The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL⁺ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual-conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL⁺ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.

With the normalization and institutionalization of national centralized drug procurement(NCDP)policy,a large number of generic drugs have been included in the clinical frontline,benefiting hundreds of millions of patients.At the same time,real-world studies(RWS)on generics and innovator drugs have been carried out successively,providing evidence-based support for the promotion and optimization of NCDP policy.Thispaper systematically reviewed the RWS of generic drugs in the past fiveyears of the NCDP policy,discussed and summarized the evidence of clinical efficacy,safety and cost-effectiveness of major generic drugs such as anti-infective drugs,cardiovascular drugs,neuropsychotics,hypoglycemic drugs,and anti-tumor drugs,and analyzed the current RWS status of generic drugs.Overall,the clinical effectiveness and safety of domestic generic drugs are basically the same as that of the innovator drugs,and there is no statistically significant difference,while generic drugs are more cost-effective.Current research still reveals shortcomings in in data quality and integrity,standardization and rigor of research methods,study coverage and population diversity,pharmacoeconomic evaluation and long-term safety monitoring,which point out the direction for later research in this field.Throughsystematic integration and analysis of the RWS of generic drugs,this review is expected to improve public awareness and recognition of NCDP policy,and provide an important reference for promoting the in-depth implementation of NCDP policy.

Objective To describe and analyze the epidemiological characteristics of scrub typhus in Huai'an, Jiangsu Province from 2006 to 2024 and explore the long-term incidence trend and distribution of high-risk areas, and to formulate targeted prevention and control strategies. Methods The scrub typhus case report data of Huai'an from 2006 to 2024 in the Chinese Disease Prevention and Control Information System were extracted for descriptive analysis. Results A total of 898 cases of scrub typhus were reported in Huai'an, with an average annual incidence rate of 0.96 per 100 000 from 2006 to 2024. There was a turning point in the incidence trend of scrub typhus in 2011. From 2006 to 2011, the annual percentage change (APC) was 47.09% (95% CI: 7.53 - 859.39), and the upward trend was statistically significant (P < 0.05). From 2012 to 2024, the APC was -2.12% (95% CI: -29.09 - 3.75), and the downward trend was not statistically significant. October and November were the high-incidence months, and the total concentration from 2006 to 2024 was 0.93, indicating that scrub typhus had strict seasonality. The circular distribution method estimated that the peak period of the epidemic was from October 11th to November 25th, and the peak day of incidence was November 3rd. Jinhu County was a high-incidence area. The ratio of male to female cases was 1.03. The age group with the highest reported incidence was 40 to < 80 years old. The occupation with the highest proportion was farmers, accounting for 78.03%. Conclusion From 2006 to 2024, scrub typhus in Huai'an shows a peak every 3 - 4 years. Middle-aged and elderly farmers are the key population at risk, and Jinhu County is a key area. In the future, targeted health education should be carried out to effectively control the prevalence of scrub typhus.

Objective To explore the value of inflammatory load index(IBI)in the diagnosis and prognosis of gastric cancer patients.Methods Clinical data of patients who underwent gastric cancer surgery in the Department of General Surgery of the Second Hospital of Lanzhou University from January 2016 to December 2018 were retrospectively analyzed,and the patients were divided into the high IBI group and the low IBI group based on the optimal cut-off value of IBI.ROC curve was used to determine the optimal cut-off value of IBI,and the survival curve was constructed using the Kaplan-Meier method,and the differences between groups were examined using the Log-rank test.Cox regression analysis was performed to study the prognostic factors of gastric cancer patients.Results The best cut-off value for IBI diagnosis was 8.796,and the best cut-off value for prognosis was 28.75.IBI was related to the clinical case characteristics of gastric cancer patients,such as surgical access,the degree of differentiation,CK7,CK20,LMP-1,and Ki-67(P＜0.05).The results of univariate analysis showed that intraoperative bleeding,preoperative CEA,preoperative CA125,preoperative CA199,IBI,tumor diameter size,margins of incision,vascular invasion,nerve invasion,pT stage and pN stagewere the influencing factors on the prognosis of gastric cancer patients(P＜0.05).The results of multifactorial regression analysis showed that intraoperative bleeding,preoperative CEA,preoperative CA199,IBI,tumor diameter size,pT stage and pN stagewere independent risk factors affecting the prognosis of gastric cancer patients(P＜0.05).The median OS of patients in the high IBI group and low IBI group were 32.9 months and 74.8 months,respectively,with statistically significant differences(P＜0.001).Conclusion IBI is an independent risk factor for poor prognosis of patients with gastric cancer,and it has a good predictive value in diagnosis and prognosis.

