Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Objective:To examine the impact of sleep quality on cognitive function in older adults with mild cognitive impairment(MCI)and explore the potential mediating role of depression.Methods:Using a cross-sectional design, we conducted an on-site questionnaire survey among 310 elderly individuals with MCI in Haishu District, Ningbo City from April to June 2021.Out of the 310 questionnaires collected, 299 were deemed valid.The survey encompassed gathering basic demographic information of the participants, as well as administering the Montreal Cognitive Assessment Scale, Patient Health Questionnaire Depression Scale, and Pittsburgh Sleep Quality Index Scale.Results:The cognitive functions of patients with MCI were found to be positively related to their education level( F=3.89, P<0.05).The correlation analysis indicated that sleep quality was positively correlated with depression( r=0.40, P<0.01)and negatively correlated with cognitive function( r=-0.22, P<0.01).Furthermore, a significant negative correlation was observed between depression and cognitive function( r=-0.20, P<0.01).The mediation analysis revealed that depression played a role in mediating the influence of sleep quality on cognitive function, with a mediation effect of -0.02(95% CI: -0.03--0.01). Conclusions:The cognitive function of elderly individuals with MCI can be significantly affected by sleep quality, with depression playing a mediating role.

Objective:To investigate the role of a simple Nomogram model in evaluating the severity of mycoplasma pneumoniae pneumonia (MPP) in adults.Methods:The clinical data of 162 patients with MPP who received treatment in Wenzhou Central Hospital from March 2015 to October 2022 were retrospectively analyzed. These patients were divided into a severe group ( n = 67) and a common group ( n = 95) according to whether they were diagnosed with severe MPP. The clinical data of patients were recorded. Fourteen clinical variables were screened, including age, sex, onset season, fever, heat peak, fever duration, cough duration, white blood cell count, percentage of neutrophils, percentage of lymphocytes, hemoglobin, platelet count, C-reactive protein, and procalcitonin. Multivariate logistic regression analysis of statistically significant variables in univariate analysis was performed. The Nomogram model was constructed with the R language software package (version 3.6.2). The model was verified with a calibration curve and receiver operating characteristic curve. Results:Univariate analysis results showed that in the severe group, the fever peak ( Z = 5.03, P < 0.001) was higher, fever duration ( χ2 = 27.55, P < 0.001), and cough duration ( χ2 = 28.72, P < 0.001) were longer, white cell count ( t = 2.93, P = 0.004), percentage of neutrophils ( t = 9.08, P < 0.001), C-reactive protein ( t = 35.05, P < 0.001), and procalcitonin level ( t = 15.09, P < 0.001) were greater compared with the common group. The percentage of lymphocytes ( t = 1.16, P < 0.001), hemoglobin level ( t = 1.22, P < 0.001), and platelet count ( t = 2.82, P < 0.001) in the severe group were significantly lower than those in the common group. Multivariate logistic regression analysis results showed that heat peak, cough duration, and C-reactive protein were positively correlated with the severity of MPP (all P < 0.05). The percentage of lymphocytes, hemoglobin concentration, and platelet count were negatively correlated with the severity of MPP (all P < 0.05). The establishment and validation results of the Nomogram model showed that the accuracy of the model was good, with a sensitivity of 88.73%, a specificity of 77.61%, and a C-index of 0.904. Conclusion:Heat peak, cough duration, percentage of lymphocytes, platelet count, and C-reactive protein are closely related to the severity of early MPP. A simple Nomogram model can be one of the tools for early assessment of the severity of MPP.

OBJECTIVE: To explore the genetic basis for a child featuring congenital insensitivity to pain (CIP). METHODS: Targeted capture and next generation sequencing (NGS) was carried out for the proband. Suspected pathogenic variants were confirmed by Sanger sequencing of the proband and his parents. RESULTS: The proband was found to harbor compound heterozygous variants of SCN9A gene, namely c.1598delA (p.N533Ifs*31) and c.295_296delCGinsAT (p.R99I), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic, and neither was reported previously. CONCLUSION The compound heterozygous variants of the SCN9A gene probably underlay the CIP in this child. Above finding has enabled genetic counseling for this family.
Channelopathies ; Child ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; NAV1.7 Voltage-Gated Sodium Channel/genetics* ; Pain Insensitivity, Congenital/genetics*

Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8⁺ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Objective : To investigate the pathogenic factors and clinical manifestations of contact stomatitis, and to provide references for its clinical diagnosis and prevention. Methods: The data of 55 subjects with contact stomatitis were analyzed retrospectively, including age, gender, pathogenic factors, type of lesions and site of occurrence. Results: Among the 55 patients, contact stomatitis occurred at all ages, 19 were male, 36 were female, and the ratio of males to females was 1∶1.89. Among 55 patients, 78.18% (43/55) were caused by oral mucosal contact with dental materials: amalgam fillings accounted for 52.73% (29/55), metal crowns accounted for 9.09% (5/55), removable denture plastic bases accounted for 9.09% (5/55), resin fillings accounted for 5.45% (3/55), and alginate impression materials accounted for 1.82% (1/55); 21.82% (12/55) were caused by oral mucosal contact with food and daily necessities. The clinical manifestations of contact stomatitis include lichenoid reaction, erythema and erosion. The most common site of contact stomatitis was the cheek, followed by the tongue, and the lips, and the gingival and palatal areas were relatively rare. In the buccal mucosa, the incidence of lichenoid reaction was 55% (22/40), which was higher than that of erosion (20%) and erythema (25%), and the difference was statistically significant (P < 0.05). For tongue, lip, gingiva and palate, there was no significant difference in the incidence of the three lesion types（P > 0.05）. Conclusion Contact stomatitis occurred at all ages, and there are more female patients than males with contact stomatitis. Dental materials, especially metal and acrylic materials (such as the plastic base of removable dentures, resin fillings, adhesives, and self-setting plastics), are the main pathogenic factors. In buccal mucosa, the incidence of lichenoid reaction is higher.

