N1-methyladenosine(m1A)RNA methylation is critical for regulating mRNA translation;however,its role in the development,progression,and immunotherapy response of head and neck squamous cell carcinoma(HNSCC)remains largely unknown.Using Tgfbr1 and Pten conditional knockout(2cKO)mice,we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels.Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis.Mechanistically,TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis,upregulating programmed death-ligand 1(PD-L1)expression.Moreover,m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus(oHSV),contributing to reactive PD-L1 upregulation.Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth,representing a promising strategy to alleviate resistance.These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression,providing a mutually reinforcing combination immunotherapy approach.

Objective:To investigate the relationship between cerebrovascular variation and the occurrence and recurrence of cerebral infarction, and provide a theoretical basis for the precise prevention and treatment of cerebral infarction.Methods:Totally 13 939 patients who underwent magnetic resonance imaging(MRI) and magnetic resonance angiography(MRA) examination at the Second Affiliated Hospital of Shandong First Medical University from January 2020 to December 2021 were grouped according to clinical symptoms combined with the imaging report, including 4 412 cases in the cerebral infarction group and 9 527 cases in the control group.2 048 patients in the cerebral infarction group were eventually enrolled in the study according to the inclusion and exclusion criteria, including 1 479 cases of initial cerebral infarction and 569 cases of recurrent cerebral infarction.SPSS 25.0 statistical software was used for data analysis.The χ2 test was used to compare the incidence of cerebral infarction with different cerebrovascular variations.Univariate analysis of suspected risk factors for recurrent cerebral infarction was performed with χ2 test, nonparametric test and t test.The binary logistic regression was used to analyze independent risk factors of recurrent cerebral infarction. Results:The incidence of cerebral infarction in the dual-system cerebrovascular variant patients, the single-system cerebrovascular variant patients, and the non-cerebrovascular variant patients were 40.9%, 30.7% and 31.8% respectively.The incidence of cerebral infarction in the dual-system cerebrovascular variant patients was the highest compared with those in the single-system cerebrovascular variant patients and the non-cerebrovascular variant patients (both P<0.05). The incidence rates of embryonic posterior cerebral artery, vertebral artery dominance, and bilateral common origin anterior cerebral arteries were 14.09%, 10.76% and 5.32%, respectively.The incidence of bilateral common origin anterior cerebral arteries in the cerebral infarction group was significantly higher than that in the control group and the difference was statistically significant.Patients with cerebral infarction who were familial aggregation ( OR=2.207, 95% CI=1.591-3.062), hyperhomocysteinemia ( OR=1.262, 95% CI=1.014-1.570), hypertension ( OR=1.461, 95% CI=1.114-1.918), diabetes mellitus ( OR=1.348, 95% CI=1.072-1.694), coronary heart disease ( OR=1.491, 95% CI=1.196-1.858) were more likely to recurrent cerebral infarction ( P<0.05), and patients with cerebral infarction had a significantly increased risk of recurrent cerebral infarction with age ( OR=1.031, 95% CI=1.020-1.042, P<0.05). Conclusion:Dual-system cerebrovascular variation and bilateral common origin anterior cerebral arteries are risk factors for cerebral infarction.

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.
Humans ; Autophagy ; Carcinoma, Squamous Cell/pathology* ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 beta/metabolism* ; Head and Neck Neoplasms/pathology* ; Neoplastic Stem Cells/pathology* ; Squamous Cell Carcinoma of Head and Neck/pathology* ; Lysosome-Associated Membrane Glycoproteins

