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 application and safety of pediatric interfacility-transport with extracorporeal membrane oxygenation (ECMO) in China. Methods: The data of 48 patients transported inter-hospital from February 2016 to May 2018 were collected from the following 4 centers: pediatric intensive care unit (PICU) of Bayi Children′s Hospital Affiliated to the 7th Medical Center of PLA General Hospital, Pediatric Hospital of Fudan University, Henan Provincial People′s Hospital and Children′s Hospital of Zhejiang University School of Medicine. The data of patients′ characteristics, ECMO mode and wean rate, and mortality were reviewed, which was further compared with the data of 57 compatible inner-hospital ECMO cases with t test, Rank sum test or chi-square test. Results: All the 48 interfacility-transports were accomplished by ambulance on land, with an average transfer distance of (435±422) km. The incidence of ECMO complications was 13% (6 case), without death. There were no significant differences in lactic acid, PaO₂ or SaO₂ before and after transport (4.0 (2.0, 7.5) vs. 3.0 (1.5, 6.0) mmol/L, Z=-1.579, P>0.05; 112(47, 405) vs. 166(122, 240) mmHg (1 mmHg=0.133 kPa), Z=-0.104, P>0.05; 0.97±0.02 vs. 0.96±0.03, t=1.570, P>0.05). Instead, PaCO₂ and pH were significantly different ((47±8) vs. (42±5) mmHg, t=2.687, P<0.05; 7.3±0.2 vs. 7.5±0.2, t=3.379, P<0.05). The total ECMO weaned rate was 73% (35/48) and the survival rate was 67% (32/48). No significant differences in demographic characteristics, ECMO mode or duration, transport distance or duration, or complications existed between the survival group and the death group (7/25 vs. 2/14, χ²=0.615, P>0.05; 4/28 vs. 2/14, χ²=0, P>0.05; (405±404) vs. (493±465) km, t=0.525, P>0.05; (5±4) vs. (5±5) h, t=0.388, P>0.05; 166 (128, 239) vs. 187(52, 405) h, Z=-0.104, P>0.05; 3/32 vs. 3/16, χ²=0.734, P>0.05). The lowest lactate value in survival group before ECMO transport was significantly lower than that in the death group ((5±5) vs. (8±6) mmol/L, t=2.151, P<0.05). There were neither significant differences in age, ECMO mode or support pattern (9/39 vs. 15/42, χ²=0.845, P>0.05; 6/42 vs. 7/50, χ²=0.001, P>0.05; 29/19 vs. 38/19, χ²=0.441, P>0.05), nor in ECMO weaned rate, survival rate or complications between interfacility-transport group and inner-hospital group (35/48 vs. 37/57, χ²=0.775, P>0.05; 32/48 vs. 35/57, χ²=0.313, P>0.05; 20/48 vs. 22/57, χ²=0.102, P>0.05). Conclusion With appropriate transport equipment and mature teams who handle problems timely during the transport, critically ill children could be safely transported to the destination with ECMO.

Objective:To observe influence of alprostadil injection on contrast-induced nephropathy (CIN) in high risk patients after percutaneous coronary intervention (PCI).Methods: A total of 263 CIN high risk (CIN risk score ≥16 scores) patients were selected.According to random number table, patients were randomly divided into routine treatment group (n=121, received routine hydration therapy) and alprostadil group (n=142, received additional alprostadil injection based on routine treatment group).Serum creatinine (SCr), glomerular filtration rate(GFR), cystatin C (CysC) and β trace protein (β-TP) level before, 48h and 72h after PCI were measured and compared, and incidence rate of CIN, percentage of blood purification therapy and mortality were compared between two groups.Results: Compared with before PCI, there was significant rise in SCr level and significant reduction in GFR in both groups on 48h and 72h after PCI (P<0.01 all);Compared with routine treatment group, there were significant reductions in levels of SCr [72h: (190.04±28.92) μmol/L vs.(141.10±21.18) μmol/L], and significant rise in GFR [72h: (26.0±4.4) ml/min vs.(36.4±4.9) ml/min], and levels of CysC[72h: (1.75±0.74) mg/L vs.(1.47±0.55) mg/L] and β-TP [72h: (1.53±0.50) mg/L vs.(1.22±0.38) mg/L] significantly decreased in alprostadil group on 48h and 72h after PCI, P<0.05 or <0.01;there were significant reductions in incidence rate of CIN (30.6% vs.18.3%) and percentage of blood purification therapy (10.7% vs.3.5%) in alprostadil group, P=0.001, 0.045 respectively.There was no significant difference in mortality between two groups, P=0.728.Conclusion: Alprostadil injection can significantly improve kidney function, reduce incidence rate of CIN and percentage of blood purification therapy in CIN high risk patients after PCI, which is worth extending.

Objective To study the influence of Ivor-Lewis surgery on lung function and quality of life of elderly patients with esophageal cancer .Methods 122 elderly patients with esophageal cancer were randomly divided into the observation group and the control group ,61 cases in each group .The control group was given Sweet surgery , observation group was given Ivor-Lewis surgery.The operative time,blood loss,number of lymph node dissection , drainage and hospitalization time were observed .Postoperative lung function 3 days after operation and life quality of patients 3 months after operation were compared between the two groups .Results The operative time,blood loss, drainage,and hospital stay in the observation group were (162.4 ±30.4) min,(260.1 ±33.7) mL,(1 254.1 ± 311.2)mL,(11.2 ±3.1)d,which were significantly lower than (201.6 ±33.6)min,(315.2 ±41.3)mL,(1 928.3 ± 346.1)mL,(17.6 ±3.6)d in the control group (t=3.627,4.662,2.716,3.772,all P<0.05).The number of lymph node dissection in the observation group was more than the control group (t=9.062,P<0.05).Before treat-ment,FEV1,FVC and PEF had no significant differences (t=0.612,0.301,0.772,all P>0.05).After treatment for 3 days,FEV1 of the control group and observation group were (1.89 ±0.47)L,(2.18 ±0.42)L;FVC were (2.44 ± 0.31)L,(2.87 ±0.25)L.PEF were (4.01 ±0.26)L/s,(4.52 ±0.29)L/s.After treatment for 3 days,FEV1,FVC and PEF in the control group were significantly decreased (t=4.162,3.997,5.012,all P<0.05).In the observation group,FEV1,FVC before and postoperative 3 days had no significant differences (t=1.032,0.924,all P>0.05), 3 days after treatment,PEF of the observation group was significantly decreased (t=3.128,P<0.05).After treat-ment for 3 days,FEV1 ,FVC and PEF of the observation group were significantly higher than those of the control group (t=5.186,3.017,3.112,P<0.05).Before surgery,scores of life quality in the control group and observation group were (5.41 ±1.83)points and (5.31 ±1.77)points.After surgery were (7.01 ±2.16)points and (8.35 ±2.27) points.Quality of life in two groups were improved after operation .Life quality of the observation group was significantly higher than the control group (t=2.864 4,P<0.05).Conclusion Ivor-Lewis surgical procedures can significantly improve lung function and quality of life in elderly patients with esophageal cancer .