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.

Pulmonary complications， the most common postoperative complications of lung cancer， not only affect the quality of life of the patients after surgery but also increase the prognostic risks of postoperative recurrence and metastasis， threatening the life safety. At present， a multidisciplinary model of diagnosis and rehabilitation with integrated traditional Chinese medicine （TCM） and Western medicine has been initially formed under the guidance of the concept of rapid rehabilitation post operation for lung cancer. However， the treatment that only aims at shortening hospital stay and reducing the incidence of postoperative complications does not pay enough attention to the postoperative functional rehabilitation of the lung and the impact of follow-up adjuvant therapy， which affects the completeness of rehabilitation. This paper classifies the typical postoperative symptoms and manifestations of lung cancer into five groups： Lung system， emotion， digestive tract， pain， and nerve. On this basis， this paper summarizes the three core pathogeneses of postoperative complications of lung cancer as failure of Qi to ascend and descend leading to insecurity of defensive exterior， vessel block leading to Qi stagnation and fluid retention， and lung Qi deficiency leading to spleen and kidney deficiency. Accordingly， this paper proposes the treatment principle of protecting healthy Qi and treating Qi with the core of descending-tonifying-ascending-dispersing Qi and puts forward three treatment methods. The first is replenishing Qi and consolidating exterior， and expelling phlegm and regulating lung. The second is replenishing Qi and promoting blood flow to resolve stasis and relieving pain. The third is replenishing Qi and tonifying lung， and invigorating spleen and tonifying kidney. Furthermore， this paper elaborates on the pathogenesis and treatment principles of four common postoperative complications： Lung infection， pleural effusion， atelectasis， and bronchopleural fistula. On the basis of Western medical treatment， the TCM treatment characteristics of treating symptoms in the acute phase and eradicating the root cause in the chronic phase should be played. While dispelling the pathogen， measures should be taken to protect the healthy Qi， including tonifying lung Qi， regulating spleen Qi， and replenishing kidney Qi. This study summarizes the pathogenesis and treatment strategy of common postoperative complications of lung cancer according to the principle of protecting healthy Qi and treating Qi， aiming to provide guidance for the future treatment of postoperative complications of lung cancer.

Objective To investigate the clinical characteristics and influencing factors of thyroid function abnormality (TFA) in patients with malignant tumors receiving programmed death-1 (PD-1) inhibitor therapy, and its correlation with PD-1 inhibitors. Methods A retrospective analysis was conducted on the clinical data and biochemical indicators of 669 patients with malignant tumors who received PD-1 inhibitor therapy. Of these, 561 patients maintained normal thyroid function (normal group), while 108 developed TFA (TFA group). Baseline characteristics, PD-1 inhibitor type, tumor type, and other indice were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to identify related factors for TFA development. Additionally, the relationship between PD-1 inhibitors and TFA types was further analyzed within the TFA group. Results The rates of patients treated with pembrolizumab and with respiratory tumors were significantly higher in TFA group than those in the normal group (P＜0.01). Multivariate logistic regression analysis revealed that treatment with pembrolizumab and with respiratory tumor increased 5.350 and 1.514 times than tislelizumab and digestive tumor for risk of TFA development, respectively (P＜0.01). Within the TFA group, hypothyroidism was the predominant type (75, 69.4%); treatment with pembrolizumab increased 2.999 times than tislelizumab for development risk of hyperthyroidism (P＝0.042). Conclusions Among patients with malignant tumors treated with PD-1 inhibitors, pembrolizumab is more frequently associated with TFA, and patients with respiratory tumors were at a higher risk of developing TFA. Clinicians should closely monitor thyroid function in patients with respiratory tumors treated with pembrolizumab.

