Changes in the serum metabolomics of polycystic ovary syndrome before and after compound oral contraceptive treatment.

Background: Polycystic ovary syndrome (PCOS) is both a common endocrine syndrome and a metabolic disorder that results in harm to the reproductive system and whole-body metabolism. This study aimed to investigate differences in the serum metabolic profiles of patients with PCOS compared with healthy controls, in addition to investigating the effects of compound oral contraceptive (COC) treatment in patients with PCOS. Materials and methods: 50 patients with PCOS and 50 sex-matched healthy controls were recruited. Patients with PCOS received three cycles of self-administered COC treatment. Clinical characteristics were recorded, and the laboratory biochemical data were detected. We utilized ultra-performance liquid chromatography-high-resolution mass spectrometry to study the serum metabolic changes between patients with PCOS, patients with PCOS following COC treatment, and healthy controls. Result: Patients with PCOS who received COC treatment showed significant improvements in serum sex hormone levels, a reduction in luteinising hormone levels, and a significant reduction in the levels of biologically active free testosterone in the blood. Differential metabolite correlation analysis revealed differences between PCOS and healthy control groups in N-tetradecanamide, hexadecanamide, 10E,12Z-octadecadienoic acid, and 13-HOTrE(r); after 3 months of COC treatment, there were significant differences in benzoic acid, organic acid, and phenolamides. Using gas chromatography-mass spectrometry to analyse blood serum in each group, the characteristic changes in PCOS were metabolic disorders of amino acids, carbohydrates, and purines, with significant changes in the levels of total cholesterol, uric acid, phenylalanine, aspartic acid, and glutamate. Conclusion: Following COC treatment, improvements in sex hormone levels, endocrine factor levels, and metabolic levels were better than in the group of PCOS patients receiving no COC treatment, indicating that COC treatment for PCOS could effectively regulate the levels of sex hormones, endocrine factors, and serum metabolic profiles.

A Diketopyrrolopyrrole-Based All-in-One Nanoplatform for Self-Reinforcing Mild Photothermal Therapy Cascade Immunotherapy for Tumors.

Mild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high-temperature tumor ablation. However, its progress is hindered by the limited availability of high-performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high-performance organic small-molecule PTAs and utilize it to construct a multifunctional nano-theranostic platform. By incorporating additional acceptors and appropriate π-bridges, a diketopyrrolopyrrole-based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near-infrared (NIR) region. Subsequently, BDB is co-coated with the heat shock protein (HSP) inhibitor tanespimycin (17-AAG) using the functional amphiphilic polymers DSPE-Hyd-PEG2000-cRGD to form an all-in-one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real-time through NIR-II fluorescence/photoacoustic/photothermal imaging, and release 17-AAG on demand to enhance mild PTT. Additionally, the mild PTT has been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti-tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

Nivalones CF, four new meroterpenoids from Rhododendron nivale.

Four new meroterpenoids, namely nivalones CF (1-4), along with a known meroterpenoid, cannabiorcicyclolic acid (5), were isolated from the branches and leaves of Rhododendron nivale. The chemical structures of compounds 1-4 were elucidated through comprehensive spectroscopic analyses, including NMR, UV-Vis, IR, ECD spectroscopy, as well as HR-ESI-MS. The isolated compounds were evaluated for their anti-inflammatory and neuroprotective properties. The inhibitory activity of compound 5 against lipopolysaccharide (LPS)-induced nitric oxide (NO) production was initially demonstrated, showcasing an IC50 value of 21.1 µM. Additionally, both compounds 2 and 5 displayed a notable effect on the viability of H2O2-damaged SH-SY5Y cells, indicating their significant neuroprotection effects.

Sevoflurane blocks KLF5-mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury.

BACKGROUND: Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved. METHODS: The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen-glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection. RESULTS: Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells. CONCLUSIONS: Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.

Clinical and Imaging Characteristics of Contrast-enhanced Mammography and MRI to Distinguish Microinvasive Carcinoma from Ductal Carcinoma In situ.

