Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Glucocorticoids play a critical role in initiating parturition in most mammals, including humans. In humans, their labor-promoting mechanisms primarily involve promoting estrogen and prostaglandin synthesis, inducing functional progesterone withdrawal, and facilitating membrane rupture. However, the administration of synthetic glucocorticoids—whether intramuscular, intravenous, or intra-amniotic—can variably trigger labor and may even contribute to the development of fetal programming of adult diseases. Clinically, synthetic glucocorticoids are primarily used in threatened preterm pregnant women to enhance fetal lung maturation and improve neonatal outcomes, rather than to intervene in the delivery process. Therefore, strict control over the timing and dosage of synthetic glucocorticoids is essential to balance their benefits for fetal lung development against the risks of unintended labor induction.

Objective:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.Methods:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).Results:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c. 1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright′s hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c. 2T>C (p.Met1? ) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. Conclusion:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of comorbid genetic diseases.

Objective:This study aims to explore the characteristics of body temperature(BT)of the elderly population in China and the relationship with health status.Methods:This is a cross-sectional study.The data were derived from the China Health and Nutrition Study(CHNS)in 2015.A total of 4 176 elderly people over 60 years old were enrolled for analysis(1968 males, and 2208 females). The participants were divided into three groups according to their BT values: hypothermia group(BT<36.5℃), moderate BT group(36.5℃≤BT<37.0℃), and hyperthermia group(37.0℃≤BT<37.5℃). The differences in health status among each group were compared based on the disease conditions(four-week prevalence rate)in the past four weeks.Multivariate logistic regression analysis was performed to explore the relationships between BT and the four-week prevalence rate.Results:Among the elderly population included in the analysis, the average age was 68.4 ± 6.9 years(ranging from 60 to 99 years). The average BT of the elderly was 36.40 ± 0.37℃(males: 36.42 ± 0.37℃; females: 36.38 ± 0.37℃).3 348 study subjects were aged between 60-74 years old, while 828 study subjects were aged between75-99 years old.The older the age, the lower the body temperature.Of the participants, 2 212(53.0%)elderly people belonged to the hypothermia group, 1 656(39.6%)belonged to the moderate BT group, and 308(7.4%)belonged to the hyperthemia group.Among 4 176 elderly people, a total of 1368 had suffered from disease in the past four weeks(31.3%)The four-week prevalence rates of each group were as follows: the hypothermia group(33.1%), the moderate BT group(29.8%); hyperthemia group(26.6%)( χ2=8.403, P=0.015). Multivariable logistic regression analysis indicated that for every 1℃ increases in BT among the elderly, the four-week prevalence rate decreased by 22%( OR=0.78, 95% CI=0.65-0.94, P=0.01). Conclusions:The BT of the elderly is generally lower than the current standard, and the lower the BT, the higher the four-week prevalence rate.Raising the BT of the elderly may help them improve their physical condition.

Objective:To investigate the influence and mechanism of bone marrow mesenchymal stem cells (BMSCs) overexpressing growth arrest specific 6, i.e. GAS6/BMSCs on full-thickness skin defect wounds in diabetic mice.Methods:This study was an experimental study. Twelve 8-week-old male C57BL/6J mice were divided into a control wound group with only full-thickness skin defects and a diabetic wound group with diabetic full-thickness skin defects according to the random number table method, with 6 mice in each group. The wound healing rates were calculated at 3, 7, 14, and 21 days after injury. At 21 days after injury, wound tissue specimens were collected for hematoxylin-eosin staining to observe the histopathological conditions; Masson staining was performed to detect collagen deposition; immunohistochemical staining was performed to detect the number of proliferating cell nuclear antigen (PCNA)-positive cells and CD31-positive cells, representing cell proliferation and capillary density, respectively; immunofluorescence staining was performed to detect the number of F4/80 and myeloperoxidase (MPO) double-positive cells, indicating efferocytosis. Two 4-week-old male C57BL/6J mice were used to extract BMSCs, and GAS6/BMSCs were constructed through adenovirus transfection and successfully identified. Eighteen 8-week-old male C57BL/6J mice were used to create diabetic full-thickness skin defect wound models and divided into phosphate buffered solution (PBS) group, BMSC group, and GAS6/BMSC group (with 6 mice in each group) according to the random number table method. Immediately after injury, PBS, BMSC single-cell suspension, and GAS6/BMSC single-cell suspension were injected locally into the wounds of the three groups of mice, respectively. The wound healing rates were calculated, and the cell proliferation, capillary density, and efferocytosis were detected at the same time points as the previous experiments.Results:At 3, 7, 14, and 21 days after injury, the wound healing rates of mice in diabetic wound group were significantly lower than those in control wound group (with t values of 7.99, 8.62, 9.80, and 5.85, respectively, P<0.05). Compared with those in control wound group, the wound tissue of mice in diabetic wound group showed the infiltration of a large number of inflammatory cells and reduced collagen deposition at 21 days after injury. At 21 days after injury, the number of PCNA-positive cells and CD31-positive cells in the wound tissue of mice in diabetic wound group were significantly less than that in control wound group (with t values of 6.61 and 5.38, respectively, P<0.05). At 21 days after injury, the number of F4/80 and MPO double-positive cells in the wound tissue of mice in diabetic wound group was 3.3±0.8, which was significantly less than 12.7±1.8 in control wound group ( t=11.00, P<0.05). At 14 and 21 days after injury, the wound healing rates of mice in BMSC group were significantly higher than those in PBS group ( P<0.05); at 3, 7, 14, and 21 days after injury, the wound healing rates of mice in GAS6/BMSC group were significantly higher than those in BMSC group ( P<0.05). At 21 days after injury, the number of PCNA-positive cells in the wound tissue of mice in BMSC group was significantly higher than that in PBS group ( P<0.05), and the number of PCNA-positive cells and CD31-positive cells in the wound tissue of mice in GAS6/BMSC group were significantly higher than that in BMSC group ( P<0.05). At 21 days after injury, the number of F4/80 and MPO double-positive cells in the wound tissue of mice in BMSC group was 4.2±1.2, which was similar to 3.5±1.1 in PBS group ( P>0.05); the number of F4/80 and MPO double-positive cells in the wound tissue of mice in GAS6/BMSC group was 8.2±1.2, which was significantly more than that in BMSC group ( P<0.05). Conclusions:Dysfunctional efferocytosis of macrophage exists in the full-thickness skin defect wounds of diabetic mice, while GAS6/BMSC can promote wound healing by restoring the efferocytosis of macrophages.