Chloroquine and hydroxychloroquine are both classic 4-aminoquinoline antimalarial drugs with similar chemical structures and mechanisms of action. As the toxicity and side effects of hydroxychloroquine are lower than those of chloroquine, hydroxychloroquine is the main clinical application at present, with good efficacy and safety. Chloroquine and hydroxychloroquine are widely used in the clinic because of their immunosuppressive, anti-inflammatory, antiviral, antitumor and photoprotective effects. The main mechanisms by which chloroquine/hydroxychloroquine inhibits immunity include inhibiting lysosome activity, autophagy, immune response signaling pathways production of proinflammatory cytokines. Chloroquine stabilizes the lysosomal membrane and reduces the release of lysosomal enzymes. As a prostaglandin antagonist, chloroquine can reduce the production of prostaglandins and leukotrienes, thus playing an anti-inflammatory role. Chloroquine/hydroxychloroquine can inhibit virus proliferation in the early stage of virus replication by inhibiting the glycosylation of the angiotensin converting enzyme 2 receptor. At present, hydroxychloroquine has been found to have significant efficacy in discoid lupus erythematosus, oral lichen planus, chronic cheilitis, pemphigus foliaceus, Sjögren’s syndrome and other stomatological diseases. However, eye damage is the most important adverse reaction of hydroxychloroquine, and its occurrence is related to the cumulative dose of drugs.

Objective To construct sensitive, scientific and practical breast nursing quality evaluation indicators, and provide evidence for hospital breast nursing quality evaluation and monitoring. Methods Potential sensitive indicators of nursing quality were initially built by referencing the development process of the nursing quality indicators national database system of United States, by retrieving the domestic and foreign documents, by combining with breast cancer diagnosis and treatment guidelines, nursing textbooks, and nursing negative events, by clinical investigation and group discussion. An expert survey paper was prepared and three rounds surveys were conducted to revise and fix the sensitive indicators of breast nursing quality. Results The positive coefficients of the three rounds of expert consultation were 100％ , the authoritative coefficients of the three rounds were 0.847,0.851,0.849, respectively. The coordination coefficient of the three rounds of experts was 0.371-0.476、0.597-0.736、0.739-0.873, P<0.01, and finally 4 sensitive indicators of breast specialist care quality were established. Conclusions The nursing quality sensitive indicators were constructed by Delphi method. They comply with the principles of scientificity and rigorousness, and have the characteristics of breast nursing. They can be verified by clinical practices in the role of nursing quality control and evaluation, and gradually achieve effective data sharing to clinical guidelines to help the development of specialist care.

Objective: We investigated the clinical characteristics and the most important risk factors of urinary calculi in children. Methods: Using Cochrane Library, PubMed, ProQuest, ELEVIER Science Direct, Embase, Springerlink, China National Knowledge Infrastructure (CNKI), and Wanfang database, we reviewed literature on clinical characteristics of urinary calculi in children from January 2003 to September 2018, and data was analyzed using STATA 14.0. Results: Incidence of calculi in male children was 62.1% [95% CI (57.2%, 67.1%)]. 39.4% [95% CI (26.5%, 52.2%)] children with urolithiasis had a family history of positive stones, 25.3% [95% CI (19.2%, 31.3%)] had a history of urinary infection, and 16.6% [95% CI (12.3%, 20.9%)] had abnormal urinary anatomy. In addition, urinary calculi were most commonly found in the kidney [63.6%, 95% CI (49.9%, 77.3%)], followed by ureter [17.2%, 95% CI (13.4%, 21.0%)], and bladder [12.4%, 95% CI (6.9%, 18.7%)]. The single component of urinary calculi in children accounted for 58.8% [95% CI(48.7%, 68.9%)], the most common component was calcium oxalate [49.4%, 95% CI (36.7%, 62.1%)], followed by uric acid [7.9%, 95% CI (4.1%, 11.6%)]. The most common urinary metabolic disorders were hypernatremia [38.8%, 95% CI (27.9%, 49.7%)], followed by hypercalciuria [33.4%, 95% CI (27.3%, 39.4%)]. Conclusions Heredity metabolic abnormalities, urinary tract infection, and anatomical structural abnormalities are important risk factors of urinary calculi in children. Stone recurrence could be reduced and prevented by regulating metabolic disorders, managing urinary tract infection, and correcting anatomical abnormality.

Objective To explore the perception of clinical learning environment,career maturity,and professional identity as well as their associations among 3+2 nursing undergraduates.Method Totally 198 3+2 nursing undergraduate students from two provincial medical colleges in Shandong province were enrolled.Results Mean scores for clinical learning environment,career maturity and professional identity were (3.44 ± 0.54),(3.31 ± 0.37) and (3.63 ± 0.62),respectively.Clinical learning environment and career maturity (P＜0.001) were positivelyassociated with 3+2 nursing undergraduates' professional identity.Conclusions Clinical learning environment,career maturity and professional identity of 3 +2 nursing undergraduates areat a moderate level.Interventions to facilitate clinical learning environments and career maturity will foster the growth of professional identity.