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*

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*

Comprehensive experiments course is a bridge for higher vocational students to integrate theoretical knowledge with production practice. The article introduces that our biological pharmacy department is committed to the principles of "promotion of teaching, learning and construction through skills competition so as to integrate education and training". By taking penicillin fermentation process as an example, reform has been made in several aspects including teaching objectives, teaching content and teaching methods. We integrate the practical operation of fermentation equipment with virtual simulation software to develop a two-way interactive course. By reducing the subjective dependence, the quantitative management and evaluation of fermentation process parameter control were put into place, which efficiently integrated the skills competition with practical teaching. Improved teaching performance has been achieved over recent years, which may facilitate the reform and practice of similar courses based on skills competition.
Humans ; Clinical Competence ; Learning ; Students ; Technology ; Biological Products

Objective:To investigate the pathogen spectrum of acquired immunodeficiency syndrome (AIDS) patients with pulmonary opportunistic infections in the local area, and to evaluate the clinical application of metagenomic next-generation sequencing (mNGS) in these patients.Methods:From January to December 2021, AIDS patients with pulmonary infections admitted to Zhongnan Hospital of Wuhan University were enrolled. Their bronchoalveolar lavage fluid (BALF) was subjected to mNGS and coventional pathogen detection.Routine pathogen detection methods included smear, culture, polymerase chain reaction (PCR), and immunochromatographic colloidal gold. Fisher′s exact probability method was used for statistical analysis.Results:A total of 69 patients were included, and all of them were tested positive for mNGS. Among them, 53 cases (76.8%) were positive for fungi and viruses, 40 cases (58.0%) were positive for bacteria (excluding Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM)), six cases were positive for MTB, 11 cases were positive for NTM, and seven cases were positive for other pathogens. Mixed infections with two or more pathogens were found in 89.9%(62/69) of the patients. Among the conventional pathogen detections of BALF, 79.7%(55/69) of the patients were positive for pathogens, including 42 cases positive for Pneumocystis jirovecii PCR, 16 cases positive for BALF culture, nine cases positive for MTB PCR, and five cases positive for Cryptococcus antigen. The total detection rate of mNGS was 100.0%(69/69), which was higher than that of the conventional pathogen detection rate of 79.7%(55/69), and the difference was statistically significant (Fisher′s exact probability method, P<0.001). The specificity of mNGS detection was 88.4%. Combining clinical and two detection methods, the top five pathogens were Pneumocystis jirovecii (62.3%(43/69)), Candida (29.0%(20/69)), MTB (20.3%(14/69)), NTM and Talaromyces marneffei (15.9%(11/69), each). Fifty-three patients (76.8%) had co-infection with virus. Conclusions:The main cause of pulmonary infection in AIDS patients in this area is mixed infection, and Pneumocystis jirovecii is the most common pathogen. mNGS could significantly improve the pathogen detection rate in AIDS patients with pulmonary infections.

Objective:To analyze the clinical features, treatment, and outcomes of fetal/neonatal atrial flutter (AFL) at the onset of the perinatal period to improve the management of this condition.Methods:This retrospective study analyzed the clinical data, treatment, and follow-up results of fetal/neonatal AFL cases transferred to Shanghai Children's Medical Center from November 2013 to August 2021. Clinical characteristics, cardioversion procedures, and outcomes were summarized. Descriptive method was used for statistical analysis.Results:A total of 21 fetuses/neonates presenting with AFL in the perinatal period were involved in this study, including 17 males and four females. Ten of them were born at full term, and 11 were preterms. All of the patients were delivered by cesarean section at 32 to 41 gestational weeks [ (36.6±1.9) weeks] with a birth weight of 2 130 to 4 450g [ (3 059±528) g]. Increased fetal heart rate was all detected after 32 weeks of gestation, and three of them were diagnosed with AFL by fetal echocardiography before being born. The heart rate remained elevated in all cases after birth. All were diagnosed as AFL based on an electrocardiogram on the day of birth, which showed a 2 to 6 over one ratio of atrioventricular conduction. Among the six cases of cardiac insufficiency and low blood pressure complicated by dyspnea and cyanosis, the symptoms were relieved in four cases after mask oxygenation and two cases after ventilation. Among the 21 cases, one was converted spontaneously to normal sinus rhythm and the other 20 recovered after medication or electrical cardioversion. Seven cases were initially treated by drug conversion with a success rate of 5/7 and hospitalized for 23 d (13-25 d). There was one with cardiac insufficiency before treatment and three newly developed cardiac insufficiency during treatment among the seven cases. Thirteen cases were offered electrical cardioversion initially, and the success rate of cardioversion was 12/13. There were five cases of cardiac insufficiency before treatment, while no new cases of cardiac insufficiency was reported during treatment. The duration of hospitalization was 11 d (9-14 d). Apart from one case, the rest 20 infants were followed up from one month to eight years old, and no recurrence was reported.Conclusions:For fetal/neonatal AFL with the onset during the perinatal period, the symptoms mainly manifest in late pregnancy. Its diagnosis depends on fetal echocardiography before birth or electrocardiogram after birth, and electrical cardioversion is a fast and effective measure. While the prognosis of perinatal-onset AFL is generally good.

