PXDN as a pan-cancer biomarker and promotes tumor progress via immune inhibition in nasopharyngeal carcinoma.

Background: Investigating oncogenes and the mechanisms driving oncogenic processes in human tumors is imperative for the development of efficient therapies. Peroxidasin (PXDN) has been reported to play a critical role in tissue development and homeostasis. However, the role of PXDN in the occurrence and development of Nasopharyngeal Carcinoma (NPC) remains unknown. Methods: Data from multiple databases, including GEO and TCGA, were used to analyze the expression levels of PXDN. Taking nasopharyngeal carcinoma as an example, in vitro experiments were conducted to explore the biological functions of PXDN. Overexpression of stable cell lines was achieved through lentiviral infection, cell proliferation was examined using CCK8 and BrdU incorporation assays, and clone formation experiments were performed to assess cell growth. Transwell and wound healing assays were employed to evaluate cell invasion and migration abilities. Additionally, immunofluorescence staining with multiple targets was used to analyze the immune microenvironment of the tumor tissues. Co-culture experiments, followed by clone formation and CFSE incorporation assays, were conducted to observe the impact of NPC stable cell lines on T cells. Flow cytometry was performed to detect surface markers and cytokines in T cells after co-culture to assess T cell function. Results: PXDN was highly expressed in multiple tumors, and its high expression and mutation profile were correlated with poor survival. Functionally, PXDN plays a crucial role in promoting oncogenic processes by enhancing NPC cell proliferation and metastasis. Mechanistically, PXDN activates extracellular matrix (ECM) signaling pathways while simultaneously inhibiting T-cell infiltration and activation, thereby facilitating cancer progression. Conclusion: We characterized PXDN as a valuable biomarker for pan-cancer diagnosis and prognosis. We also uncovered new oncogenic roles for PXDN in promoting cancer progression and regulating T-cell immunosuppressive function in NPC.

Comparing Lenvatinib/Pembrolizumab with Atezolizumab/Bevacizumab in Unresectable Hepatocellular Carcinoma: A Real-World Experience with Propensity Score Matching Analysis.

BACKGROUND: The combination of anti-angiogenic therapy and immune checkpoint inhibitors has revolutionized the management of unresectable hepatocellular carcinoma (uHCC). While an early-phase study demonstrated promising outcomes for lenvatinib plus pembrolizumab (L+P) in treating uHCC, the LEAP-002 trial did not meet its primary endpoint. However, the comparative efficacy between L+P and atezolizumab plus bevacizumab (A+B) as first-line treatment remains a topic of uncertainty. This study aimed to assess the effectiveness and safety of L+P in contrast to A+B among patients diagnosed with uHCC. METHODS: We conducted a retrospective analysis of enrolled patients with uHCC who received L+P or A+B as initial systemic treatment at Chang Gung Memorial Hospital from June 2019 to December 2022. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by modified RECIST were compared. RESULTS: 121 patients were recruited, with 37 receiving L+P and 84 receiving A+B. Among them, 95 (78.5%) patients were BCLC stage C, and 99 (81.8%) patients had viral etiology for HCC, predominantly chronic HBV (68.6%). Both the L+P and the A+B groups demonstrated comparable OS (18.2 months versus 14.6 months, p = 0.35) and PFS (7.3 months versus 8.9 months, p = 0.75). The ORR and DCR were similar. After propensity score matching, the results remained consistent between the matched patients. Treatment-related adverse events of any grade occurred in 30 (81.1%) in the L+P group and 62 (73.8%) in the A+B group. CONCLUSIONS: Our findings suggest that L+P and A+B exhibit comparable efficacy and safety profiles in real-world settings.

Plastid LPAT1 is an integral inner envelope membrane protein with the acyltransferase domain located in the stroma.