Objective: To analyze the epidemiological characteristics and spatial-temporal clustering characteristics of pulmonary tuberculosis in Huangpu District, Shanghai Municipality from 2009 to 2023, so as to provide the evidence for formulating targeted pulmonary tuberculosis prevention and control strategies. Methods: Data of registered pulmonary tuberculosis cases in Huangpu District from 2009 to 2023, including gender, age, occupation, and pathogenetic test results, were collected from the Tuberculosis Management Information System of the China Disease Prevention and Control Information System. The registered incidence was calculated, and the trend was analyzed using the annual percent change (APC) and average annual percent change (AAPC). Spatial distribution pattern was analyzed using kernel density estimation and the average nearest neighbor methods. The temporal-spatial clustering characteristics of pulmonary tuberculosis were identified using the spatio-temporal scan analysis. Results: A total of 2 726 pulmonary tuberculosis cases were registered in Huangpu District from 2009 to 2023. The registered incidence decreased from 31.20/100 000 in 2009 to 15.06/100 000 in 2023 (AAPC=-6.156%, P<0.05). A sharp declining trend was particularly observed from 2017 to 2023 (APC=-11.355%, P<0.05). Among them, 1 239 were pathogen-positive, and the pathogen positivity rate increased from 40.80% in 2009 to 71.05% in 2023 (P<0.05). There were 1 906 male cases and 820 female cases, with a male-to-female ratio of 2.32∶1. There were 798 cases aged 45-<60 years and 981 retirees, accounting for 29.27% and 35.99%, respectively. Temporal-spatial clustering analysis revealed spatial clustering areas during both 2009-2016 and 2017-2023 (both P<0.05). The clustering area for 2009-2016 was located in the central-eastern part of Huangpu District, with the clustering time in 2012. The clustering area for 2017-2023 was in the southwestern part, with the clustering time in 2017. Conclusions The registered incidence of pulmonary tuberculosis in Huangpu District showed a downward trend from 2009 to 2023. The spatial clustering areas were identified in the central-eastern part in Huangpu District in 2012 and the southwestern part in 2017.

Diterpenoid ferruginol is a key intermediate in biosynthesis of active ingredients such as tanshinone and carnosic acid.However, the traditional process of obtaining ferruginol from plants is often cumbersome and inefficient. In recent years, the increasingly developing gene editing technology has been gradually applied to the heterologous production of natural products, but the production of ferruginol in microbe is still very low, which has become an obstacle to the efficient biosynthesis of downstream chemicals, such as tanshinone. In this study, miltiradiene was produced by integrating the shortened diterpene synthase fusion protein,and the key genes in the MVA pathway were overexpressed to improve the yield of miltiradiene. Under the shake flask fermentation condition, the yield of miltiradiene reached about(113. 12±17. 4)mg·L~(-1). Subsequently, this study integrated the ferruginol synthase Sm CYP76AH1 and Sm CPR1 to reconstruct the ferruginol pathway and thereby realized the heterologous synthesis of ferruginol in Saccharomyces cerevisiae. The study selected the best ferruginol synthase(Il CYP76AH46) from different plants and optimized the expression of pathway genes through redox partner engineering to increase the yield of ferruginol. By increasing the copy number of diterpene synthase, CYP450, and CPR, the yield of ferruginol reached(370. 39± 21. 65) mg·L~(-1) in the shake flask, which was increased by 21. 57-fold compared with that when the initial ferruginol strain JMLT05 was used. Finally, 1 083. 51 mg·L~(-1) ferruginol was obtained by fed-batch fermentation, which is the highest yield of ferruginol from biosynthesis so far. This study provides not only research ideas for other metabolic engineering but also a platform for the construction of cell factories for downstream products.
Saccharomyces cerevisiae/genetics* ; Diterpenes/metabolism* ; Metabolic Engineering ; Fermentation ; Abietanes

[This corrects the article DOI: 10.11909/j.issn.1671-5411.2017.08.005.].

OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.
Carcinoma, Hepatocellular/drug therapy* ; Proto-Oncogene Proteins c-met/metabolism* ; Liver Neoplasms/drug therapy* ; Signal Transduction/drug effects* ; Animals ; Humans ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Amphibian Venoms/therapeutic use* ; Cell Line, Tumor ; Neoplasm Metastasis ; Cell Survival/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Neoplasm Invasiveness ; Mice, Inbred BALB C ; Mice, Nude ; Mice ; Male ; Bufanolides/therapeutic use* ; Protein Precursors ; Prothrombin ; Biomarkers

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave 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*