Objective To explore the value of inflammatory load index(IBI)in the diagnosis and prognosis of gastric cancer patients.Methods Clinical data of patients who underwent gastric cancer surgery in the Department of General Surgery of the Second Hospital of Lanzhou University from January 2016 to December 2018 were retrospectively analyzed,and the patients were divided into the high IBI group and the low IBI group based on the optimal cut-off value of IBI.ROC curve was used to determine the optimal cut-off value of IBI,and the survival curve was constructed using the Kaplan-Meier method,and the differences between groups were examined using the Log-rank test.Cox regression analysis was performed to study the prognostic factors of gastric cancer patients.Results The best cut-off value for IBI diagnosis was 8.796,and the best cut-off value for prognosis was 28.75.IBI was related to the clinical case characteristics of gastric cancer patients,such as surgical access,the degree of differentiation,CK7,CK20,LMP-1,and Ki-67(P＜0.05).The results of univariate analysis showed that intraoperative bleeding,preoperative CEA,preoperative CA125,preoperative CA199,IBI,tumor diameter size,margins of incision,vascular invasion,nerve invasion,pT stage and pN stagewere the influencing factors on the prognosis of gastric cancer patients(P＜0.05).The results of multifactorial regression analysis showed that intraoperative bleeding,preoperative CEA,preoperative CA199,IBI,tumor diameter size,pT stage and pN stagewere independent risk factors affecting the prognosis of gastric cancer patients(P＜0.05).The median OS of patients in the high IBI group and low IBI group were 32.9 months and 74.8 months,respectively,with statistically significant differences(P＜0.001).Conclusion IBI is an independent risk factor for poor prognosis of patients with gastric cancer,and it has a good predictive value in diagnosis and prognosis.

With the normalization and institutionalization of national centralized drug procurement(NCDP)policy,a large number of generic drugs have been included in the clinical frontline,benefiting hundreds of millions of patients.At the same time,real-world studies(RWS)on generics and innovator drugs have been carried out successively,providing evidence-based support for the promotion and optimization of NCDP policy.Thispaper systematically reviewed the RWS of generic drugs in the past fiveyears of the NCDP policy,discussed and summarized the evidence of clinical efficacy,safety and cost-effectiveness of major generic drugs such as anti-infective drugs,cardiovascular drugs,neuropsychotics,hypoglycemic drugs,and anti-tumor drugs,and analyzed the current RWS status of generic drugs.Overall,the clinical effectiveness and safety of domestic generic drugs are basically the same as that of the innovator drugs,and there is no statistically significant difference,while generic drugs are more cost-effective.Current research still reveals shortcomings in in data quality and integrity,standardization and rigor of research methods,study coverage and population diversity,pharmacoeconomic evaluation and long-term safety monitoring,which point out the direction for later research in this field.Throughsystematic integration and analysis of the RWS of generic drugs,this review is expected to improve public awareness and recognition of NCDP policy,and provide an important reference for promoting the in-depth implementation of NCDP policy.

Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.