RATIONALE AND OBJECTIVES: The prognosis of ductal carcinoma in situ with microinvasion (DCISM) is more similar to that of small invasive ductal carcinoma (IDC) than to pure ductal carcinoma in situ (DCIS). It is particularly important to accurately distinguish between DCISM and DCIS. The present study aims to compare the clinical and imaging characteristics of contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) between DCISM and pure DCIS, and to identify predictive factors of microinvasive carcinoma, which may contribute to a comprehensive understanding of DCISM in clinical diagnosis and support surveillance strategies, such as surgery, radiation, and other treatment decisions. MATERIALS AND METHODS: Forty-seven female patients diagnosed with DCIS were included in the study from May 2019 to August 2023. Patients were further divided into two groups based on pathological diagnosis: DCIS and DCISM. Clinical and imaging characteristics of these two groups were analyzed statistically. The independent clinical risk factors were selected using multivariate logistic regression and used to establish the logistic model [Logit(P)]. The diagnostic performance of independent predictors was assessed and compared using receiver operating characteristic (ROC) analysis and DeLong's test. RESULTS: In CEM, the maximum cross-sectional area (CSAmax), the percentage signal difference between the enhancing lesion and background in the craniocaudal and mediolateral oblique projection (%RSCC, and %RSMLO) were found to be significantly higher for DCISM compared to DCIS (p = 0.001; p < 0.001; p = 0.008). Additionally, there were noticeable statistical differences in the patterns of enhancement morphological distribution (EMD) and internal enhancement pattern (IEP) between DCIS and DCISM (p = 0.047; p = 0.008). In MRI, only CSAmax (p = 0.012) and IEP (p = 0.020) showed significant statistical differences. The multivariate regression analysis suggested that CSAmax (in CEM or MR) and %RSCC were independent predictors of DCISM (all p < 0.05). The area under the curve (AUC) of CSAmax (CEM), %RSCC (CEM), Logit(P) (CEM), and CSAmax (MR) were 0.764, 0.795, 0.842, and 0.739, respectively. There were no significant differences in DeLong's test for these values (all p > 0.10). DCISM was significantly associated with high nuclear grade, comedo type, high axillary lymph node (ALN) metastasis, and high Ki-67 positivity compared to DCIS (all p < 0.05). CONCLUSION: The tumor size (CSAmax), enhancement index (%RS), and internal enhancement pattern (IEP) were highly indicative of DCISM. DCISM tends to express more aggressive pathological features, such as high nuclear grade, comedo-type necrosis, ALN metastasis, and Ki-67 overexpression. As with MRI, CEM has the capability to help predict when DCISM is accompanying DCIS.

The causal relationship between atopic dermatitis and brain cancer: A bidirectional Mendelian randomization study.

BACKGROUND: Atopic dermatitis ranks among the prevalent skin disorders. Research has indicated a potential association with brain cancer. Yet, establishing a direct causal relationship between atopic dermatitis and brain cancer continues to be challenging. MATERIALS AND METHODS: We extracted single nucleotide polymorphisms (SNPs) significantly associated with atopic dermatitis (sample size = 382 254) at a genome-wide level from a large Finnish Genome-Wide Association Study (GWAS) dataset (n cases = 15 208, n controls = 367 046). Summary data for 372 622 cases of brain cancer (n cases = 606, n controls = 372 016) were obtained via the IEU Open GWAS database. We employed the Inverse Variance Weighted (IVW) method as our primary analytical approach for Mendelian Randomization (MR) analysis. Additionally, heterogeneity was measured using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger 、Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses. RESULTS: The risk of brain cancer increases with the presence of atopic dermatitis, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs),(OR = 1.0005; 95% CI = 1.0001, 1.0009; p = 0.0096). However, when conducting the analysis in reverse, no significant link was observed. CONCLUSION: The findings from our study indicate a causative link between atopic dermatitis and brain cancer, highlighting the importance of conducting broader clinical investigations into their potential association going forward.

Utility of somatosensory- and motor-evoked potential change thresholds in surgical treatment for thoracic spinal stenosis based on different pathologies.