Objective To investigate whether exposure pathways influence the distribution pattern and toxicity of polystyrene nanoplastics(PSNPs)in hepatic cells.Methods Male C57BL/6J wild-type healthy mice aged 6 to 8 weeks old and weighed 18 to 22 g were administered with PSNPs via gavage or tail vein injection.Then,we tracked PSNPs distribution in the major organs of mice via an in vivo imaging system(IVIS).After that,we analyzed the cellular accumulation patterns in hepatic cell subpopulations(hepatocytes and Kupffer cells)using immunofluorescence and transmission electron microscopy(TEM).300 nm PSNPs were administered via gastric gavage or tail vein injection,and 70 nm PSNPs were injected via the portal vein.The cellular localization of PSNPs in the liver was analyzed using immunofluorescence.Subsequently,using AML-12 cells,a normal mouse liver cell line,as the parenchymal hepatocyte model,the uptake of PSNPs in AML-12 cells was analyzed by confocal laser scanning microscope(CLSM).Flow cytometry was performed to observe and quantify PSNPs uptake,and to analyze the underlying endocytosis mechanisms.IVIS was used to analyze PSNPs uptake features in vivo.Finally,using mouse macrophage line RAW264.7 as a Kupffer cell model and AML-12 cells as a parenchymal hepatocyte model,the cell-type-specific toxic effects induced by 100 μg/ml PSNPs were examined through transcriptomics and metabolomics analyses.Results IVIS revealed predominant hepatic accumulation of PSNPs regardless of exposure pathways via intragastric gavage or tail vein injection.Immunofluorescence/TEM demonstrated exposure pathway-dependent cellular distribution:intragastric PSNPs were localized mainly in hepatocytes,while intravenous PSNPs were accumulated in Kupffer cells.Changes in particle size(300 nm vs.70 nm)did not alter the cellular distribution pattern,while 70 nm PSNPs injected via the portal vein accumulated in Kupffer cells,which suggested that the cell-type-specific distribution of PSNPs in the liver was independent of PSNPs size and might be related to the transport of PSNPs in the gastrointestinal tract.Flow cytometry showed that PSNPs uptake by AML-12 was time-dependent and that the underlying endocytosis mechanism involved pathways mediated by clathrin(P<0.000 1),macropinocytosis(P=0.002 6),and lipid rafts(P<0.000 1).Findings on PSNPs distribution in blood revealed that the uptake of PSNPs by hepatocytes exhibited a rate saturation phenomenon.Multi-omics analysis identified distinct toxicity patterns:PSNPs disrupted lipid metabolism and neurotransmitter homeostasis in AML-12 cells and induced inflammation and oxidative stress in Kupffer cells.Conclusion Exposure pathways mediate the hepatic cell-type-specific distribution of PSNPs,thereby altering the downstream toxicological consequences induced by exposure to PSNPs.

OBJECTIVE: To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously. METHODS: Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01). RESULTS: Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c.1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright's hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c.2T>C (p.Met1?) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. CONCLUSION When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of co-morbid genetic diseases.
Child, Preschool ; Female ; Humans ; Male ; Class Ia Phosphatidylinositol 3-Kinase/genetics* ; Comorbidity ; Exome Sequencing ; Mutation ; Rare Diseases/genetics* ; Retrospective Studies ; Adolescent

Objective:To construct an evidence-based practice program for dietary management of patients with non-dialysis chronic kidney disease (CKD) based on best evidence and to evaluate the effectiveness of its application.Methods:The best evidence for dietary management of non-dialysis CKD patients was summarized. From September to October 2022, following the evidence clinical transformation model of the Fudan University Centre for Evidence-based Nursing, the best evidence was screened and evidence-based practice program were developed, taking into account patients' wishes, expert opinions, and clinical contexts. From November 2022 through March 2023, baseline reviews, analysis of barriers and facilitators were implemented. Between April 2023 and April 2024, evidence-based practice was carried out in the Department of Nephrology of the Second Affiliated Hospital of Guangzhou Medical University to compare the implementation rate of review indicators at the system, practitioner, and patient levels, and practitioners' knowledge before and after the application of evidence.Results:A total of 14 review indicators were developed. The implementation rate of the 12 review indicators and the practitioners' knowledge of the CKD diet were elevated after the evidence-based practice ( P<0.05) . Conclusions:Evidence-based practice program for dietary management of patients with non-dialysis CKD has a positive effect on improving practitioners' knowledge of non-dialysis CKD diets, implementation rate of dietary management behaviors, and patients' dietary behaviors.