Background The human body is usually exposed to a variety of heavy metals at the same time, and different types and concentrations of heavy metals may have complex interactions during their absorption and metabolism in the human body. Seminal fructose is an important energy source for sperm movement. A large number of studies have shown that metal exposure may impair semen quality, and seminal fructose is an important factor affecting male reproduction, so it is necessary to investigate the relationship between mixed heavy metal exposure and seminal fructose to explore the mechanism of semen quality damage caused by metal exposure. Objective To understand the status of common heavy metal exposure in men of childbearing age in Puyang City, Henan Province, and to study the relationship between mixed exposure to heavy metals and seminal fructose, as well as potential interactions among heavy metals. Methods Volunteers were recruited from the Puyang Maternal and Child Health Hospital Reproductive Center for a cross-sectional survey on general demographic characteristics, smoking, alcohol consumption, and other information. Semen samples were collected to detect 12 metals such as vanadium (V), manganese (Mn), cobalt (Co), nickel (Ni), zinc (Zn), selenium (Se), silver (Ag), cadmium (Cd), barium (Ba), thallium (Tl), iron (Fe), and lead (Pb) in seminal plasma and seminal fructose. After correcting for selected confounding factors, a Bayesian kernel machine regression (BKMR) model was used to evaluate the impact of seminal plasma heavy metal mixed exposure and its interactions on seminal fructose. Results A total of 825 adult males were enrolled. The concentrations in M (P₂₅, P₇₅) of V, Mn, Co, Ni, Zn, Se, Ag, Cd, Ba, Tl, Fe, and Pb in seminal plasma were 0.39 (0.28, 0.54), 12.31 (8.92, 17.52), 0.26 (0.18, 0.38), 5.15 (3.32, 8.64), 182159.80 (121847.80, 199144.50), 13.61 (10.55, 17.68), 0.03 (0.02, 0.04), 0.34 (0.27, 0.46), 8.64 (5.94, 13.43), 0.06 (0.05, 0.08), 168.74 (114.17, 259.45), and 1.69 (1.15, 2.36) μg·L⁻¹ respectively. The Spearman correlation results indicated that there was a negative correlation between V, Mn, Co, Zn, Se, Ba, Tl, or Fe in seminal plasma and seminal fructose (P<0.05), and the values of r (95%CI) were −0.044 (−0.087, −0.001), −0.129 (−0.171, −0.087), −0.055 (−0.099, −0.012), −0.099 (−0.143, −0.056), −0.053 (−0.097, −0.010), −0.068 (−0.111, −0.025), −0.095 (−0.138, −0.052), and −0.082 (−0.125, −0.039), respectively. The results of multiple linear regression indicated that there was a negative correlation between the exposure level of Cd, Mn, Zn, Ag, Ba, Tl, or Fe in seminal plasma and seminal fructose (P<0.05), the values of associated β (95%CI) were −0.551 (−0.956, −0.147), −0.315 (−0.419, −0.212), −0.187 (−0.272, −0.103), −0.161 (−0.301, −0.021), −0.188 (−0.314, −0.062), −1.159 (−2.170, −0.147), and −0.153 (−0.230, −0.076), respectively. The BKMR model analysis showed that seminal fructose level decreased with the increase of plasma metal mixed exposure concentration. Compared with all metal exposure at P₅₀, the seminal fructose level decreased by 0.2374 units when all metal exposure was at P₇₅. Seminal plasma Zn [posterior inclusion probabilities (PIPs)=1.0000] had the strongest effect on seminal fructose, followed by Mn (PIPs=0.5872), Se (PIPs=0.5656), and Ba (PIPs=0.5398). The univariate exposure-response curve showed a negative approximate linear correlations between Ba or Mn and seminal fructose, a positive linear correlation between Se and seminal fructose, and an approximate inverted U-shaped association between Zn and seminal fructose. No significant interaction between studied metals was found. Conclusion Mixed metal exposure may lead to decrease of seminal fructose, in which Zn, Mn, Se, and Ba may play an important role. Mn and Zn exposure may reduce the level of seminal fructose, Se may increase the level of seminal fructose, and there may be a threshold effect between Zn exposure and seminal fructose level. No interaction between different metals on seminal fructose is found.

Esophageal cancer (EC) is one of the most fatal cancers worldwide. According to GLOBOCAN 2020, it was estimated that there were 600, 000 new EC cases and 540 000 EC deaths, while nearly half of all newly diagnosed cases of EC and associated deaths worldwide occurred in China. The annual incidence and mortality of EC have been reduced in the last 20 years in China. However, the early symptoms and signs of EC are not easily distinguished and the disease tends to be within the middle and late stage of pathogenesis when identified, leading to its low 5-year survival rate. Therefore, it could help effectively reduce the burden of EC by clarifying its etiology and risk factors, as well as taking preventive and early diagnosis measures. This article reviews the epidemiology, etiology, screening and early diagnosis of EC in China, to provide systematic references for EC prevention and control.

One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.