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.

BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

OBJECTIVE: To investigate the clinical efficacy of thoracoscopic minimally invasive surgery with nickel-titanium shape memory alloy wrap bone plate versus rib periosteal internal fixation in patients with multiple rib fractures (MRF) and flail chest. METHODS: A retrospective analysis was performed on 100 patients with MRF and flail chest treated with thoracoscopic minimally invasive surgery and internal fixation with rib fracture preservation between January 2019 and December 2022, including 54 males and 46 females, aged from 20 to 65 years old, with an average age of (38.0±18.0)years old. The duration of the disease ranged from 8 to 21 days. According to the different surgical methods, the patients were divided into control group and study group, with 50 patients in each group. The control group consisted of 23 males and 27 females, with an average age of (38.35±18.05) years old, who underwent rib preservation periosteal internal fixation. In the study group, there were 31 males and 19 females, with an average age of (38.15±17.99) years old, treated with thoracoscopic nickel-titanium shape memory alloy circumferential bone plate. The pulmonary function indices, electrocardiographic monitoring indices, pain severity, levels of inflammatory factors, complications, rehabilitation indices, and therapeutic efficacy were compared between the two groups before and after treatment. RESULTS: All patients were followed up for 6 months. After 3 days of treatment, the heart rate of both groups was (102.43±13.74) beats per minute vs (86.26±8.06) beats per minute, respiratory rate (28.45±3.40) breaths per minute vs (22.05±2.85) breaths per minute, blood oxygen saturation (89.68±3.66)% vs (98.46±4.84)%, rest pain (3.5±0.5) points vs (2.6±0.6) points, movement pain (3.6±0.5) points vs (2.5±0.5) points, and these differences were statistically significant(P<0.05). The levels of Interleukin-6 (IL-6) (102.30±17.00) pg·ml^-1 vs (85.68±21.20) pg·ml^-1 and tumor necrosis factor-alpha (TNF-α)(33.44±4.85) pg·ml^-1 vs (18.14±4.28) pg·ml^-1 in both groups exhibited an increase post-treatment, while the C-reactive protein (CRP) (75.51±10.54) mg·L^-1 vs (60.75±9.84) mg·L^-1 demonstrated a decrease compared to pre-treatment levels. Furthermore, the study group displayed significantly lower levels than the control group (P<0.05). After 10 days of treatment, the peak expiratory flow rate (3.31±0.52) L·s^-1 vs (5.69±0.74) L·s^-1, forced expiratory volume (1.46±0.29) L vs (2.06±0.38) L, and forced vital capacity (2.68±0.95) L vs (4.26±1.05) L of both groups exhibited significant improvements compared to pre-treatment levels. Moreover, the study group demonstrated significantly higher values than the control group (P<0.05). The incidence of postoperative complications in the study group was significantly lower compared to the control group (6 cases vs 14 cases, P<0.05). Additionally, the duration of bone callus formation(9.50±1.40) days and fracture healing (72.20±8.32) days in the study group was significantly shorter compared to the control group(11.35±2.15) days, (93.70±9.90) days (P<0.001). CONCLUSION Compared with traditional rib-preserving internal fixation, patients with MRF and flail chest treated with minimally invasive internal fixation with thoracoscopic nickel-titanium shape memory alloy surround bone plate have better therapeutic effect, because of less surgical trauma, less pain and inflammatory reaction, fewer postoperative pulmonary complications, faster and better recovery of lung function, and thus promote the recovery of patients.
Humans ; Male ; Female ; Middle Aged ; Adult ; Retrospective Studies ; Rib Fractures/surgery* ; Aged ; Minimally Invasive Surgical Procedures/methods* ; Flail Chest/surgery* ; Thoracoscopy/methods* ; Fracture Fixation, Internal/methods*

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

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*

Objective To investigate the current situation and influencing factors of latent tuberculosis infection(LTBI)among close contacts of positive etiology pulmonary tuberculosis(PTB)patients,provide basis for formula-ting intervention measures for LTBI.Methods A multi-stage stratified cluster random sampling method was used to select close contacts of positive etiology PTB patients from 39 districts and counties in Chongqing City as the study objects.Demographic information was collected by questionnaire survey and the infection of Mycobacterium tuberculosis was detected by interferon gamma release assay(IGRA).The influencing factors of LTBI were analyzed by x2 test and binary logistic regression model.Results A total of 2 591 close contacts were included,the male to female ratio was 0.69∶1,with the mean age of(35.72±16.64)years.1 058 cases of LTBI were detected,Myco-bacterium tuberculosis latent infection rate was 40.83％.Univariate analysis showed that the infection rate was dif-ferent among peoples of different age,body mass index(BMI),occupation,education level,marital status,wheth-er they had chronic disease or major surgery history,whether they lived together with the indicator case,and whether the cumulative contact time with the indicator case ≥250 hours,difference were all statistically significant(all P＜0.05);infection rate presented increased trend with the increase of age and BMI(both P＜0.001),and decreased trend with the increase of education(P＜0.05).Logistic regression analysis showed that age 45-54 years old(OR=1.951,95％CI:1.031-3.693),age 55-64 years old(OR=2.473,95％CI:1.279-4.781),other occupations(OR=0.530,95％CI:0.292-0.964),teachers(OR=0.439,95％CI:0.242-0.794),students(OR=0.445,95％CI:0.233-0.851),junior high school education or below(OR=1.412,95％CI:1.025-1.944),BMI＜18.5 kg/m2(OR=0.762,95％CI:0.586-0.991),co-living with indicator cases(OR=1.621,95％CI1.316-1.997)and cumu-lative contact time with indicator cases ≥250 hours(OR=1.292,95％CI:1.083-1.540)were the influential fac-tors for LTBI(all P＜0.05).Conclusion The close contacts with positive etiology PTB have a high latent infection rate of Mycobacterium tuberculosis,and it is necessary to pay attention to close contacts of high age,farmers,and frequent contact with patients,and take timely targeted interventions to reduce the risk of occurrence of disease.

