Optimization of polydimethylsiloxane (PDMS) surface chemical modification and formulation for improved T cell activation and expansion.

Adoptive T cell therapy has undergone remarkable advancements in recent decades; nevertheless, the rapid and effective ex vivo expansion of tumor-reactive T cells remains a formidable challenge, limiting their clinical application. Artificial antigen-presenting substrates represent a promising avenue for enhancing the efficiency of adoptive immunotherapy and fostering T cell expansion. These substrates offer significant potential by providing flexibility and modularity in the design of tailored stimulatory environments. Polydimethylsiloxane (PDMS) silicone elastomer stands as a widely utilized biomaterial for exploring the varying sensitivity of T cell activation to substrate properties. This paper explores the optimization of PDMS surface modification and formulation to create customized stimulatory surfaces with the goal of enhancing T cell expansion. By employing soft PDMS elastomer functionalized through silanization and activating agent, coupled with site-directed protein immobilization techniques, a novel T cell stimulatory platform is introduced, facilitating T cell activation and proliferation. Notably, our findings underscore that softer modified elastomers (Young' modulus E∼300 kPa) exhibit superior efficacy in stimulating and activating mouse CD4+ T cells compared to their stiffer counterparts (E∼3 MPa). Furthermore, softened modified PDMS substrates demonstrate enhanced capabilities in T cell expansion and Th1 differentiation, offering promising insights for the advancement of T cell-based immunotherapy.

A discrete-event simulation model for assessing operating room efficiency of thoracic, gastrointestinal, and orthopedic surgeries.

BACKGROUND: In hospital management, pinpointing steps that most enhance operating room (OR) throughput is challenging. While prior literature has utilized discrete event simulation (DES) to study specific strategies such as scheduling and resource allocation, our study examines an earlier planning phase, assessing all workflow stages to determine the most impactful steps for subsequent strategy development. METHODS: DES models real-world systems by simulating sequential events. We constructed a DES model for thoracic, gastrointestinal, and orthopedic surgeries summarized from a tertiary Chinese hospital. The model covers preoperative preparations, OR occupation, and OR preparation. Parameters were sourced from patient data and staff experience. Model outcome is OR throughput. Post-validation, scenario analyses were conducted for each department, including: (1) improving preoperative patient preparation time; (2) increasing PACU beds; (3) improving OR preparation time; (4) use of new equipment to reduce the operative time of a selected surgery type; three levels of improvement (slight, moderate, large) were investigated. RESULTS: The first three improvement scenarios resulted in a 1%-5% increase in OR throughput across the three departments. Large reductions in operative time of the selected surgery types led to approximately 12%, 33%, and 38% increases in gastrointestinal, thoracic, and orthopedic surgery throughput, respectively. Moderate reductions resulted in 6%-17% increases in throughput and slight reductions of 1%-7%. CONCLUSIONS: The model could reliably reflect OR workflows of the three departments. Among the options investigated, model simulations suggest that improving OR preparation time and operative time are the most effective.

Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway.

Premature ovarian failure (POF) caused by chemotherapy is a growing concern for female reproductive health. The use of metformin (MET), which has anti-oxidative and anti-inflammatory effects, in the treatment of POF damaged by chemotherapy drugs remains unclear. In this study, we investigated the impact of MET on POF caused by cyclophosphamide (CTX) combined with busulfan (BUS) and M1 macrophages using POF model mice and primary granule cells (GCs). Our findings demonstrate that intragastric administration of MET ameliorates ovarian damage and alleviates hormonal disruption in chemotherapy-induced POF mice. This effect is achieved through the reduction of inflammatory and oxidative stress-related harm. Additionally, MET significantly relieves abnormal inflammatory response, ROS accumulation, and senescence in primary GCs co-cultured with M1 macrophages. We also observed that this protective role of MET is closely associated with the AMPK/PPAR-γ/SIRT1 pathway in cell models. In conclusion, our results suggest that MET can protect against chemotherapy-induced ovarian injury by inducing the expression of the AMPK pathway while reducing oxidative damage and inflammation.

Inhibit ALDH3A2 reduce ovarian cancer cells survival via elevating ferroptosis sensitivity.