KEY MESSAGE: The N-terminal transmembrane domain of LPAT1 crosses the inner membrane placing the N terminus in the intermembrane space and the C-terminal enzymatic domain in the stroma. Galactolipids mono- and di-galactosyl diacylglycerol are the major and vital lipids of photosynthetic membranes. They are synthesized by five enzymes hosted at different sub-chloroplast locations. However, localization and topology of the second-acting enzyme, lysophosphatidic acid acyltransferase 1 (LPAT1), which acylates the sn-2 position of glycerol-3-phosphate (G3P) to produce phosphatidic acid (PA), remain unclear. It is not known whether LPAT1 is located at the outer or the inner envelope membrane and whether its enzymatic domain faces the cytosol, the intermembrane space, or the stroma. Even the size of mature LPAT1 in chloroplasts is not known. More information is essential for understanding the pathways of metabolite flow and for future engineering endeavors to modify glycerolipid biosynthesis. We used LPAT1 preproteins translated in vitro for import assays to determine the precise size of the mature protein and found that the LPAT1 transit peptide is at least 85 residues in length, substantially longer than previously predicted. A construct comprising LPAT1 fused to the Venus fluorescent protein and driven by the LPAT1 promoter was used to complement an Arabidopsis lpat1 knockout mutant. To determine the sub-chloroplast location and topology of LPAT1, we performed protease treatment and alkaline extraction using chloroplasts containing in vitro-imported LPAT1 and chloroplasts isolated from LPAT1-Venus-complemented transgenic plants. We show that LPAT1 traverses the inner membrane via an N-terminal transmembrane domain, with its N terminus protruding into the intermembrane space and the C-terminal enzymatic domain residing in the stroma, hence displaying a different membrane topology from its bacterial homolog, PlsC.

Investigating brain-gut microbiota dynamics and inflammatory processes in an autistic-like rat model using MRI biomarkers during childhood and adolescence.

Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines-interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)-were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.

In vitro drug testing using patient-derived ovarian cancer organoids.

BACKGROUND: Ovarian cancer is the most lethal gynecological cancer. As the primary treatment, chemotherapy has a response rate of only 60-70% in advanced stages, and even lower as a second-line treatment. Despite guideline recommendations, which drugs will be most effective remains unclear. Thus, a strategy to prioritize chemotherapy options is urgently needed. Cancer organoids have recently emerged as a method for in vitro drug testing. However, limited clinical correlations have been assessed with test results from cancer organoids, particularly in gynecological cancers. We therefore aimed to generate patient-derived organoids (PDOs) of ovarian cancer, to assess their drug sensitivities and correlations with patient clinical outcomes. METHODS: PDOs were generated from fresh tumors obtained during surgical resection, which was then cultured under matrix gel and appropriate growth factors. Morphological and molecular characterization of PDOs were assessed by phase contrast microscopy and paraffin-embedded histopathology. Expressions of PAX8, TP53, WT1, CK7, and CK20 were tested by immunohistochemical staining and compared with parental tumor tissues and the human protein atlas database. PDOs were subjected to in vitro drug testing to determine drug sensitivity using Titer-Glo® 3D Cell Viability Assay. PDO viability was measured, and area under the curve calculated, to compare responses to various compounds. Correlations were calculated between selected patients' clinical outcomes and in vitro drug testing results. RESULTS: We established 31 PDOs. Among them, 28 PDOs can be expanded, including 15, 11, and 2 from ovarian, endometrial, and cervical cancers, respectively. The PDOs preserved the histopathological profiles of their originating tumors. In vitro drug testing of 10 ovarian cancer PDOs revealed individual differential responses to recommended drugs, and interpersonal heterogeneity in drug sensitivity, even with the same histology type. Among four patients who were platinum sensitive, resistant, or refractory, PDO drug responses correlated well with their clinical courses. CONCLUSION: In vitro drug testing using ovarian cancer organoids is feasible and correlates well with patient clinical responses. These results may facilitate development of precision chemotherapy and personalized screening for repurposed or new drugs.

A comparison between nail-plate constructs and the plate-on-plate technique in the treatment of proximal femoral peri-implant fracture.