Objective:To analyze the performance of emergency response to 2019 novel coronavirus (2019-nCoV) positive cases in an international test competition in an Winter Olympic Game venue and provide evidences for the COVID-19 prevention and control in similar competitions.Methods:A retrospective analysis on the epidemiological investigation and nucleic acid test results of the cases, the implementation of prevention and control measures, including the communication with sport teams and others, was conducted.Results:The positive cases of 2019-nCoV among entering people were detected before entry, at airport, hotel and venue. Two positive cases were reported before entry, 2 positive cases infected previously and 3 asymptomatic cases were reported after the entry. The venue public health team and local CDC conducted epidemiological investigation and contact assessment jointly in a timely and efficient manner. No local secondary transmission occurred, but the nucleic acid test results of positive persons fluctuated, posing serious challenges to the implementation of prevention and control measures.Conclusion:In large scale international competition, there is high risk of imported COVID-19. It is necessary to fully consider the fluctuation of nucleic acid test results, the criteria for determination and cancellation of positive results and give warm care to positive cases in the emergency response.

Objective To investigate the effect of miR-148a on the chemosensitivity of cervical cancer HeLa cells to cisplatin and its related mechanism. Methods Cervical cancer HeLa cells were cultured in vitro and the concentration gradient of cisplatin was set to detect IC₂₀ value. Control group, mimic control group, miR-148a mimic group, inhibitor control group and miR-148a inhibitor group were set up. qRT-PCR was used to detect the expression of miR-148a and STAT3 mRNA after transfection. After 4 μmol/L cisplatin treatment, the proliferation of HeLa cells was detected by MTT assay; the apoptosis and cell cycle distribution were detected by flow cytometry; Western blot was used to detect the protein expression of p-STAT3/STAT3, CyclinD1, Bcl-2, Bax and Cleaved caspase-3. Results The IC₂₀ of cisplatin on HeLa cells was about 4 μmol/L. Compared with the mimic control group, the level of miR-148a in the miR-148a mimic group was significantly increased, and the level of STAT3 mRNA was significantly decreased (P < 0.05). Compared with the inhibitor control group, the level of miR-148a in HeLa cells in miR-148a inhibitor group was significantly decreased, and the level of STAT3 mRNA was significantly increased (P < 0.05). On the basis of cisplatin treatment, compared with the mimic control group, the apoptosis rate, G₀/G₁ phase cell ratio, the protein levels of Bax and Cleaved caspase-3 were significantly increased in miR-148a mimic group, while OD value, the proportions of cells in S and G₂/M phase, the protein levels of p-STAT3/STAT3, CyclinD1, Bcl-2 were significantly decreased (P < 0.05); compared with the inhibitor control group, the above indicators of HeLa cells in miR-148a inhibitor group changed significantly in the opposite direction (P < 0.05). Conclusion MiR-148a could enhance the chemosensitivity of cervical cancer HeLa cells to cisplatin by targetedly inhibiting STAT3.