BACKGROUND CONTEXT: Thoracic spinal stenosis (TSS) is secondary to different pathologies that differ in clinical characteristics and surgical outcomes. PURPOSE: This study aimed to determine the optimal warning thresholds for combined somatosensory-evoked potentials (SSEP) and motor-evoked potentials (MEP) for predicting postoperative neurological deterioration in surgical treatment for TSS based on different pathologies. Additionally, we explored the correlation between SSEP/MEP monitoring and postoperative spinal neurological function. STUDY SETTING: Retrospective study. PATIENT SAMPLE: Two hundred and five patients. OUTCOME MEASURES: We obtained perioperative modified Japanese Orthopedic Association (mJOA) scores to assess spinal neurological function. METHODS: The data collected in this study included demographic data, intraoperative neurophysiological monitoring (IONM) signals, and perioperative neurological function assessments. To determine the optimal IONM warning threshold, a receiver operating characteristic (ROC) curve was used. Additionally, Pearson correlation analysis was conducted to determine the correlation between IONM signals and clinical neurological conditions. RESULTS: A total of 205 consecutive patients were eligible. Forty-one patients had thoracic disc herniation (TDH), 14 had ossification of the posterior longitudinal ligament (OPLL), 124 had ossification of the ligamentum flavum (OLF), and 26 had OPLL+OLF. The mean mJOA scores before surgery and 3 months after surgery were 7.0 and 7.9, respectively, resulting in a mean mJOA recovery rate (RR) of 23.1%. The average postoperative mJOA RRs for patients with TDH, OPLL, OLF, and OPLL+OLF were 24.8%, 10.4%, 26.8%, and 11.2%, respectively. Patients with OPLL+OLF exhibited a more stringent threshold for IONM changes. This included a lower amplitude cutoff value (a decrease of 49.0% in the SSEP amplitude and 57.5% in the MEP amplitude for short-term prediction) and a shorter duration of waveform change (19.5 minutes for SSEP and 22.5 minutes for MEP for short-term prediction). On the other hand, patients with TDH had more lenient IONM warning criteria (a decrease of 49.0% in SSEP amplitude and 77.5% in MEP amplitude for short-term prediction; durations of change of 25.5 minutes for SSEP and 32.5 minutes for MEP). However, OPLL patients or OLF patients had moderate and similar IONM warning thresholds. Additionally, there was a stronger correlation between the SSEP amplitude variability ratio and the JOA RR in OPLL+OLF patients, while the correlation was stronger between the MEP amplitude variability ratio and the JOA RR for the other three TSS pathologies. CONCLUSIONS: Optimal IONM change criteria for prediction vary depending on different TSS pathologies. The optimal monitoring strategy for prediction varies depending on TSS pathologies.

Modified technique of Hepatojejunostomy for biliary tract reconstruction after resection of tumors affecting the perihilar region: a case series.

BACKGROUNDS: Radical resection is the most effective treatment for perihilar tumors. Biliary tract reconstruction after resection is one of the key steps in this surgery. Mucosa-to-mucosa cholangiojejunostomy is traditionally performed, in which the bile ducts at the resection margin are separately anastomosed to the jejunum. However, this approach is associated with long operative time and high risk of postoperative complications. The present study presents a modified technique of hepatojejunostomy and its outcomes. METHODS: The data of patients who underwent hepatojejunostomy using the modified technique at the Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China, from January 2016 to December 2021, were retrospectively analyzed. RESULTS: A total of 13 patients with perihilar tumors underwent R0 resection and bilioenteric reconstruction using the modified hepatojejunostomy technique during the study period. During the operation, the alignment of the bile duct stumps was improved, the posterior wall of the anastomosis was reinforced, internal stents were placed in the smaller bile ducts, external stents were placed in the larger bile ducts, and hepatojejunostomy was performed using 4 - 0 prolene. No serious postoperative complications, such as death or bile leakage, occurred during the hospitalization. Furthermore, there were no cases of biliary stricture or cholangitis after the six-month follow-up period. CONCLUSION: The modified hepatojejunostomy technique is a safe and effective technique of biliary reconstruction after the resection of perihilar tumors. This can be easily performed for difficult cases with multiple bile ducts that require reconstruction after resection.

Compression Therapy after Thermal Ablation of Varicose Veins: A Meta-Analysis.

