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*

Currently, there are practical and technical difficulties in the construction of clinical questions in the development of clinical practice guidelines. Clinicians or guideline developers seldom construct clinical questions based the actual case scenario, leading to some information loss between structured and actual clinical connotation. To overcome this challenge, we proposed a case-guided questions construction approach, and carried out case research and verification in the formulation of the guideline. We found that this method could more efficiently and scientifically assist the formulation of clinical questions, and provide reference for clinicians or guideline developers.

BACKGROUND:Shujin Jiannao Prescription is an empirical formula for the treatment of cerebral palsy in Dongzhimen Hospital,Beijing University of Chinese Medicine,with clear clinical efficacy,but the specific mechanism needs to be elucidated. OBJECTIVE:To explore the possible mechanism of Shujin Jiannao Prescription in treating cerebral palsy. METHODS:Sixty-four 7-day-old Sprague-Dawley rats were randomly divided into a normal group(n=12)and a model group(n=52).An animal model was established by the Rice-Vannucci method.After successful modeling,52 model rats were randomly divided into control model group(n=12),minocycline group,and the low-,medium-,and high-dose groups of the Shujin Jiannao Prescription(n=10 per group).Rats in the minocycline group were given 40 mg/kg·d minocycline by gavage;rats in the low-,medium,and high-dose groups were given 4,8,and 16 g/kg·d Shujin Jiannao Prescription granules by gavage,respectively;and rats in the normal group and control model group were given an equal dose of normal saline by gavage.Medication in each group was given once a day for 1 week.The rats in each group were evaluated behaviorally using suspension test,abnormal involuntary movement score,and Bederson score.The pathological changes of the cerebral cortex were observed by hematoxylin-eosin staining.The levels of tumor necrosis factor α,interleukin 1β,and interleukin 10 in the cerebral cortex were determined using ELISA.The positive expressions of Janus kinase 2(JAK2),phosphorylated Janus kinase 2(p-JAK2),phosphorylated signal transducer and activator of transcription 3(p-STAT3)in the cerebral cortex were detected using immunohistochemistry.The protein expression levels of JAK2,p-JAK2,and p-STAT3 were detected using western blot. RESULTS AND CONCLUSION:Compared with the normal group,the suspension test score and involuntary movement score were decreased in the control model group(P＜0.01 or P＜0.05).The pathological results showed structural disruption of nerve cells,formation of large numbers of vacuoles,cell swelling,and increased intercellular space in the control model group.In addition,the expressions of tumor necrosis factor α and interleukin 1β in the cerebral cortex were significantly increased(P＜0.01),the expression of interleukin 10 was decreased(P＜0.05),and the protein expressions of JAK2,p-JAK2,and p-STAT3 in the cerebral cortex were significantly increased(P＜0.01)in the control model group compared with the normal group.Compared with the model group,minocycline and Shujin Jiannao Prescription at each dose could improve the behavioral indexes of rats(P＜0.01 or P＜0.05)and ischemic-hypoxic pathological changes were attenuated,with only a small amount of necrotic nerve cells and a few vacuoles,and reduced intercellular space.Moreover,the expressions of tumor necrosis factor α and interleukin 1β in the cerebral cortex were decreased in each drug group compared with the control model group(P＜0.05),while the protein expressions of JAK2,p-JAK2,and p-STAT3 in the cerebral cortex were significantly decreased(P＜0.01).The most obvious improvement was observed in the high-dose Shujin Jiannao Prescription group.To conclude,Shujin Jiannao Prescription can inhibit inflammation in the cerebral cortex of rats with hypoxic-ischemic brain injury.The mechanism may be related to the regulation of the JAK2/STAT3 signaling pathway.

Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Objective:To review the application of pediatric magnetic resonance enterography (MRE) at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from 2012 to 2023, and to provide referenceable data for MRE use in complex pediatric clinical scenarios.Methods:This study was a cross-sectional study. The clinical and imaging data from children aged≤18 years who underwent MRE at Tongji Hospital between December 2012 and December 2023 were retrospectively analyzed. Out of 186 children who intended to receive the MRE examination, 12 failed, remainder 174 participants (mean age 14±4 years, range 1 month to 18 years) were included. Participants were categorized into an inflammatory bowel disease (IBD) group (118 cases) and a non-IBD group (56 cases), and further divided by age into infants (0-6 years, 8 cases), children (7-12 years, 37 cases), and adolescents (13-18 years, 129 cases). The overall image quality and the intestinal filling quality were scored using a 5-point scale. Statistical analyses included χ2 tests for age distribution, history of intestinal reconstruction surgery, and MRE success rates between IBD and non-IBD groups. Mann-Whitney U test was employed to compare subjective image quality scores between the abovementioned two groups. The Kruskal-Wallis test was used to detect the differences among the three age groups. Results:The success rate of MRE significantly increased with age: 66.7% (8/12) in infants, 88.1% (37/42) in children, and 97.7% (129/132) in adolescents ( χ2=15.39, P<0.001). A statistically significant difference in age distribution was observed between the IBD and non-IBD groups ( χ2=17.94, P<0.001). The proportion of infants in the non-IBD group was 14.3% (8/56), which was higher than that of the IBD group. The majority of the IBD group were adolescents, accounting for 78.8% (93/118). There was a statistically significant difference in the intestinal reconstruction surgery history ( χ2=2.83, P=0.005). The non-IBD group had a higher incidence of intestinal reconstructive surgery (21.4%, 12/56), compared to the IBD group (6.8%, 8/118). MRE intestinal filling quality or overall image quality scores between the IBD and non-IBD groups or among different age sub-groups were not statistically significant ( P>0.05). Conclusion:Juvenilization of non-IBD children and intestinal reconstructive surgery history could make the inspection more complex. High-quality imaging can still be achieved by adhering to technical specifications.