Objective: To reveal the molecular mechanism underlying the compatibility of Salvia miltiorrhiza Bge (S. miltiorrhiza, Dan Shen) and C. tinctorius L. (C. tinctorius, Hong Hua) as an herb pair through network pharmacology and subsequent experimental validation. Methods: Network pharmacology was applied to construct an active ingredient-efficacy target-disease protein network to reveal the unique regulation pattern of S. miltiorrhiza and C. tinctorius as herb pair. Molecular docking was used to verify the binding of the components of these herbs and their potential targets. An H9c2 glucose hypoxia model was used to evaluate the efficacy of the components and their synergistic effects, which were evaluated using the combination index. Western blot was performed to detect the protein expression of these targets. Results: Network pharmacology analysis revealed 5 pathways and 8 core targets of S. miltiorrhiza and C. tinctorius in myocardial protection. Five of the core targets were enriched in the hypoxia-inducible factor-1 (HIF-1) signaling pathway. S. miltiorrhiza-C. tinctorius achieved vascular tone mainly by regulating the target genes of the HIF-1 pathway. As an upstream gene of the HIF-1 pathway, STAT3 can be activated by the active ingredients cryptotanshinone (Ctan), salvianolic acid B (Sal. B), and myricetin (Myric). Cell experiments revealed that Myric, Sal. B, and Ctan also exhibited synergistic myocardial protective activity. Molecular docking verified the strong binding of Myric, Sal. B, and Ctan to STAT3. Western blot further showed that the active ingredients synergistically upregulated the protein expression of STAT3. Conclusion The pharmacodynamic transmission analysis revealed that the active ingredients of S. miltiorrhiza and C. tinctorius can synergistically resist ischemia through various targets and pathways. This study provides a methodological reference for interpreting traditional Chinese medicine compatibility.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

Pharmacokinetics of traditional Chinese medicine(TCM)is a discipline that adopts pharmacokinetic research methods and techniques under the guidance of TCM theories to elucidate the dynamic changes in the absorption,distribution,metabolism and excretion of active ingredients,active sites,single-flavour Chinese medicinal and compounded formulas of TCM in vivo.However,the sources and components of TCM are complex,and the pharmacodynamic substances and mechanisms of action of the majority of TCM are not yet clear,so the pharmacokinetic study of TCM is later than that of chemical medicines,and is far more complex than that of chemical medicines,and its development also confronts with challenges.The pharmacokinetic study of TCM originated in the 1950s and has experienced more than 70 years of development from the initial in vivo study of a single active ingredient,to the pharmacokinetic and pharmacodynamic study of active ingredients,to the pharmacokinetic study of compound and multi-component of Chinese medicine.In recent years,with the help of advanced extraction,separation and analysis technologies,gene-editing animals and cell models,multi-omics technologies,protein purification and structure analysis technologies,and artificial intelligence,etc.,the pharmacokinetics of TCM has been substantially applied in revealing and elucidating the pharmacodynamic substances and mechanisms of action of Chinese medicines,research and development of new drugs of TCM,scientific and technological upgrading of large varieties of Chinese patent medicines,as well as guiding the rational use of medicines in clinics.Pharmacokinetic studies of TCM have made remarkable breakthroughs and significant development in theory,methodology,technology and application.In this paper,the history of the development of pharmacokinetics of TCM and the progress of cutting-edge research was reviewed,with the aim of providing ideas and references for the pharmacokinetics of TCM and related research.

Objective To investigate the efficacy and safety of ultrafiltration therapy in elderly patients with congestive heart failure(CHF)and frailty.Methods A total of 88 hospitalized elderly patients with CHF and frailty were randomly assigned to the ultrafiltration group(n=44)and the control group(n=44).The control group treated with standard drug therapy.The ultrafiltration group treated with ultrafiltration,however,diuretics were not used during ultrafiltration treatment.Efficacy assessment was compared between the two groups,including patient body weight,N-terminal pro-brain natriuretic peptide(NT-proBNP)levels at 48 hours after treatment,dyspnea severity scores at 48 hours and 1 week after treatment,hospitalization duration and readmission rate within 3 months.Safety assessment parameters included serum creatinine,urea nitrogen,Na+and K+concentration at 48 hours after treatment and creatinine level 1 week after treatment.Results Efficacy assessment indicated that at 48 hours after treatment,both groups showed a significant reduction in patient body weight and NT-proBNP levels compared to pre-treatment levels(P＜0.05).However,there were no significant difference in body weight and NT-proBNP levels before and after treatment between the two groups(P＞0.05).Dyspnea severity scores for both groups increased at 48 hours after treatment,then decreased at 1 week after treatment.The ultrafiltration group exhibited higher dyspnea severity scores than that of the control group at 48 hours after treatment(P＜0.05).The length of hospital stay and the rate of re-hospitalization within 3 months were lower in the ultrafiltration group compared to those of the control group(P＜0.05).Safety assessment revealed that there were no significant differences in serum urea nitrogen and Na+levels before and 48 hours after treatment between the two groups(P＞0.05).However,serum K+levels were higher after 48-hours treatment in the ultrafiltration group than those of the control group(P＜0.05).There were no significant changes in creatinine levels before and after treatment in the control group(P＞0.05),while creatinine levels were lower 1 week after treatment in the ultrafiltration group compared to those of pre-treatment and 48 hours after treatment,and were lower than those of the control group(P＜0.05).Conclusion Ultrafiltration is a safe and effective method for elderly patients with CHF and frailty.