Ovarian cancer (OC) is a malignant gynecologic tumor with high morbidity and mortality. As a newly discovered mode of programmed cell death, ferroptosis has been involved in various pathological processes of kinds of tumors in recent years. Aldehyde dehydrogenase 3 family member A2 (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. ALDH3A2 has been shown to be associated with ferroptosis in acute myeloid leukemia (AML), but the mechanism remains unclear. In this study, we analyzed the TCGA and GTEx databases and showed that high ALDH3A2 expression predicted poor prognosis in ovarian cancer. Further studies found that knockout or overexpression of ALDH3A2 correspondingly increased or attenuated the ferroptosis sensitivity of ovarian cancer cells. And sequencing revealed that ALDH3A2 knockout led to the activation of lipid metabolic, GSH metabolic, phospholipid metabolic, and aldehyde metabolic pathways, suggesting that ALDH3A2 induced changes in the sensitivity of ovarian cancer cells to ferroptosis by affecting these metabolic processes. Our results provide a new promising therapeutic strategy for the treatment of OC.

Congenital Intestinal Malrotation in Newborns: Laparoscopic Ladd's Procedure versus Open Laparotomy.

OBJECTIVE: To assess the efficacy and safety of laparotomic or laparoscopic Ladd's procedure in newborns with congenital malrotation. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pediatric Surgery, Ganzhou Maternal and Child Health Care Hospital, Ganzhou JiangXi province, China, from January 2015 to December 2021. METHODOLOGY: The clinical data of newborns with malcorrection were retrospectively analysed. Patients were divided into laparotomy group (64 cases) and laparoscopy group (30 cases), according to the surgery they had been subjected. The patients who had the severe malformations, underwent the laparoscopic Ladd's procedure at the first 10 cases, and had found bowel necrosis during operation were excluded. The general data such as lengths of operation, intraoperative blood loss, time-to-diet, lengths of hospital stay, and postoperative complications were compared between the two groups. RESULTS: Crude comparisons showed that the laparoscopy increased the lengths of operative time (70.0 vs. 110.0 minutes, p <0.001) but decreased the postoperative complications (25.0% vs. 6.7%, p=0.035). The intraoperative blood loss, time-to-diet, and lengths of hospital stay between the two groups were not statistically significant (p=0.109, 0.065, and 0.858 respectively). The intestinal volvulus in the two groups (43.8% vs. 80.0%, p=0.001) had statistical differences. Using modified Poisson regression analysis, adjusting for confounding differences of midgut volvulus, lengths of operation time and intraoperative blood loss, and laparoscopic Ladd's showed a significant decrease in postoperative complications (RR=0.13,95%CI 0.03-0.54, p=0.005). CONCLUSION: Laparoscopic Ladd's procedure is feasible to treat neonatal malrotation and is associated with lower postoperative complications of newborns with congenital malrotation. KEY WORDS: Newborns, Congenital malrotation, Laparoscopy, Laparotomy, Complications.

Polymeric nanoparticles-Promising carriers for cancer therapy.

Polymeric nanoparticles (NPs) play an important role in controlled cancer drug delivery. Anticancer drugs can be conjugated or encapsulated by polymeric nanocarriers, which are known as polymeric nanomedicine. Polymeric nanomedicine has shown its potential in providing sustained release of drugs with reduced cytotoxicity and modified tumor retention, but until now, few delivery systems loading drugs have been able to meet clinical demands, so more efforts are needed. This research reviews the current state of the cancer drug-loading system by exhibiting a series of published articles that highlight the novelty and functions from a variety of different architectures including micelles, liposomes, dendrimers, polymersomes, hydrogels, and metal-organic frameworks. These may contribute to the development of useful polymeric NPs to achieve different therapeutic purposes.

Effect of Propofol Intravenous Anesthesia Combined with Press-Needle Therapy on Analgesic Effect during Painless Abortion.

Objective: To discover the effect of propofol intravenous anesthesia along with press-needle therapy on analgesic effect during painless abortion. Methods: A total of 128 cases who experienced painless abortion in our hospital from January 2019 to August 2021 were recruited as the research subjects. They were categorized into control and observation groups through the haphazard number table approach, with 64 patients in each group. Propofol intravenous anesthesia was given to the control group, and the observation group was given combined anesthesia with press-needle on this basis. Ramsay score, hemodynamic indexes, operation-related indexes, and postoperative recovery were studied between the two groups before anesthesia (T0), at the time of uterine aspiration (T1), promptly following the operation (T2), and at the recovery time of directional force (T3). The stress state and the level of pain mediators in the two groups of sufferers were observed at each time period, and the visual analogue scale (VAS) was employed to assess the degree of postoperative uterine contraction pain. Results: Ramsay score at T1 and T2 time points in observation group was lesser than that in control group (P < 0.05). There existed no meaningful discrepancies in operation time and recovery time between both groups (P > 0.05). The total dosage of propofol in the observation group was lesser compared to that in the control group, and the recovery time of directional force was much shorter compared to that in the control group (P < 0.05). There existed no meaningful discrepancies in perioperative diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) between both groups (P > 0.05). The levels of norepinephrine (NE), cortisol (Cor), glucose (GLU) and substance P (SP), prostaglandin E2 (PGE2), and 5-hydroxytryptophan (5-HT) in the observation group were lesser than those in the control group immediately after surgery and 24 hours following the operation (P < 0.05). There existed no meaningful discrepancies in vaginal bleeding time, endometrial thickness 3 weeks after operation, and time to start menstruating between both groups (P > 0.05). The score of VAS for the observation group was lesser than that of the control group at 10 min and 30 min after operation (P < 0.05). There existed no substantial discrepancy in the incidence of negative reactions between both groups (P > 0.05). Conclusion: Propofol intravenous anesthesia combined with press-needle therapy can ameliorate the analgesic impacts during painless abortion, reduce postoperative uterine contraction pain, inhibit the release of postoperative pain mediators, and improve the stress state of the body.

