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

Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this research, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:enhanced green fluorescent protein (eGFP)) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot (WB), and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine, a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.

Diabetic kidney disease (DKD) with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression. Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials. In this study, we integrated large-scale plasma proteomics, genetic-driven causal inference, and experimental validation to identify prioritized targets for DKD using the UK Biobank (UKB) and FinnGen cohorts. Among 2844 diabetic patients (528 with DKD), we identified 37 targets significantly associated with incident DKD, supported by both observational and causal evidence. Of these, 22% (8/37) of the potential targets are currently under investigation for DKD or other diseases. Our prospective study confirmed that higher levels of three prioritized targets-insulin-like growth factor binding protein 4 (IGFBP4), family with sequence similarity 3 member C (FAM3C), and prostaglandin D2 synthase (PTGDS)-were associated with a 4.35, 3.51, and 3.57-fold increased likelihood of developing DKD, respectively. In addition, population-level protein-altering variants (PAVs) analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD, through the classic NLR family pyrin domain containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) apoptotic axis. Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.

Objective: To assess the presence of vector-borne pathogens [including Zika virus (ZIKV), dengue virus (DENV), chikungunya virus (CHIKV), and Plasmodium (PLAS)] among voluntary blood donors in Wenshan Zhuang and Miao Autonomous Prefecture (referred to as Wenshan), so as to provide a basis for formulating blood safety-related strategies. Methods: Blood samples from voluntary blood donors in Wenshan from June to August 2022 to 2024 were selected. Real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to test 20 426 samples for ZIKV RNA, DENV RNA, and CHIKV RNA; and 19 765 samples were tested for PLAS DNA. Results: All 20 426 samples tested for ZIKV RNA, DENV RNA, and CHIKV RNA were negative; similarly, all 19 765 samples tested for PLAS DNA were negative. Conclusion: The risk of ZIKV, DENV, CHIKV, and PLAS infection among voluntary blood donors in Wenshan is relatively low. Routine surveillance for these pathogens as endemic diseases is not currently warranted. It is recommended to adjust the screening strategy based on the dynamic situation of local epidemiology control and prevention.

Objective: To investigate the characteristics of rabies-exposed population in Wenzhou City, Zhejiang Province from 2014 to 2023, so as to provide insights into the prevention and control of rabies. Methods: Data of rabies-exposed population in Wenzhou City from 2014 to 2023 were collected through Wenzhou Rabies-Exposed Population Summary Sheet reported by dog injury clinics. The species of animals causing injuries, exposure time, exposure grade, exposure site, and post-exposure treatment were descriptively analyzed. Results: Totally 709 900 patients were admitted to dog injury clinics in Wenzhou City from 2014 to 2023, and the exposure rate showed an increasing trend (Z=7.238, P<0.001), with an average annual exposure rate of 750.75/105. The number of cases with exposure to rabies peaked in July (79 230 cases, 11.16%) and August (78 570 cases, 11.07%). Dogs were predominant animals causing injuries (448 900 cases, 63.23%), and the exposure rate showed a downward trend (Z=-5.921, P<0.001); cats were the second (175 142 cases, 24.67%), and the exposure rate showed an upward trend (Z=23.314, P<0.001). The upper (379 695 cases, 53.49%) and lower limbs (287 521 cases, 40.50%) were the main exposure sites. There were 21 034 cases (2.96%) exposed to head and face, and the exposure rate of head and face showed an upward trend (Z=3.549, P<0.001). Grade II exposure was the most common (403 881 cases, 56.89%), and the exposure rate showed an upward trend (Z=8.769, P<0.001). The proportion of using human rabies immune globulin was 23.13% in Grade III exposed population, showing a downward trend (Z=-12.848, P<0.001). Conclusions The exposure rate of rabies in Wenzhou City showed an upward trend from 2014 to 2023, with July and August as the peak months of exposure. Injuries mainly caused by dogs, while the exposure rate of cat bites showed an upward trend. The proportion of using human rabies immune globulin needs to be improved.