STUDY DESIGN: A single-centre, retrospective cohort study. OBJECTIVES: To compare the clinical outcomes between nail-plate constructs and the plate-on-plate technique in the treatment of proximal femoral peri-implant fracture (PFPIF). METHODS: Thirty-seven patients with PFPIF treated at our hospital were included. All patients underwent at least 1-year follow-up. Imaging studies and medical records, including walking ability, complications, and functional outcomes 1 year after surgery, were thoroughly reviewed. RESULTS: Twenty patients were treated with nail-plate constructs. Seventeen patients were treated with the plate-on-plate technique. The average surgical times in the plate-on-plate technique and nail-plate construct groups were 119.4 ± 23.4 min and 246.3 ± 48.0 min, respectively. The average blood losses in the plate-on-plate technique and nail-plate construct groups were 124.7 ± 41.6 mL and 434.3 ± 170.8 mL, respectively. The plate-on-plate technique group had a significantly shorter surgical time and less blood loss than the nail-plate construct group. No statistically significant differences were found in union time, ambulation status, 36-item Short Form Health Survey score, and complication rate between the two groups. CONCLUSION: The plate-on-plate technique can be considered an alternative option to reduce operation time and blood loss in the treatment of PFPIF, especially for older patients and those who are less capable of sustaining long-term operation and anaesthetic exposure.

MicroRNA-376a-3p sensitizes CPT-11-resistant colorectal cancer by enhancing apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) through the IGF1R/PI3K/AKT pathway.

Colorectal cancer (CRC) remains the third most prevalent type of cancer worldwide contributing to an estimated 10 % of all cancer cases. CPT-11 is one of the first-line drugs for CRC treatment. Unfortunately, the development of drug resistance significantly exacerbates the adverse impact of CRC. Consequent tumor recurrences and metastasis, years after treatment are the frequently reported incidences. MicroRNAs (miRNA) are short non-coding RNA with the functionality of gene suppression. The insulin-like growth factor type 1 receptor (IGF1R) is a tyrosine kinase receptor frequently upregulated in cancers and is associated with cell survival and drug resistance. MiRNAs are frequently reported to be dysregulated in cancers including CRC. Evidence suggests that dysregulated miRNAs have direct consequences on the biological processes of their target genes. We previously demonstrated that miRNA-376a-3p is upregulated in CPT-11responsive, CRC cells upon treatment with CPT-11. We therefore aimed to investigate the involvement of miRNA-376a-3p in CPT-11 resistance and its probable association with IGF1R-mediated cancer cell survival. Our experimental approach used knockdown and overexpression experiments supplemented with western blot, RT-qPCR, flow cytometry, MTT, and migration assays to achieve our aim. Our data reveals the mechanism through which IGF1R and miRNA-376a-3p perpetrate and attenuate CPT-11 resistance respectively. MiRNA-376a-3p overexpression negatively regulated the IGF1R-induced cell survival, PI3K/AKT pathway, and reversed the epithelial-mesenchymal transition, hence sensitizing resistant cells to CPT-11. Our findings suggests that the miRNA-376a-3p/IGF1R axis holds promise as a potential target to sensitize CRC to CPT-11 in cases of drug resistance.