Cost-Effectiveness Analysis of the Application of a Porcine-Derived Fibrin Sealant for the Treatment of Cerebrospinal Fluid Leak in China.

PURPOSE: This study aimed to evaluate the cost-effectiveness of a porcine-derived fibrin sealant (PFS) for treating cerebrospinal fluid (CSF) leaks in cranial surgery compared with sutures alone from the perspective of public hospital management in China. METHODS: A decision tree model of cranial surgery patients with intraoperative CSF leak was constructed in R 3.6.3. The cost-effectiveness of using PFS with dural sutures was compared versus using sutures alone. Efficacy and safety data were obtained from a randomized controlled, single-blinded clinical trial that enrolled 200 patients (NCT03110783). Effectiveness was measured as the success rate of CSF leak treatment and the rate of postoperative complication. Hospital procurement costs were used to provide cost measurements from the hospital administrator's perspective. FINDINGS: The PFS strategy had a higher success rate of CSF leak treatment (97.81% vs 49.21%) and a lower complication rate (9.49% vs 14.29%), based on results from the clinical trial. Using PFS also resulted in cost savings amounting to $374.97 in additional intraoperative CSF leak repairs ($18.07 vs $393.04) and $66.68 in postoperative complication treatment ($131.90 vs $198.58). Both one-way sensitivity analysis and probabilistic sensitivity analysis confirmed that the model results were stable against input variations. IMPLICATIONS: The decision tree analysis revealed that using PFS in conjunction with sutures was associated with improved clinical performance and lower overall costs. PFS in combination with sutures is the dominant strategy for treating CSF leak from the perspective of hospital decision-makers.

A real world cost-minimization analysis comparing the use of different endoscopic staplers in video-assisted thoracic surgery lobectomy procedures.

Aim: China's cost-containment measures increasingly focus solely on the prices of consumable medical supplies without taking a broader perspective on differences in features and overall costs. This study compared two types of endoscopic staplers in video-assisted thoracoscopic surgery (VATS) lobectomy. Materials & methods: Electronic medical records for video-assisted thoracoscopic surgery from 2016 to 2017 were collected from a hospital in Anhui province. Two cohorts were retroactively defined based on stapler type. Total costs were compared using a cost-minimization analysis model. Probabilistic sensitivity analysis was performed. Results: In the base case, the group using more expensive staplers achieved overall cost savings of about $300 per procedure. Sensitivity analysis confirmed this result in 86.5% of cases. Conclusion: A price-only supply selection strategy may have unintended cost consequences.

Economic burden of readmission due to postoperative cerebrospinal fluid leak in Chinese patients.

Aim: This real-world data study investigated the economic burden and associated factors of readmissions for cerebrospinal fluid leakage (CSFL) post-cranial, transsphenoidal, or spinal index surgeries. Methods: Costs of CSFL readmissions and index hospitalizations during 2014-2018 were collected. Readmission cost was measured as absolute cost and as percentage of index hospitalization cost. Factors associated with readmission cost were explored using generalized linear models. Results: Readmission cost averaged US$2407-6106, 35-94% of index hospitalization cost. Pharmacy costs were the leading contributor. Generalized linear models showed transsphenoidal index surgery and surgical treatment for CSFL were associated with higher readmission costs. Conclusion: CSFL readmissions are a significant economic burden in China. Factors associated with higher readmission cost should be monitored.

Classifying 2-year recurrence in patients with dlbcl using clinical variables with imbalanced data and machine learning methods.