Di-(2-ethylhexyl) phthalate (DEHP) is currently one of the most widely used plasticizers, widely found in all kinds of items, such as children’s toys and food packaging materials, but also added to wallpaper, cable protective agents and other building decoration materials. DEHP is toxic and absorbed by the human body through respiratory tract, digestive tract and skin contact, which can cause damage to multiple systems, especially the male reproductive system, and testis is an important target organ. Oxidative stress injury is the core mechanism of spermatogenesis disorder caused by DEHP. DEHP exposure can cause oxidative stress or reactive oxygen species (ROS) increase in germ cells, and on this basis, promote cell apoptosis or cause excessive autophagy. The toxicity of DEHP to Leydig cells is mainly to interfere with the synthesis of steroid hormones. For Sertoli cells, ferroptosis and destruction of the blood-testis barrier are common injury mechanisms. In addition, gene methylation caused by DEHP not only affects the spermatogenic process, but also has epigenetic effects on offspring. In this paper, we reviewed the pathological damage, germ cell toxicity and epigenetic effects of DEHP on testis, and focused on the damage and molecular mechanism on testicular spermatogenic cells, Leydig cells and Sertoli cells. Future research is required to elucidate the body’s clearance mechanism and treatment plan after exposure to DEHP and whether DEHP will damage the function of myoid cells. It is hoped that this can provide new ideas for prevention and treatment of male reproductive disorders resulting from long-term exposure to plastic products.

OBJECTIVE To observe the short-term efficacy and safety of venetoclax combined with homoharringtonine and cytarabine in the treatment of acute myeloid leukemia （AML）. METHODS The data of 40 newly diagnosed AML patients admitted to our hospital from October 2022 to November 2023 were retrospectively collected and divided into observation group and control group according to treatment plan， with 20 cases in each group. The patients in the control group were given Daunorubicin hydrochloride for injection+Cytarabine for injection， and the patients in the observation group were given Venetoclax tablets+ Homoharringtonine injection+Cytarabine for injection. The patients in both groups were given relevant medicine， with 28 days as one cycle. The short-term efficacy， negative rate of minimal residual disease （MRD）， duration of granulocyte deficiency， duration of platelet （PLT） ＜20×109 L－1， transfusion volume of suspended red blood cells and platelet， and the occurrence of adverse drug reactions were evaluated in both groups after 1 cycle of induction chemotherapy. RESULTS The complete remission or complete remission with incomplete hematologic recovery （CR/CRi） rate in the observation group was significantly higher than control group （P＜0.05）， and the negative rate of MRD in the observation group was also significantly higher than control group （P＜0.05）. However， in low-， medium- and high-risk patients， there was no statistical significance in CR/CRi rates between the two groups （P＞0.05）. There were no significant differences in the duration of agranulocytosis， the duration of PLT ＜20×109 L－1， the amount of suspended red blood cell transfusion， the amount of platelet transfusion， the incidence of hematologic toxicity and the incidence of non-hematologic toxicity between 2 groups （P＞0.05）. CONCLUSIONS Venetoclax combined with homoharringtonine and cytarabine show good short-term efficacy and safety in the treatment of AML.

A dose reconstruction algorithm for electrionic portal imaging device(EPID)based on calibration and calculation is developed.The raw data of EPID in continuous acquisition mode are corrected for dark field and gain,and the gray level features of bright field are used to determine the field boundary.Subsequently,MU calibration,off-axis calibration and field size calibration are performed on the EPID data,and dose reconstruction is carried out based on the calibrated superimposed flux and the Monte Carlo model of the linac head.Nine cases of IMRT plans are selected for verification and measurement using EPID and MapCheck separately,and the passing rates between the two tools are compared under different gamma criteria(3%/3 mm and 2%/2 mm).For a planned case,the average passing rates of multiple cases verified by MapCheck under the two criteria were 99.02%±1.28%and 90.84%±4.49%,and the average passing rates of the EPID reconstruction models were 98.86%±1.19%and 91.39%±4.80%.Compared with MapCheck,the EPID reconstruction algorithm based on calibration and calculation has no significant difference in the passing rate of IMRT plan verification(P＞0.05),which meets the clinical requirements of dose verification.