Innovative integration of lung ultrasound and wearable monitoring for predicting pulmonary complications in colorectal surgery: A prospective study.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common in patients who undergo colorectal surgery. Studies have focused on how to accurately diagnose and reduce the incidence of PPCs. Lung ultrasound has been proven to be useful in preoperative monitoring and postoperative care after cardiopulmonary surgery. However, lung ultrasound has not been studied in abdominal surgeries and has not been used with wearable devices to evaluate the influence of postoperative ambulation on the incidence of PPCs. AIM: To investigate the relationship between lung ultrasound scores, PPCs, and postoperative physical activity levels in patients who underwent colorectal surgery. METHODS: In this prospective observational study conducted from November 1, 2019 to August 1, 2020, patients who underwent colorectal surgery underwent daily bedside ultrasonography from the day before surgery to postoperative day (POD) 5. Lung ultrasound scores and PPCs were recorded and analyzed to investigate their relationship. Pedometer bracelets measured the daily movement distance for 5 days post-surgery, and the correlation between postoperative activity levels and lung ultrasound scores was examined. RESULTS: Thirteen cases of PPCs was observed in the cohort of 101 patients. The mean (standard deviation) peak lung ultrasound score was 5.32 (2.52). Patients with a lung ultrasound score of ≥ 6 constituted the high-risk group. High-risk lung ultrasound scores were associated with an increased incidence of PPCs after colorectal surgery (logistic regression coefficient, 1.715; odds ratio, 5.556). Postoperative movement distance was negatively associated with the lung ultrasound scores [Spearman's rank correlation coefficient (r), -0.356, P < 0.05]. CONCLUSION: Lung ultrasound effectively evaluates pulmonary condition post-colorectal surgery. Early ambulation and respiratory exercises in the initial two PODs will reduce PPCs and optimize postoperative care in patients undergoing colorectal surgery.

PRSS50-mediated inhibition of MKP3/ERK signaling is crucial for meiotic progression and sperm quality.

Serine protease 50 (PRSS50/TSP50) is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially, PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout ( Prss50 -/- ) mice ( Mus musculus), which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore, dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50 -/- mice, accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and elevated levels of MAP kinase phosphatase 3 (MKP3), a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50 -/- mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.

Endometrial cancer risk stratification using MRI radiomics: corroborating with choline metabolism.

BACKGROUND AND PURPOSE: Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism. MATERIALS AND METHODS: From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance. RESULTS: Rad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO's 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019). CONCLUSIONS: Development of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov on 2015-08-01 with Identifier NCT02528864.

Cancer-Associated-Fibroblast-Mediated Paracrine and Autocrine SDF-1/CXCR4 Signaling Promotes Stemness and Aggressiveness of Colorectal Cancers.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide, and cancer-associated fibroblasts (CAFs) play a major role in the tumor microenvironment (TME), which facilitates the progression of CRC. It is critical to understand how CAFs promote the progression of CRC for the development of novel therapeutic approaches. The purpose of this study was to understand how CAF-derived stromal-derived factor-1 (SDF-1) and its interactions with the corresponding C-X-C motif chemokine receptor 4 (CXCR4) promote CRC progression. Our study focused on their roles in promoting tumor cell migration and invasion and their effects on the characteristics of cancer stem cells (CSCs), which ultimately impact patient outcomes. Here, using in vivo approaches and clinical histological samples, we analyzed the influence of secreted SDF-1 on CRC progression, especially in terms of tumor cell behavior and stemness. We demonstrated that CAF-secreted SDF-1 significantly enhanced CRC cell migration and invasion through paracrine signaling. In addition, the overexpression of SDF-1 in CRC cell lines HT29 and HCT-116 triggered these cells to generate autocrine SDF-1 signaling, which further enhanced their CSC characteristics, including those of migration, invasion, and spheroid formation. An immunohistochemical study showed a close relationship between SDF-1 and CXCR4 expression in CRC tissue, and this significantly affected patient outcomes. The administration of AMD3100, an inhibitor of CXCR4, reversed the entire phenomenon. Our results strongly suggest that targeting this signaling axis in CRC is a feasible approach to attenuating tumor progression, and it may, therefore, serve as an alternative treatment method to improve the prognosis of patients with CRC, especially those with advanced, recurrent, or metastatic CRC following standard therapy.

Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1.

BACKGROUND: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

A randomized controlled experiment testing the use of virtual reality to trigger cigarette craving in people who smoke.

