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:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

Objective To investigate the chemical composition from the flowers of Callerya speciosa,and reveal the metabolites difference at different flowering periods based on metabolomics technology.Methods The primary and secondary metabolites,volatile chemical components in flowers of C.speciosa were analyzed combined by GC-MS and UPLC-Q-Exactive MS.Principal component analysis(PCA),orthogonal partial least squares-discriminant analysis(OPLS-DA),and hierarchical cluster analysis(HCA)were performed to identify differential metabolites.Results A total of 332 compounds were identified by UPLC-Q-Exactive MS,mainly including secondary metabolites such as flavonoids,triterpenoids,phenylpropanoids.A total of 297 compounds were identified by GC-MS,mainly including primary metabolites and volatile chemical components,such as organic acids,amino acids,saccharides,heterocycles,alcohols.The PCA analysis demonstrated that the metabolites of the four flowering periods were divided into two groups:bud,initial bloom and blooming periods clustered into one group,while wilting period clustered into the other group,the main differences were filtered and identified as flavonoids and triterpenoids,organic acids,respectively.Compared to the upright type,the flowers of vine type contained more characteristic flavonoids as differential metabolites during the bud,initial bloom and blooming periods,and some flavonoids decrease gradually with the development of flowering.Conclusion The results indicated that the flowers of C.speciosa possessed abundant active flavonoid metabolites for further utilization,and the best harvest stage is initial bloom,the best harvest plant is vine type.This study provides a scientific basis for the scientific development and rational use of the flowers of C.speciosa.

Objective:To study the treatment outcomes of combining percutaneous transhepatic one-step biliary fistulation (PTOBF) followed by two stages cholangioscopic treatment for type Ⅰ and Ⅱa hepatolithiasis which developed after Roux-en-Y cholangiojejunostomy, and in treatment of cholangiojejunostomy stenosis.Methods:The clinical data of 95 patients with type Ⅰ and Ⅱa hepatolithiasis which developed after Roux-en-Y cholangiojejunostomy and were treated at Shandong Second Provincial General Hospital from September 2016 to December 2020 were analyzed retrospectively. There were 36 males and 59 females, with the age of (51.2±15.3) years (range 14 to 75 years). These patients initially underwent PTOBF rigid choledochoscopy, followed by electronic choledochoscopy via the fistula tract after 6-8 weeks. The hepatolithiasis removal, complications and hepatolithiasis recurrence rates, and the cholangio-intestinal anastomotic stenosis rate and treatments were recorded. The follow-up was performed to analyse prognosis.Results:All 95 patients successfully underwent PTOBF rigid choledochoscopy and electronic choledochoscopy via the fistula tract. In 92 patients (96.8%), stones were completely removed. In 3 patients, small amounts of peripheral bile duct stones were left behind. Of 49 patients had cholangio-intestinal anastomotic strictures. On cholangioscopic examination, the strictures were caused by anastomotic knots in the suture line in 25 patients and cicatricial stenosis in 24 patients. After biliary balloon dilation and removal of anastomotic suture line knots, the strictures were relieved in 49 patients. There were 2 patients who developed biliary bleeding and 2 patients pleural effusion after PTOBF rigid choledochoscopy. Hepatolithiasis recurred in 4 patients in 6 to 36 months later.Conclusion:PTOBF followed by two stages cholangioscopic treatment were safe and effective in treatment of type Ⅰ and Ⅱa hepatolithiasis after Roux-en-Y cholangiojejunostomy. A high hepatolithiasis removal rate was obtained. Balloon dilation and removal of biliary intestinal anastomotic suture knots effectively relieved biliary intestinal anastomotic stenosis. The long-term results needs to be further determined.

Objective: To investigate the effects of buccal acupuncture on analgesia, immune indicators, and expression levels of Survivin and Livin proteins in patients with advanced-stage primary liver cancer. Methods: Eighty patients with advanced-stage primary liver cancer were selected and divided into control and treatment groups according to the difference in treatment modalities, with 40 patients in each group. The control group received transcatheter arterial chemoembolization (TACE), and the treatment group received buccal acupuncture in addition to TACE. The recent efficacy, analgesic effect, liver function, serum tumor markers, Survivin and Livin protein expression levels in liver cancer tissue, and immune indexes were analyzed and compared between the two groups. Results: The objective response rate (ORR) and disease control rate (DCR) of the treatment group were 37.5％ and 77.5％, respectively, which were significantly higher than those of the control group (22.5％ and 52.5％), and the recent efficacy of the treatment group was significantly better than that of the control group (P<0.05). The onset of analgesia in the treatment group was significantly faster than that in the control group (P<0.05), the duration of analgesia was significantly longer than that in the control group (P<0.05), and the numeric rating scale (NRS) score of pain after treatment was significantly lower than that in the control group (P<0.05). In the treatment group, the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin/globulin (A/G) were significantly lower than those in the control group (P<0.05), and the serum levels of alpha-fetoprotein (AFP), alpha-L-fucosidase (AFU), and carcinoembryonic antigen (CEA) were significantly lower than those in the control group (P<0.05), and the expression levels of Survivin and Livin in liver cancer tissue were significantly lower than those in the control group (P<0.05); CD4+ and CD4+/CD8+ in the treatment group were significantly higher than those in the control group, and CD8+ was significantly lower than that in the control group after treatment (P<0.05). Conclusion: Buccal acupuncture can reduce the degree of pain and liver function damage in patients with advanced- stage primary liver cancer and lower the serum tumor marker levels, and its mechanism of action may be related to the down-regulation of Survivin and Livin protein expression levels in the liver cancer tissue and the regulation of the immune function.