BACKGROUND: Treatments are limited for patients with relapsed/refractory Diffuse large B-cell lymphoma (DLBCL), and their survival rate is low. Prediction of the recurrence hazard for each patient could provide a reference regarding chemotherapy regimens for clinicians to extend patients' period of long-term remission. As current strategies cannot satisfy such need, we have established predictive models to classify patients with DLBCL with complete remission who had recurrences in 2 years from ones who did not. METHODS: We assessed 518 patients with DLBCL and measured 52 variables of each patient. They were treated between January 2011 and July 2016. 17 variables were first selected by variable selection methods (including Lasso, Adaptive Lasso, and Elastic net). Then, we set classifiers and probability models for imbalanced data by combining the SMOTE sampling, cost-sensitive, and ensemble learning (consisting of AdaBoost, voting strategy, and Stacking) methods with the machine learning methods (Support Vector Machine, BackPropagation Artificial Neural Network, Random Forest), respectively. Last, assessed their performance. RESULTS: The disease stage and other 5 variables are significant indicators for recurrence. The SVM with AdaBoost ensemble learning method modeling by SMOTE data performs the best (Sensitivity=97.3%, AUC=96%, RMSE=19.6%, G-mean=96%) in all classifiers. The SVM with AdaBoost method(AUC=98.7%, RMSE=17.7%, MXE=12.7%, Cal mean=3.2%, BS0=2.5%, BS1=4%, BSALL=3.1%) and random forest (AUC=99.5%, RMSE=19.8%, MXE=16.2%, Cal mean=9.1%, BS0=4.8%, BS1=2.9%, BSALL=3.9%) both modeling by SMOTE sampling data perform well in probability models. CONCLUSIONS: This predictive model has high accuracy for almost all DLBCL patients and the six indicators can be recurrence signals.

Preparation and characterization of protein-resistant hydrogels for soft contact lens applications via radical copolymerization involving a zwitterionic sulfobetaine comonomer.

We aimed to introduce hydrophilic sulfobetaine-type zwitterionic groups to macromolecular chains of copolymers to construct novel copolymer hydrogels with anti-protein-fouling performance that could be used as soft contact lens (SCL) materials. Using hydroxyethyl methacrylate (HEMA), N-vinyl pyrrolidinone (NVP) and sulfobetaine methacrylate (SBMA) as comonomers, several copolymer hydrogels with different SBMA contents, poly(HEMA-NVP-SBMA), are synthesized via radical copolymerization in an aqueous phase. Surface chemistry, structural morphologies, water contact angle (WCA), equilibrium water content (EWC), visible light transmittance and tensile mechanical properties are investigated. The prepared hydrogels exhibit a closed-type porous structure. With increasing SBMA content in the comonomer mixture, the prepared copolymer hydrogel pore size gradually increases up to the micron level, WCA tends to decrease, EWC tends to increase, and visible light transmittance slightly increases, but their tensile mechanical properties decline. The amounts of protein Lyz and BSA adsorbed on the copolymer hydrogels and on commercially available EASY DAY® SCLs as a control are also determined by protein adsorption tests. The amount of protein adsorbed on the copolymer hydrogel decreases with increasing SBMA content. For the hydrogel prepared using the comonomer mixture with 5.0 wt % SBMA, the amount of adsorbed Lyz is 0.91 µg/cm2, which corresponds to only 56.8% of the amount adsorbed on EASY DAY® SCLs. Thus, novel SCL materials with high water content and excellent anti-protein-fouling performance were efficiently constructed by introducing sulfobetaine-type zwitterionic groups into a traditional polymer hydrogel system.

A meta-analysis of randomized controlled trials comparing the efficacy and safety of anastrozole versus tamoxifen for breast cancer.

Whether anastrozole has superior effects to tamoxifen for breast cancer remains controversial. Therefore, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of anastrozole versus tamoxifen as adjuvant therapy in breast cancer. A systematic literature search of PubMed, Web of Science, Embase, and Cochrane library were performed to evaluate the survival benefits and toxicity profiles of patients with breast cancer who were treated with anastrozole or tamoxifen. The main outcome measures included disease-free survival (DFS), recurrence-free survival (RFS), overall survival (OS), overall response rate (ORR), and adverse events. Hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a fixed-effects model or random-effects model. Nine RCTs with a total of 15,300 patients met the inclusion criteria and were included in this meta-analysis. Pooled estimates suggested that, anastrozole was associated with a significantly improvement in DFS (HR=0.72, 95%CI: 0.55-0.94; P=0.016), and ORR (RR=1.21, 95% CI: 1.05-1.39; P=0.009) than tamoxifen. But it did not prolong OS (HR=0.96, 95%CI: 0.77-1.21; P=0.751). Compared with tamoxifen, anastrozole induced a higher incidence of arthralgia (RR=1.55, 95%CI: 1.20-1.99; P=0.001) and bone pain (RR=1.31, 95%CI: 1.05-1.62; P=0.015), as well as a lower incidence of vaginal bleeding (RR=0.51, 95%CI: 0.28-0.93; P=0.029), vaginal discharge (RR=0.31, 95%CI: 0.12-0.82; P=0.017), and thromboembolic events (RR=0.39, 95%CI: 0.28-0.55; P<0.001). Based on the current evidence, patients with breast cancer would benefit from the anastrozole treatment.