Automated delivery of therapy in virtual reality (VR) has the potential to be used for smoking cessation. Most obviously, it could be used to practise and establish alternative reactions to smoking cues. The first step in treatment development is to show that VR environments can trigger sufficient cravings in smokers. We evaluated a new VR public house outdoor scenario with 100 individuals who smoked daily. Participants were randomly assigned to the VR scenario with smoking cues or a neutral experience in VR. The VR experiences were presented in a standalone VR headset. Before and after VR, we collected self-reported craving scores for cigarettes and alcohol using the Tobacco Craving Questionnaire (TCQ) and visual analogue scales (VAS). Physiological data were also collected. Compared to the neutral condition, exposure to the smoking cues led to a large increase in craving for a cigarette (TCQ ß = 11.44, p < 0.0001, Cohen's d = 1.10) and also a moderate increase in craving for alcohol ( ß = 0.7 , p = 0.017 , d = 0.50 ) . There were no significant physiological differences between the two conditions. These results provide good evidence that VR experiences can elicit strong craving for cigarettes. The programming can be part of developing a new VR cognitive therapy to help people reduce smoking.

Insights about cervical lymph nodes: Evaluating deep learning-based reconstruction for head and neck computed tomography scan.

Purpose: This study aimed to investigate differences in cervical lymph node image quality on dual-energy computed tomography (CT) scan with datasets reconstructed using filter back projection (FBP), hybrid iterative reconstruction (IR), and deep learning-based image reconstruction (DLIR) in patients with head and neck cancer. Method: Seventy patients with head and neck cancer underwent follow-up contrast-enhanced dual-energy CT examinations. All datasets were reconstructed using FBP, hybrid IR with 30 % adaptive statistical IR (ASiR-V), and DLIR with three selectable levels (low, medium, and high) at 2.5- and 0.625-mm slice thicknesses. Herein, signal, image noise, signal-to-noise ratio, and contrast-to-noise ratio of lymph nodes and overall image quality, artifact, and noise of selected regions of interest were evaluated by two radiologists. Next, cervical lymph node sharpness was evaluated using full width at half maximum. Results: DLIR exhibited significantly reduced noise, ranging from 3.8 % to 35.9 % with improved signal-to-noise ratio (11.5-105.6 %) and contrast-to-noise ratio (10.5-107.5 %) compared with FBP and ASiR-V, for cervical lymph nodes (p < 0.001). Further, 0.625-mm-thick images reconstructed using DLIR-medium and DLIR-high had a lower noise than 2.5-mm-thick images reconstructed using FBP and ASiR-V. The lymph node margins and vessels on DLIR-medium and DLIR-high were sharper than those on FBP and ASiR-V (p < 0.05). Both readers agreed that DLIR had a better image quality than the conventional reconstruction algorithms. Conclusion: DLIR-medium and -high provided superior cervical lymph node image quality in head and neck CT. Improved image quality affords thin-slice DLIR images for dose-reduction protocols in the future.

Local vascular Klotho mediates diabetes-induced atherosclerosis via ERK1/2 and PI3-kinase-dependent signaling pathways.

BACKGROUND AND AIMS: Diabetes is one of the major causes of cardiovascular disease (CVD). As high as 29 % of patients with diabetes develop atherosclerosis. Vascular Smooth Muscle Cells (VSMCs) are a key mediator in the pathogenesis of atherosclerosis, generating pro-inflammatory and proliferative characteristics in atherosclerotic lesions. METHODS: We used human atherosclerotic samples, developed diabetes-induced atherosclerotic mice, and generated loss of function and gain of function in Klotho human aortic smooth muscle cells to investigate the function of Klotho in atherosclerosis. RESULTS: We found that Klotho expression is decreased in smooth muscle actin-positive cells in patients with diabetes and atherosclerosis. Consistent with human data, we found that Apoe knockout mice with streptozotocin-induced diabetes fed on a high-fat diet showed decreased expression of Klotho in SMCs. Additionally, these mice showed increased expression of TGF-ß, MMP9, phosphorylation of ERK and Akt. Further, we utilized primary Human Aortic Smooth Muscle Cells (HASMCs) with d-glucose under dose-response and in time-dependent conditions to study the role of Klotho in these cells. Klotho gain of function and loss of function studies showed that Klotho inversely regulated the expression of atherosclerotic markers TGF-ß, MMP2, MMP9, and Fractalkine. Further, High Glucose (HG) induced Akt, and ERK1/2 phosphorylation were enhanced or mitigated by endogenous Klotho deficiency or its overexpression respectively. PI3K/Akt and MAPK/ERK inhibition partially abolished the HG-induced upregulation of TGF-ß, MMP2, MMP9, and Fractalkine. Additionally, Klotho knockdown increased the proliferation of HASMCs and enhanced α-SMA and TGF-ß expression. CONCLUSIONS: Taken together, these results indicate that local vascular Klotho is involved in diabetes-induced atherosclerosis, which is via PI3K/Akt and ERK1/2-dependent signaling pathways.

