Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.

Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

Biological Therapies for Atopic Dermatitis: A Systematic Review.

BACKGROUND: Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD. OBJECTIVE: This work aims to summarize both label and off-label biologics on AD treatment in phase II and phase III stages, and compile evidence on the efficacy of the most-studied biologics. METHODS: We conducted a comprehensive literature search through PubMed, EMBASE, and ClinicalTrials.gov to identify all documented biological therapies for AD. The criteria were further refined to focus on those treatments with the highest evidence level for AD with at least one randomized clinical trial supporting their use. Only studies or articles published in English were enrolled in this study. FINDINGS: Primary searches identified 525 relevant articles and 27 trials. Duplicated articles and papers without a full text were excluded. Only completed trials were enrolled. We included 28 randomized controlled trials, 4 unpublished trials, 2 observational studies, and 1 meta-analysis. Eight kinds of biologics, including IL-4/IL-13 inhibitors, JAK inhibitors, anti-IL-13 antibodies, anti-IL-22 antibodies, anti-IL-33 antibodies, thymic stromal lymphopoietin inhibitor (TSLP), OX40 antibodies, and H4R-antagonists were included in this work. Dupliumab, as the most widely used and investigated biologic, was reported in 1 meta-analysis and 4 trials exploring its long-term use and application in both adults and pediatric patients. Besides dupilumab, four other IL-4/IL-13 inhibitors recruited were all randomized, clinical trials at phase 2-3 stage. Six different kinds of JAK inhibitors were summarized with strong evidence revealing their significant therapeutic effects on AD. There were 3 trials for nemolizumab, an anti-IL-13 antibody, all of which were in the phase 2 clinical trial stage. Results showed nemolizumab could be another alternative therapy for moderate-to-severe AD with long-term efficiency and safety. CONCLUSION: The biological therapies with the most robust evidence on efficacy and long-term safety for AD treatment include dupilumab, barcitinib, abrocitinib, and delgocitinib. Most of the biologics mentioned in this review were still at the exploratory stage. This review will help practitioners advise patients seeking suitable biological therapies and offer experimental study directions for treatment.

Analysis on the application value of goal-directed fluid therapy in patients undergoing laparoscopy-assisted radical gastrectomy with fast-track anesthesia.

OBJECTIVE: To explore the application value of goal-directed fluid therapy (GDFT) in patients undergoing laparoscopy-assisted radical gastrectomy with fast-track anesthesia. METHODS: From December 2016 to December 2019, 74 patients who underwent laparoscopy-assisted radical gastrectomy under the concept of enhanced recovery after surgery (ERAS) in gastrointestinal Surgery department of Tongling People's Hospital were selected as research participants. They were divided into two groups: the routine group (patients were treated with conventional fluids) (n=37) and the GDFT group (patients were treated with GDFT) (n=37). In the two groups, patients were compared in terms of intraoperative fluid inflow and outflow, hemodynamic indexes before operation for 30 min (T0), after anesthesia induction for 30 min (T1), during operation for 0.5 h (T2) and 1.5 h (T3) and after operation (T4), postoperative complications, postoperative recovery, mini-mental state examination (MMSE) scores on the first day (d0) before operation and the first day (d1), the third day (d2) and the seventh day (d3) after operation, and inflammatory factor levels. RESULTS: The amount of crystal input, colloid, blood loss, fluid replacement and urine volume in the GDFT group were significantly less than those in the routine group (P < 0.05). From T1 to T4, the values of mean arterial pressure (MAP) and central venous pressure (CVP) in the GDFT group were higher than those in the routine group (p < 0.05). The total incidence of postoperative complications in the GDFT group was lower than that in the routine group (P < 0.05). Compared with those in the routine group, the postoperative anus exhaust time, the first time of starting to eat, the time of leaving bed, the duration of stay in the postanesthesia care unit and the hospital stay were significantly shorter in the GDFT group (P < 0.05). From D1 to D3, the MMSE score in the GDFT group was higher than that in the routine group, while the levels of C-reactive protein (CPR), interleukin 6 (IL-6) and procalcitonin (PCT) were lower than those in the routine group (P < 0.05). CONCLUSION: GDFT has a better effect on the rapid rehabilitation of patients undergoing laparoscopy-assisted radical gastrectomy during fast-track anesthesia, and it also has a positive effect on maintaining the stability of hemodynamics, reducing systemic inflammation and decreasing postoperative complications.

Effect of general anesthesia combined with epidural anesthesia on circulation and stress response of patients undergoing hysterectomy.