Objective:To summarize the clinical features,diagnosis and treatment of multisystem inflammatory syndrome in children (MIS-C) after novel coronavirus infection(COVID-19),so as to improve the early recognition of MIS-C.Methods:The general information,clinical manifestations,treatment and length of hospital stay of fifteen children diagnosed with MIS-C and hospitalized in the Department of Cardiology,Children's Hospital,Capital Institute of Pediatrics from December 1，2022 to January 31，2023 were retrospectively analyzed.Fifteen children were divided into shock group( n=6) and non-shock group( n=9) according to the criteria of shock,and the differences in general conditions and laboratory examinations before treatment were compared between two groups. Results:The mean age of fifteen children were (3.28±2.48) years (ranging from 9 months to 7.9 years),with a male to female ratio of 4:1.The mean time interval from COVID-19 to the onset of MIS-C was (30.60±9.91) days.The novel coronavirus vaccination rate was 7%.Fever,enlarged lymph nodes,cracked lips and a strawberry tongue were present in all children,with just one exhibiting peeling of the hands and feet.Compared with the non-shock group,patients in the shock group were older,the level of platelet decreased significantly,the level of procalcitonin,interleukin-10,N-terminal pro-brain natriuretic peptide(NT-proBNP) and ferritin significantly increased,the left ventricular ejection fraction and left ventricular fractional shortening decreased significantly,and the Z score of left ventricular end-systolic diameter significantly increased,and there were significant differences between two groups ( P<0.05).All 15 patients were treated with human intravenous immunoglobulin,and five patients with severe myocarditis and shock accepted combined high-dose methylprednisolone pulse therapy over a period of five days,with the doses gradually tapering off afterwards.The mean hospital stay of all patients was (11.00±4.80) days,while the mean shock correction time of six patients was (5.14±2.12) days.After six months of follow-up,15 patients showed excellent prognosis with coronary lesions recovered and without any new complications. Conclusion:Generally,MIS-C tends to occur 3-6 weeks after COVID-19,with more boys than girls.Older ones are more likely to suffer from shock.Focusing on NT-proBNP and cardiac function indicators could identify shock early.High-dose methylprednisolone pulse therapy may be effective and benefit for prognosis improvement in children complicated with both shock and severe myocarditis.

The incidence of prostate cancer has shown an obvious upward trend in recent years.18F-fluorodeoxyglucose(FDG)is a broad-spectrum imaging agent for cancer,but there is a " blind zone" in the application of prostate cancer.Therefore,exploring prostate imaging agents with better performance can help to make up the deficiency.At present,there are a number of positron imaging agents for prostate cancer,but the overall advantage is not obvious.Recently,a new imaging agent,68Ga-prostate specific membrane antigen(PSMA),has been demonstrated its better value in clinical application of prostate cancer.This review summarizes the research progress of 68 Ga-PSMA,

OBJECTIVE: To explore the efficacy of individualized subcutaneous immunotherapy (SCIT) in allergic rhinitis(AR) maintain phase. METHOD: Compare nasal symptom scores (VAS) and special disease scale--nasal conjunctivitis quality of life questionnaire(RQLQ) score after 3 years treatment to evaluate the therapeutic effect of each group and the level of improving patients quality of life. Take patients' blood to detect the serum level of IL-10 by enzyme linked immunosorbent test (enzyme linked immunosorbent assay). RESULT: After 3 years treatment, there was no difference of VAS between the conventional SCIT group and the individualized SCIT group. ELISA results showed that the level of IL-10 was significantly higher in the drug symptomatic treatment group than that in the healthy group, the levels of IL-10 were significantly lower in the conventional SCIT group and the individualized SCIT group than that in the healthy group, but there was no difference between the conventional SCIT and the individualized SCIT group. CONCLUSION After 3 years treatment, there was no difference between conventional and individualized SCIT groups. But the efficacy of the conventional and individualized SCIT groups were significantly better than that in the drug symptomatic treatment group.
Desensitization, Immunologic ; Enzyme-Linked Immunosorbent Assay ; Humans ; Injections, Subcutaneous ; Interleukin-10 ; blood ; Precision Medicine ; Quality of Life ; Rhinitis, Allergic ; drug therapy ; Surveys and Questionnaires

Glucocorticoids (GC) are increasingly being used to treat chronic rhinosinusitis, its efficacy and safety are the focus of attention. This article will be divided into chronic rhinosinusitis with nasal polyps and without nasal polyps two subtypes discussed nasal and oral glucocorticoids in the clinical therapeutic efficacy and medication safety.
Chronic Disease ; Glucocorticoids ; therapeutic use ; Humans ; Rhinitis ; drug therapy ; Sinusitis ; drug therapy

Objective To explore the relationship between fetal heart size and gestational weeks (GW). Methods The size of left atrium (LA), right atrium (RA), left ventricle (LV), right ventricle (RV), aorta (AO), pulmonary artery (PA), foramen ovale (FO), heart area (HA), thoracic area (TA), heart circumference (HC) and thoracic circumference (TC) were measured for 512 fetal hearts at 14-39 GW. The relationship between GW and the measurement was evaluated. Results The size of fetal heart chambers, AO, PA and ventricular septum (IVS) increased with the development of GW. The PA/AO, LA/RA, LV/RV, HC/TC and HA/TA were stable compared with different GW. Conclusion Fetal heart chambers increase with the development of GW. HA is correlated well with GW.