Influence of acupuncture and moxibustion on gastrointestinal function and adverse events in gastric cancer patients after surgery and chemotherapy: a meta-analysis.

OBJECTIVE: The impact of acupuncture and moxibustion on postoperative complications and adverse events (AEs) of chemotherapy in patients with gastric cancer (GC) has been investigated. Through a meta-analysis of existing randomized controlled trials (RCTs), this study sought to strengthen the evidentiary basis to help investigators further understand the effects of moxibustion and acupuncture on postoperative complications and AEs of chemotherapy among GC patients. METHODS: Embase, Web of Science, PubMed, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP Database for Chinese Technical Periodicals were searched to collect RCTs on effects of acupuncture and moxibustion on gastrointestinal function and AEs among GC patients undergoing surgery and chemotherapy. Outcome measures included postoperative gastrointestinal recovery (bowel sound recovery time, time to first flatus/defecation/feeding), the incidence of AEs (nausea and vomiting, abdominal distension, and diarrhea), myelosuppression (white blood cells, hemoglobin, and platelet), and immune function indicators (CD3+ and CD4+). To assess quality, the Cochrane Risk of Bias Tool was utilized. Review Manager 5.4 was implemented to do the meta-analysis. RESULTS: Fifteen eligible RCTs involved 1259 patients. Meta-analysis results showed that the experimental group had a significantly shorter bowel sound recovery time (MD = - 14.57, 95% CI = [- 18.97, - 10.18], P < 0.00001), time to first flatus (MD = - 17.56, 95% CI = [- 22.23, - 12.88], P < 0.00001), time to first defecation (MD = - 17.05, 95% CI = [- 21.02, - 13.09], P < 0.00001), and time to first feeding (MD = - 23.49, 95% CI = [- 28.81, - 18.17], P < 0.00001) than the control group. There were significant decreases in the incidence of nausea and vomiting (RR = 0.46, 95% CI = [0.21, 1.02], P = 0.05) and abdominal distension (RR = 0.45, 95% CI = [0.27, 0.75], P = 0.002) observed in the experimental group in comparison with the control group. The experimental group demonstrated a significant increase in white blood cell counts in comparison with to the control group (MD = 0.89, 95% CI = [0.23, 1.55], P = 0.008). The experimental group showed significantly higher levels of CD3+ (MD = 7.30, 95% CI = [1.86, 12.74], P = 0.009) and CD4+ (MD = 2.75, 95% CI = [1.61, 3.90], P < 0.00001) than the control group. CONCLUSION: Among GC patients, acupuncture and moxibustion can aid in gastrointestinal function recovery, reduce the incidence of AEs of surgery and chemotherapy, and improve immune function.

Biomechanical evaluation of different plunger size and plunger position on removing soft contact lenses and rigid gas permeable contact lenses.