Development of Patient-specific AAV Vectors After Neutralizing Antibody Selection for Enhanced Muscle Gene Transfer.

A major hindrance in gene therapy trials with adeno-associated virus (AAV) vectors is the presence of neutralizing antibodies (NAbs) that inhibit AAV transduction. In this study, we used directed evolution techniques in vitro and in mouse muscle to select novel NAb escape AAV chimeric capsid mutants in the presence of individual patient serum. AAV mutants isolated in vitro escaped broad patient-specific NAb activity but had poor transduction ability in vivo. AAV mutants isolated in vivo had enhanced NAb evasion from cognate serum and had high muscle transduction ability. More importantly, structural modeling identified a 100 amino acid motif from AAV6 in variable region (VR) III that confers this enhanced muscle tropism. In addition, a predominantly AAV8 capsid beta barrel template with a specific preference for AAV1/AAV9 in VR VII located at threefold symmetry axis facilitates NAb escape. Our data strongly support that chimeric AAV capsids composed of modular and nonoverlapping domains from various serotypes are capable of evading patient-specific NAbs and have enhanced muscle transduction.

Inhibition of cystathionine ß-synthase is associated with glucocorticoids over-secretion in psychological stress-induced hyperhomocystinemia rat liver.

Hyperhomocysteinemia (HHcy), a pathological condition characterized by an increase in plasma concentration of total homocysteine (Hcy), is recognized as a risk factor for several diseases. The transsulfuration pathway is the main metabolic fate of Hcy utilization, which requires the activity of cystathionine ß-synthase (CBS). Our results showed the development of HHcy induced by psychological stress was mainly derived from a reduction of CBS activity in the liver, which was accompanied by a significant decrease in its mRNA level. It suggested that the hepatic CBS enzyme regulated by stress at the level of transcription would have a profound effect on circulating Hcy levels. The expression of Sp3, a negative factor for cbs transcription, obviously increased in hepatocytes nuclei of stressed rats, but Sp1 was not altered. It indicated that Sp3 was the key point of variations in cbs transcription caused by stress. Meanwhile, we detected that augmented plasma Hcy concentrations correlated with glucocordicoids (GCs) over-secretion in response to stress, and CBS mRNA levels were markedly lowered in GCs-treated rat hepatocytes. Further results found that glucocorticoids receptor (GR) expression in hepatocyte nuclei of stress rats and GR nuclear translocation ratio was increased, and the same results were proved by experiments in vitro, i.e., GR nuclear translocation and Sp3 expression was remarkably increased in GCs-treated hepatocytes. Moreover, results from ChIP suggested GCs enhanced the binding of GR to the regulatory region of the Sp3 promoter. These results indicated that GCs inhibit CBS transcription by up-regulating Sp3 in psychological stress-induced HHcy.

[Negative regulation of homocysteine metabolism by stress in rats].

To investigate the effect of stress on homocysteine metabolism in the rat and explore the mechanism as well as the key regulatory link of stress-induced hyperhomocysteinemia, male Wistar rats were treated with restraint stress while control rats received routine treatment. By HPLC-fluorometry, the homocysteine level in rat plasma was determined. Cystathionine beta-synthase (CBS) activity in blood, heart, liver and kidney was measured by radioisotope assay using [(14)C]-serine as the labeled substrate. Total RNA was isolated from rat liver after restraint stress. RT-PCR and Northern blot were used to estimate the level of CBS mRNA. The results showed that hyperhomocysteinemia was induced by restraint stress. The highest CBS enzyme activity was seen in rat livers. A decrease in hepatic activities of CBS was found in restraint stress rats. The 29.4% +/-2.5% reduction in the activity of CBS was accompanied by a 44.1% +/-3.4% decrease in its mRNA level. CBS enzyme activity was slightly elevated in the kidney of stressed rats while it was almost undeterminable in the cardiovascular system. The study suggests that stress leads to an inhibition of the transsulfuration pathway in homocysteine metabolism. The hepatic CBS influenced by stress at the level of transcription exerts a profound effect on the circulating levels of homocysteine. The liver is the key organ where stress affects homocysteine metabolism.