OBJECTIVE To understand the current status of research on traditional Chinese medicine（TCM） human resources， and to provide a reference for expanding research ideas on TCM human resources and promoting the construction of TCM talents. METHODS From January 1， 2000 to December 31， 2022， literature related to TCM human resources was collected from the three major databases of CNKI， Wanfang and VIP. Using CiteSpace 5.8 R3 software， visualization analysis was performed for the literature in terms of publication time， journal sources， authors， institutions and areas， funding， research content， keywords， etc. RESULTS A total of 324 literature related to TCM human resources in China were included， and the number of literature issued showed an upward trend， with an annual average of 14.09 literature； 161 kinds of journals were involved， core journals accounted for 18.21% of the total publication volume； a total of 23 authors had published 2 or more literature， with a total of 55 literature published （16.98%）； a total of 416 institutions were involved， mainly schools （66.83%）； 60.49% of the literature were supported by the fund. The majorities of 324 literature were survey studies （170 literature）， and most of them used self-designed questionnaires （55 literature）； the high-frequency keywords included talent training， human resources， TCM， etc. The keywords were clustered into 7 categories， such as “human resources“”talent training“”TCM industry“”TCM services“”talent training models” “fairness” and “TCM talents”. The main problems described in the literature included insufficient talent， lack of reasonable distribution of regional structure， lack of reasonable plans for talent training， and insufficient professional knowledge and abilities. Continuously cultivating high-level talents and improving employment conditions in areas with severe human resource loss were the corresponding countermeasures proposed in the literature. CONCLUSIONS The research on TCM human resources starts late but has developed rapidly overall， and the quality of research needs to be improved； the structure of research team is single and unevenly distributed geographically； there is a structural imbalance in the allocation of human resources， as well as problems such as a shortage of professional talents， low levels of education and training and incomplete development systems.

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

Objective:To summarize the effect of reverse homodigital dorsal thumb flap in repairing thumb pulp defect.Methods:A retrospective case series study was conducted to analyze the clinical data of patients with thumb pulp defects admitted to the People's Hospital of Renqiu from March 2010 to June 2020. The dorsal homodigital island flap of the proximal phalanx was designed and harvested. During the procedure, the proximal digital artery of the perforator vessels of the flap was cut off and ligated. The digital artery pedicled flap was retrograde transferred to cover the thumb pulp defect. 9-0 line was used to anastomose the dorsal digital nerve with the proper digital nerve. The donor site was repaired with a free skin graft.Results:A total of 68 cases of thumb pulp defects were enrolled, all of whom were accompanied by exposure of the tendon of the distal phalanx. There were 39 males and 29 females, aged from 18 to 63 years (average of 35.8 years). The size of the proximal dorsal island flap was 2.0 cm × 3.0 cm to 3.1 cm × 4.2 cm. All flaps and skin grafts survived, and wounds healed primarily. All patients were followed up for 6 to 28 months (mean, 10.6 months). The color, texture, and contour of the flaps were good. All repaired thumbs got the normal function of extension and flexion. At the last follow-up, the two-point discrimination of flaps was 4-11 mm.Conclusions:It has the advantages of small trauma, simple operation, and good curative effect, using the homodigital dorsal thumb flap to repair the thumb pulp defect.

Objective:To summarize the effect of reverse homodigital dorsal thumb flap in repairing thumb pulp defect.Methods:A retrospective case series study was conducted to analyze the clinical data of patients with thumb pulp defects admitted to the People's Hospital of Renqiu from March 2010 to June 2020. The dorsal homodigital island flap of the proximal phalanx was designed and harvested. During the procedure, the proximal digital artery of the perforator vessels of the flap was cut off and ligated. The digital artery pedicled flap was retrograde transferred to cover the thumb pulp defect. 9-0 line was used to anastomose the dorsal digital nerve with the proper digital nerve. The donor site was repaired with a free skin graft.Results:A total of 68 cases of thumb pulp defects were enrolled, all of whom were accompanied by exposure of the tendon of the distal phalanx. There were 39 males and 29 females, aged from 18 to 63 years (average of 35.8 years). The size of the proximal dorsal island flap was 2.0 cm × 3.0 cm to 3.1 cm × 4.2 cm. All flaps and skin grafts survived, and wounds healed primarily. All patients were followed up for 6 to 28 months (mean, 10.6 months). The color, texture, and contour of the flaps were good. All repaired thumbs got the normal function of extension and flexion. At the last follow-up, the two-point discrimination of flaps was 4-11 mm.Conclusions:It has the advantages of small trauma, simple operation, and good curative effect, using the homodigital dorsal thumb flap to repair the thumb pulp defect.