OBJECTIVE: To investigate the effect of general anesthesia combined with epidural anesthesia on circulation and stress response of patients undergoing hysterectomy. METHODS: A total of 97 patients undergoing hysterectomy in our hospital from December 2017 to December 2019 were recruited as the research participants, of whom 44 patients (general anesthesia group) received general anesthesia and 53 patients (joint group) received general anesthesia combined with epidural anesthesia during operation. The hemodynamic indexes, anesthetic effect, anesthetic recovery effect, cognitive function, and stress substance levels of the two groups were compared. RESULTS: Compared with the general anesthesia group, the SBP and HR of the patients in the joint group were more stable, and the anesthesia effect and recovery effect in the joint group were better. The MMSE score of the joint group at 6 h and 12 h after anesthesia was significantly higher than that of the general anesthesia group (P < 0.001). There was no significant difference in the levels of adrenaline and norepinephrine between the two groups before operation (P > 0.05). The levels of stress substances in the two groups increased at 30 min after operation (P < 0.001), and those in the joint group were significantly lower than those in the control group (P < 0.001). CONCLUSION: Compared with general anesthesia, general anesthesia combined with epidural anesthesia produces better anesthetic effect in hysterectomy, has less influence on patients' circulatory response and can reduce stress response.

Platelet-Rich Plasma in Female Androgenic Alopecia: A Comprehensive Systematic Review and Meta-Analysis.

Introduction: The population of young women who suffered from female pattern hair loss (FPHL) or female androgenic alopecia (AGA) is gradually increasing. Platelet-rich plasma is a novel and promising therapeutic method as a nonsurgical treatment for FPHL. Objective: To summarize different preparation methods of PRP and treatment regimes in FPHL, qualitatively evaluate the current observations, and quantitively analyze the efficacy of PRP in FPHL treatment. Methods: Six databases, MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, LILACS, and CNKI, were searched with terms "platelet-rich plasma," synonyms for AGA and FPHL. Meta-analysis was conducted with enrolled observational studies and randomized controlled trials separately. Results: We evaluated 636 studies and 12 trials from all searched databases. A total of 42 studies of 1,569 cases, including 776 female participants covering 16 randomized controlled trials and 26 observational trials, were included for qualitative synthesis study and systematic review. PRP showed positive efficacy in treating FPHL in hair density compared to the control groups with odds ratio (OR) 1.61, 95% CI 0.52-2.70, and compared to baseline with OR 1.11, 95% CI 0.86-1.37. Conclusion: PRP showed excellent efficiency as a novel therapy of FPHL through hair density evaluation. Further studies are needed to define standardized protocols, and large-scale randomized trials still need to be conducted to confirm its efficacy.

[Biodistribution of (99m)Tc-labeled anti-VEGF mAb 5-FU loaded polylactic acid nanoparticles in human gastric carcinoma xenografts].

OBJECTIVE: To prepare (99m)Tc-labeled Anti-VEGF mAb 5-FU loaded polylactic acid nanoparticles ((99m)Tc-Ab-5-FU-NPs) and investigate its biodistribution in human gastric carcinoma xenografts. METHODS: (99m)Tc-Ab-5-FU-NPs were prepared by labeling Ab-5-FU-NPs with (99m)Tc using improved Schwarz method. After isolation of (99m)Tc-Ab-5-FU-NPs using SephadexG250 column, the labeling ratio and radiochemical purity were determined using chromatography. The immunocompetence of (99m)Tc- Ab-5-FU-NPs was detected by ELISA and immunohistochemistry. (99m)Tc-Ab-5-FU-NPs were then injected via the tail vein into SCID mice bearing human gastric carcinoma, and (99m)Tc labeled mice-derived monoclonal IgG loaded polylactic acid nanoparticles were used as the control, followed by radioimmunoscintigraphic imaging at 2 and 6 h. The radioactive count and radioactive ratio of the tumor and non-tumor tissue (T/NT) in the animal models were calculated using ROI technique. After imaging at 24 h, SCID mice were sacrificed and the radioactive distribution, the %ID/g, as well as the T/NT radioactive ratio were examined, respectively. The concentrations of 5-FU in the tumor and blood were also detected using HPLC method. RESULTS: The labeling ratio of (99m)Tc-Ab-5-FU-NPs was 90%-95%. (99m)Tc-Ab-5-FU-NPs were detected in the tumor tissues by radioimmunoimaging 2 h after the injection. ID%/g in the tumor tissues at 2 and 6 h were both significantly higher than that of the control group. Both the ID%/g in tumor tissues and radioactive ratio of tumor and blood at 6 h were higher than those at 2 h, and the concentration of 5-FU in experimental group increased continuously with time and was significantly higher than that in control group. CONCLUSIONS: (99m)Tc-Ab-5-FU-NPs prepared in this study can meet the demands of radioimmunoimaging, and the anti-VEGF monoclonal antibody possesses reliable immune targeting ability. Six hours after injection, (99m)Tc-Ab-5-FU-NPs can specifically accumulate in the tumor tissues in human gastric carcinoma xenografts at high concentration.