Objective:To study the predictive value of hour-specific total serum bilirubin(TSB) nomogram combined with clinical risk factors in the risk of hyperbilirubinemia.Method:Perinatal clinical data of newborns born in Shanghai Pudong New Area Health Care Hospital for Women and Children, Shanghai Pudong New Area People's Hospital and Shanghai Pudong Hospital from August 2017 to July 2018 were collected in this prospective study. Transcutaneous bilirubin (TcB) was monitored before discharge from hospital. Enrolled neonates were followed up for 28 days. The patients were assigned to neonatal hyperbilirubinemia group (NHB) and non-hyperbilirubinemia group (Non-HB) according to the occurrence of hyperbilirubinemia. The predictive value of models for the risk of hyperbilirubinemia was evaluated by receiver operating characteristic (ROC) curves and Logistic regression analysis.Result:A total of 8 664 newborns were included in this study, with 1 196 cases of hyperbilirubinemia, with an incidence of 13.8%. Logistic regression analysis showed that maternal blood type O, premature rupture of membranes, male gender, gestational age 35~37 weeks, subcutaneous ecchymosis/cranial edema, and breastfeeding were independent risk factors for NHB ( P<0.05). The area under receiver operative characteristic curve (ROC) of predischarge bilirubin risk zone only was 0.874(95% CI 0.861~0.885, P<0.05)and for all independent risk factors was 0.664 (95% CI 0.647~0.680, P<0.05). The area under ROC curve was 0.891 (95% CI 0.880~0.902, P<0.05) by combining predischarge bilirubin risk zone with clinical risk factors. Conclusion:Predischarge bilirubin risk zone combined with clinical risk factors can reasonably predict neonatal hyperbilirubinemia well.

Objective To explore the treatment methods and prognosis of early infection and delayed infection after intramedullary nail fixation.Methods Data of 22 cases of postoperative infections after intramedullary nail from January 2013 to August 2017 were retrospectively analyzed.There were 18 males and 4 females aged from 20 to 72 years old,with an average age of 46.8 years.14 cases were tibias and 8 cases were femurs.In the early infection group,6 cases showed swelling,heat and pain in the affected area with drainage and pus.In the late infection group,12 cases showed sinus formation and 4 cases showed no sinus tract.According to whether the infection occurred within six weeks,it was divided into early infection and delayed infection groups.Of 6 patients in early infection group,there was 1 case of septic shock which underwent removal of intramedullary nails,debridement and antibiotic bone cement stick implantation.5 cases were retained intramedullary nail and underwent local debridement treatment.Late infection occurred in 16 patients.One patient with tibia infection was given partial dressing to heal the fracture.Then the intramedullary nail was removed and intramedullary debridement was performed.Two patients with poor general condition,the intramedullary nails were removed and debridement was performed.Calcium sulphate cement was implanted and fixed with external fixation.The remaining 13 cases were treated with debridement and antibiotic cement stick implantation.We compared the differences between early and late infections of internal fixation,infection control,fracture healing,and secondary fracture fixation.Results Of the 6 patients with early infection,1 patient with septic shock removed intramedullary nails to control infection.After infection controlled,the fracture was treated with intramedullary nailing.Of the 5 patients with retained intramedullary nails,2 patients' infection were controlled and 3 were uncontrolled.After removal of the intramedullary nails the infection was control.The success rate of retaining intramedullary nails was 33.3％ (2/6).Late infection occurred in 16 cases and infection was all controlled.The fractures healed in 22 patients.The fracture healing time of 6 patients with early infection was 2-6 months,with an average of 3.67±2.08 months.The fracture healing time of 16 patients with late infection was 2-4 months (average 3.2±0.79) months.Conclusion Patients with early bone infections after femoral and tibial intramedullary nail surgery may attempt debridement therapy with retained intramedullary nails,but the failure rate is high.If the intramedullary nail fails to remain,follow the treatment of patients with delayed bone infection.For patients with delayed bone infection,because the fracture has not yet healed,thorough debridement is used after the removal of internal fixation,then calcium sulfate or antibiotic bone cement stick should be implanted and fixed with external fixation.For the second phase,we may choose plate,intramedullary nail or external fixation to fix the fractures according to the soft tissue condition.All of the fixation methods could provide good fracture healing.

Objective A series of 4 substituted salidroside derivatives were designed and synthesized .Their anti-fatigue effects were investigated .Methods With five-acetyl glucose and different 4-substituted benzyl tyrosols as the starting materi-als ,salidroside derivatives were synthesized through glycosidation and deacetylation reactions .The exercise exhaustive mice model was used to study the anti-fatigue effects of those synthesized derivatives by comparing the loading swimming time of mice .Results 10 novel salidroside derivatives were synthesized .The loading swimming tests showed that the swimming time of the mice in the positive group (salidroside) and 3a-1 group (phenethyl-β-D-glucoside) was longer than that in the control group with statistically significant difference(P<0 .05) .The swimming times for other groups were similar to control group with no statistically significant difference .Conclusion This synthetic method for salidroside derivatives was convenient and feasible for large production .The 4-hydroxyl groups on the benzene ring of salidroside and its derivatives may be the active site responsible for their anti-fatigue activity .