them, 32 648 (92.0 %) were infected heterosexually while 10 500 were infected through non-marital or non-commercial heterosexual behavior. Non-marital or non-commercial heterosexual transmission accounted for 29.6 % (10 500/35 497) of the newly reported HIV/AIDS cases, and 32.2 % (10 500/32 648) of those with heterosexual transmission. Males counted for 53.5 % (5 617/10 500) of non-marital or non-commercial heterosexual transmission and males to females ratio was 1.2∶1 (5 617∶4 883). Those married or had regular sexual partners counted for 55.9 % (5 873/10 500). Commercial heterosexual transmission appeared the main mode of HIV transmission for males (64.4 %,16 516/25 633) while main mode for females was non-marital or non-commercial heterosexual transmission and counted for 49.5 % (4 883/9 864). Results from the multivariate logistic regression analysis showed that adjusted OR of female HIV/AIDS infected HIV via non-marital or non-commercial heterosexual transmission, was 3.98 times (95 %CI: 3.78-4.20) hight than that of males. Among the group aged<50 years and the aged 50-59 years, the adjusted ORs were 1.35 times (95 %CI: 1.27-1.44) and 1.13 times (95 %CI: 1.05-1.21) hight than that of aged ≥60 years. Those who were single/divorced/widowed, the adjusted OR was 1.53 times (95 %CI: 1.45-1.61) hight than that of those married/regular partners. Those with junior high school education, high school education and above the adjusted ORs were 1.22 times (95 %CI: 1.16-1.29) and 1.18 times (95 %CI: 1.10-1.27), compared to those only with education levels of primary school or below. Conclusions:The number of HIV/AIDS cases via non-marital or non-commercial heterosexual transmission accounted for nearly 30.0 % of all the routes of HIV transmission in Guangxi, 2015-2018. Female, aged<60 years old, single/divorced/widowed and having had junior and above high school education etc., appeared as risk factors on non-marital or non-commercial heterosexual transmission, among newly reported HIV/AIDS in Guangxi.