OBJECTIVE: To investigate whether compression therapy after thermal ablation of varicose veins can improve the prognosis of patients. METHODS: Systematic research were applied for Chinese and English electronic databases(PubMed, Web of Science, Cochrane Library, CNKI, Wanfang, VIP Databases). Eligible prospective studies that comparing the efficacy of compression therapy and non-compression therapy on patients after thermal ablation of varicose veins were included. The interest outcome such as pain, quality of life (QOL), venous clinical severity score (VCSS), time to return to work and complications were analyzed. RESULTS: 10 studies were of high quality, and randomized controlled trials involving 1,545 patients met the inclusion criteria for this study. At the same time, the meta-analysis showed that the application of compression therapy improved pain (SMD: -0.51, 95% CI: -0.95, -0.07) but exhibited no statistically significant effect on QOL (SMD: 0.04, 95% CI: -0.08, 0.16), VCSS (MD: -0.05, 95% CI: -1.19, 1.09), time to return to work (MD: -0.43, 95% CI: -0.90, 0.03), total complications (RR: 0.54, 95% CI: 0.27, 1.09), and thrombosis (RR: 0.71, 95% CI: 0.31, 1.62). CONCLUSION: Compression therapy after thermal ablation of varicose veins can slightly relieve pain, but it has not been found to be associated with improvement in other outcomes.

Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer.

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC. SIGNIFICANCE: ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.

Transplantation of Cold-Stimulated Subcutaneous Adipose Tissue Improves Fat Retention and Recipient Metabolism.

BACKGROUND: Induction of beige fat for grafting is an emerging transplantation strategy. However, safety concerns associated with pharmaceutical interventions limit its wider application. Moreover, because beige fat is a special type of fat with strong metabolic functions, its effect on the metabolism of recipients after grafting has not been explored in the plastic surgery domain. OBJECTIVES: The aim of this study was to explore whether cold-induced inguinal white adipose tissue (iWAT) transplantation has a higher retention rate and beneficial effects on recipient metabolism. METHODS: C57/BL6 mice were subjected to cold stimulation for 48 hours to induce the browning of iWAT and harvested immediately. Subsequently, each mouse received a transplant of 0.2 mL cold-induced iWAT or normal iWAT. Fat grafts and recipients' iWAT, epididymal adipose tissue, and brown adipose tissue were harvested at 8 weeks after operation. Immunofluorescence staining, real-time polymerase chain reaction, and western blot were used for histological and molecular analysis. RESULTS: Cold-induced iWAT grafting had a higher mean [standard error of the mean] retention rate (67.33% [1.74%] vs 55.83% [2.94%], P < .01) and more satisfactory structural integrity than normal iWAT. Histological changes identified improved adipose tissue homeostasis after cold challenge, including abundant smaller adipocytes, higher levels of adipogenesis, angiogenesis, and proliferation, but lower levels of fibrosis. More importantly, cold-induced iWAT grafting suppressed the inflammation of epididymal adipose tissue caused by conventional fat grafting, and activated the glucose metabolism and thermogenic activity of recipients' adipose tissues. CONCLUSIONS: Cold-induced iWAT grafting is an effective nonpharmacological intervention strategy to improve the retention rate and homeostasis of grafts. Furthermore, it improves the adverse effects caused by traditional fat grafting, while also conferring metabolic benefits.

The rat as a novel model for chronic rotator cuff injuries.