BACKGROUND: To avoid risks of mucosal infection from contact lenses removal, a contact lens plunger is often used. OBJECTIVE: Given various types of contact lens plungers available on the market, no study has yet been done on mechanical effects of the contact lens plunger on contact lens removal. Here, this study used finite element analysis to investigate the effects of plunger size and plunger position on the removal of soft and rigid gas permeable (RGP) contact lenses. METHODS: First, we established finite element analysis models for the plunger, contact lens, cornea, and aqueous humor. The plunger is made of mostly silicone rubber, and the contact lenses are mainly made of soft and hard material. The part of the plunger used for removal was located either at the central or the edged position, with pulling 1 mm distance. The main parameters observation indicators of in this study were the reaction force at the fixed end of the cornea, aqueous humor, the von Mises stress of the plunger, the contact lenses, and the cornea. RESULTS: Results of this study showed that when a plunger of a larger diameter was used, the reaction force of the plunger was also larger, especially when applied to RGP lenses, which required a slightly larger force (∼0.27 N). Also, when removing a RGP lens from the edge, there was a greater stress at the edge of the contact lens (2.5799 MPa), and this caused a higher stress on both the cornea (0.0165 MPa) and the aqueous humor (0.00114 MPa). CONCLUSIONS: When using a plunger with a larger diameter to remove a RGP lens, although a larger force required, the relatively larger contact area likely reduced the stress on the cornea and aqueous humor, thereby reducing the risk of eye injury. In addition, when removing a RGP lens, the results of this study recommended it to be removed from the plunger edge, as that facilitated the removal of contact lens.

Progesterone modulates cell growth via integrin αvß3-dependent pathway in progesterone receptor-negative MDA-MB-231 cells.

Progesterone (P4) plays a pivotal role in regulating the cancer progression of various types, including breast cancer, primarily through its interaction with the P4 receptor (PR). In PR-negative breast cancer cells, P4 appears to function in mediating cancer progression, such as cell growth. However, the mechanisms underlying the roles of P4 in PR-negative breast cancer cells remain incompletely understood. This study aimed to investigate the effects of P4 on cell proliferation, gene expression, and signal transduction in PR-negative MDA-MB-231 breast cancer cells. P4-activated genes, associated with proliferation in breast cancer cells, exhibit a stimulating effect on cell growth in PR-negative MDA-MB-231 cells, while demonstrating an inhibitory impact in PR-positive MCF-7 cells. The use of arginine-glycine-aspartate (RGD) peptide successfully blocked P4-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, aligning with computational models of P4 binding to integrin αvß3. Disrupting integrin αvß3 binding with RGD peptide or anti-integrin αvß3 antibody altered P4-induced expression of proliferative genes and modified P4-induced cell growth in breast cancer cells. In conclusion, integrin αvß3 appears to mediate P4-induced ERK1/2 signal pathway to regulate proliferation via alteration of proliferation-related gene expression in PR-negative breast cancer cells.

Investigation of Degradation and Biocompatibility of Indirect 3D-Printed Bile Duct Stents.

This study proposes a bile duct stent based on indirect 3D printing technology. Four ratio materials were synthesized from lactic acid (LA) and glycolide (GA) monomers by melt polymerization: PLA, PLGA (70:30), PLGA (50:50), and PLGA (30:70). The four kinds of material powders were preliminarily degraded, and the appearance was observed with an optical microscope (OM) and a camera. The weight and appearance of the four materials changed significantly after four weeks of degradation, which met the conditions for materials to be degraded within 4-6 weeks. Among them, PLGA (50:50) lost the most-the weight dropped to 13.4%. A stent with an outer diameter of 10 mm and an inner diameter of 8 mm was successfully manufactured by indirect 3D printing technology, demonstrating the potential of our research. Then, the degradation experiment was carried out on a cylindrical stent with a diameter of 6 mm and a height of 3 mm. The weight loss of the sample was less than that of the powder degradation, and the weight loss of PLGA (50:50) was the largest-the weight dropped to 79.6%. The nano-indenter system measured the mechanical properties of materials. Finally, human liver cancer cells Hep-3B were used to conduct in vitro cytotoxicity tests on the scaffolds to test the biocompatibility of the materials. A bile duct stent meeting commercial size requirements has been developed, instilling confidence in the potential of our research for future medical applications.