Objective:To explore the effects of sulforaphane (SFN), an activator of Nrf2, on anxiety and fear memory in Alzheimer's disease(AD) model mice and mechanism.Methods:The AD mice and wild type (WT) mice with the same background were randomly divided into four groups ( n=12 for each group): wild type + normal saline group (WT+ NS), wild type + sulforaphane (WT+ SFN), AD model + normal saline group (AD+ NS) and AD model + sulforaphane group (AD+ SFN). SFN was dissolved in normal saline (0.9% NaCl) and prepared solution with concentration of 1 g/L.According to body weight, mice in WT+ SFN group and AD+ SFN group were intraperitoneally injected with SFN (10 mg/kg), and mice in WT+ NS group and AD+ NS group were intraperitoneally injected with the same volume of normal saline once a day for 30 days.The open field test was used to detect the autonomous exploration ability and anxious behavior of mice.The elevated cross maze was used to detect the anxiety of mice.Conditional fear test was used to test the fear memory behavior of mice.Finally, the expression of superoxide dismutase(SOD) and malondialdehyde(MDA) in the hippocampus and cerebral cortex were detected by ELISA.Two-way ANOVA analysis was performed using GraphPad Prism 8.0.2 software. Results:In the open field test, the percentage of time in central region in AD+ SFN group ((9.99+ 0.37)%) was higher than that of AD+ NS group ((8.47+ 0.42)%) ( q=3.842, P<0.05). In the elevated cross maze, the percentage of time in open arm of AD+ SFN group ((26.2±1.6)%) was higher than that in AD+ NS group ((15.8±1.0)%) ( q=7.452, P<0.01). In the conditional fear test, all the mice of the four groups developed the fear memory, but AD+ SFN group showed higher freezing time ratio ((64.5±3.8)%) than AD+ NS group ((51.0±4.3)%)( q=5.266, P<0.01) in the testing stage.After SFN intervention, the important indicator of oxidative stress, the expression levels of SOD in hippocampus ( q=6.370, P<0.01) and cortex ( q=7.858, P<0.01) of AD mice increased, while the level of MDA in hippocampus ( q=5.146, P<0.05) and cortex ( q=5.833, P<0.01) decreased. Conclusion:SFN may inhibit oxidative stress through Nrf2 pathway, thereby improving anxiety and fear memory in AD mice.

Objective:To investigate the therapeutic effect of reverse proximal segment dorsal flap of radial digital artery of the thumb in repairing thumb tip defects.Methods:A retrospective case series study was conducted to analyze the clinical data of 56 patients with thumb tip defects admitted to Renqiu People 's Hospital from February 2010 to October 2020. There were 37 males and 19 females，aged 17-66 years［（37.8±12.2）years］. The injury on the right side was observed in 35 patients and on the left side in 21 patients. All of them were thumb tip defects with exposed distal phalanx. Dimension of skin defects was 2.9 cm×1.8 cm-3.3 cm×2.6 cm.The reverse proximal segment dorsal flap of thumb radial digital artery was used，with the dorsal digital nerve sutured with the proper digital nerve. The donor site was repaired with free skin graft from the ulnar side of the affected forearm. The time of flap harvesting，operation time and healing of the flap were measured. At the last follow-up，the shape，texture，sensory recovery and complications of the flap were observed. One month after operation and at the latest follow-up，the upper limb function evaluation standard set up by hand surgery branch of Chinese Medical Association and Vancouver Scar Scale（VSS）score were used to evaluate the recovery of sensory function of the flap and scar formation of the donor sites，respectively. Results:All patients were followed up for 6-26 months［（13.2±6.4）months］. The time of flap harvesting ranged from 20 to 35 minutes［（26.0±5.3）minutes］. The operation time was 1-2 hours［（1.3±0.3）hours］. Blisters appeared at the distal end of the flap in 2 patients after operation，but they were not treated. After 7 days，the blisters subsided and the flaps survived. The other flaps survived successfully. The donor sites healed by first intention. At the last follow-up，the flaps showed relatively cosmetic appearance，similarities in texture，elasticity and color to the surrounding area and good sensory recovery，without scar contracture and dystrophy of interphalangeal joint. According to the upper limb function evaluation standard set up by hand surgery branch of Chinese Medical Association，56 patients exceeded S3 grade compared to none at postoperative 1 month（ P<0.01），and the VSS score was 3-7 points［（5.0±1.4）points］compared to 6-12 points［（8.8±1.5）points］at postoperative 1 month（ P<0.01）. The donor site left a linear scar，which had no significant effect on its shape and function. Conclusion:The reverse proximal segment dorsal flap of the radial digital artery of the thumb can be used to repair thumb tip defects，for it has advantages of easy operation，a high survival rate as well as good appearance and sensory function recovery，with less damage to the donor area.