Objective To evaluate the feasibility and safety of tracheal extubation in operating room for patients with end-stage chronic obstructive pulmonary disease (COPD) after single-lung transplantation. Methods Clinical data of 57 recipients who underwent single-lung transplantation due to end-stage COPD were retrospectively analyzed. According to the evaluation indexes of tracheal extubation in operating room established by our hospital, 17 recipients eligible for tracheal extubation in operating room were assigned into the operating room extubation group (OR extubation group) and 40 recipients receiving tracheal extubation in intensive care unit (ICU) were allocated in the ICU extubation group. The evaluation results of intraoperative tracheal extubation and postoperative recovery were compared between two groups. Results Compared with the ICU extubation group, recipients in the OR extubation group had higher oxygenation index, lower arterial partial pressure of carbon dioxide (PaCO₂), lower blood lactic acid level, less fluctuation range of blood pressure and fewer cases receiving extracorporeal membrane oxygenation (ECMO) during operation (all P < 0.05). Two recipients in the OR extubation group received repeated tracheal intubation at 6 and 8 h after returning to ICU, and tracheal extubation at postoperative 6 and 9 d. In the OR extubation group, time of postoperative mechanical ventilation, length of postoperative ICU and hospital stay of the recipients were shorter than those in the ICU extubation group (all P < 0.05). The incidence of grade 3 primary graft dysfunction (PGD), atrial tachyarrhythmia, continuous renal replacement therapy and 1-year survival rate did not significantly differ between two groups (all P > 0.05). Conclusions The tracheal extubation regimen in the operating room for COPD patients after single-lung transplantation established by our hospital is safe and feasible, which shortens the time of postoperative mechanical ventilation, the length of postoperative ICU and hospital stay, whereas does not increase the incidence of postoperative complications.

To explore the mechanisms by which AKR1C3 induces tumor resistance, human breast cancer cell strain MCF-7/DOX resistant to doxorubicin, MCF-7/ AKR1C3 cells for overexpression of AKR1C3 and MCF-7/DOX-KD cells for knockdown of AKR1C3 in MCF-7/DOX cells were established. Western blot analysis found that AKR1C3 was expressed at a higher level in MCF-7/DOX than MCF-7 wild type cells. Similarly, CCK-8 and DAPI confirmed that MCF-7/ AKR1C3 cells were more resistant to DOX than AKR1C3 wild types as the IC50 was increased 6 times in MCF-7/AKR1C3 cells more than in AKR1C3 wild type cells. Meanwhile, colony formation ability was also enhanced after AKR1C3 was over-expressed in MCF-7 cells.Cytoplasmic/nuclear separation analysis and IF further found that β-catenin nuclear translocation mediated by AKR1C3 was the main reason contributing to the occurrence of DOX-resistant breast cancer cells. β-catenin inhibitor, XAV939, could reverse the AKR1C3 induced doxorubicin resistance in MCF-7 cells.Results indicated that AKR1C3 could be a potential therapeutic target in breast cancer cells.

Anti-contactin associated protein-like 2 (CASPR2) antibody encephalitis is a rare autoimmune encephalitis with variable clinical symptoms and atypical imaging manifestations. The prognosis of the patients with severe disease is poor. Reversible posterior leukoencephalopathy syndrome is rarely reported in autoimmune encephalitis. The clinical data, diagnosis and treatment of a patient with anti-CASPR2 antibody encephalitis complicated with reversible posterior encephalopathy syndrome were reported, in order to improve the understanding of clinicians on the rare disease complicated with atypical imaging manifestations.

Prostate cancer is one of the most common cancers in adult men. Heat shock proteins (HSPs),as molecular chaperones widely involved in the pathogenesis,diagnosis,treatment and prognosis of various cancers,play crucial biological functions in prostate cancer and it can be considered as valuable biomarkers for cancer therapy, such as prostate-specific membrane antigen. As a member of the heat shock protein family, HSP27 is related to prostate cancer castration resistance,and its expression can promote tumor resistance,invasion and bone metastasis,making prostate cancer more invulnerable to treatments. Therefore,targeting HSP27 in prostate cancer can be perceived as one promising cancer treatment strategy. This article reviews the structure and function of HSP27,and its potential role on castration resistance and targeted therapy in order to provide a new theoretical basis for the clinical treatment of prostate cancer.