Chronic rotator cuff injuries (CRCIs) still present a great challenge for orthopaedics surgeons. Many new therapeutic strategies are developed to facilitate repair and improve the healing process. However, there is no reliable animal model for chronic rotator cuff injury research. To present a new valuable rat model for future chronic rotator cuff injuries (CRCIs) repair studies, and describe the changes of CRCIs on the perspectives of histology, behavior and MRI. Sixty male Wistar rats were enrolled and underwent surgery of the left shoulder joint for persistent subacromial impingement. They were randomly divided into experimental group (n = 30, a 3D printed PEEK implant shuttled into the lower surface of the acromion) and sham operation group (n = 30, insert the same implant, but remove it immediately). Analyses of histology, behavior, MRI and inflammatory pain-related genes expression profiles were performed to evaluate the changes of CRCIs. After 2-weeks running, the rats in the experimental group exhibited compensatory gait patterns to protect the injured forelimb from loading after 2-weeks running. After 8-weeks running, the rats in the experimental group showed obvious CRCIs pathological changes: (1) acromion bone hyperplasia and thickening of the cortical bone; (2) supraspinatus muscle tendon of the humeral head: the bursal-side tendon was torn and layered with disordered structure, forming obvious gaps; the humeral-side tendon is partially broken, and has a neatly arranged collagen. Partial fat infiltration is found. The coronal T2-weighted images showed that abnormal tendon-to-bone junctions of the supraspinatus tendon. The signal intensity and continuity were destroyed with contracted tendon. At the nighttime, compared with the sham operation group, the expression level of IL-1ß and COX-2 increased significantly (P = 0063, 0.0005) in the experimental group. The expression of COX-2 in experimental group is up-regulated about 1.5 times than that of daytime (P = 0.0011), but the expression of IL-1ß, TNF-a, and NGF are all down-regulated (P = 0.0146, 0.0232, 0.0161). This novel rat model of chronic rotator cuff injuries has the similar characteristics with that of human shoulders. And it supplies a cost-effective, reliable animal model for advanced tissue engineered strategies and future therapeutic strategies.

Osthole Activates the Cholinergic Anti-Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses.

Osthole (also known as Osthol) is the main anti-inflammatory coumarin found in Cnidium monnieri and severs as the exclusive quality-controlled component according the Chinese Pharmacopoeia. However, its underlying anti-inflammatory mechanism remains unknown. In this study, we demonstrated that Osthole treatment significantly inhibited the generation of TNF-α, but not IL-6 in the classical LPS-stimulated RAW264.7 macrophage model. In addition, LPS induced the activation of both MAPK and NF-κB signalling pathways, of which the former was dose-dependently restrained by Osthole via suppressing the phosphorylation of JNK and P38 proteins, while the phosphorylation of IκB and P65 proteins remained unaffected. Interestingly, Osthole dose-dependently up-regulated the expression of the key cholinergic anti-inflammatory pathway regulator α7nAChR, and the TNF-α inhibition effect of Osthole was also significantly alleviated by the treatment of α7nAChR antagonist methylbetaine. These results demonstrate that Osthole may regulate TNF-α by promoting the expression of α7nAChR, thereby activate the vagus nerve-dependent cholinergic anti-inflammatory pathway.

The effect of bta-miR-1296 on the proliferation and extracellular matrix synthesis of bovine mammary fibroblasts.

Mammary fibrosis in dairy cows is a chronic condition caused by mastitis, and can lead to serious culling of dairy cows resulting in huge economic losses in the dairy industry. MicroRNAs (miRNAs) exert an important role in regulating mammary gland health in dairy cows. This study investigated whether exosomal miRNAs in mammary epithelial cells can regulate the proliferation of bovine mammary fibroblasts (BMFBs) in mastitis. Liposome transfection technology was used to construct a cellular model of the overexpression and inhibition of miRNAs. The STarMir software, dual luciferase reporter gene test, real-time quantitative PCR (qRT-PCR), a Cell Counting Kit-8 (CCK-8), and a Western Blot and plate clone formation test were used to investigate the mechanism by which bta-miR-1296 regulates the proliferation of BMFBs. Target gene prediction results revealed that glutamate-ammonia ligase was a direct target gene by which bta-miR-1296 regulates cell proliferation. It was found that bta-miR-1296 significantly inhibited the proliferation of BMFBs. After BMFBs were transfected with a bta-miR-1296 mimic, mRNA expression in the extracellular matrix (ECM), α-smooth muscle actin (α-SMA), collagen type I alpha 1 chain (COL1α1) and collagen type III alpha 1 chain (COL3α1), and various cell growth factors (basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-ß1 (TGF-ß1)) were down-regulated, and the expressions of α-SMA, COL1α1, COL3α1, phospho-extracellular regulated protein kinases, phospho-protein kinase B, TGF-ß1, and phospho-Smad family member3 proteins were inhibited. In conclusion, bta-miR-1296 can inhibit the proliferation of BMFBs and the synthesis of ECM in BMFBs, thus affecting the occurrence and development of mammary fibrosis in dairy cows and laying the foundation for further studies to clarify the regulatory mechanism of mammary fibrosis.

Risk factors for recurrence of common bile duct stones after surgical treatment and effect of ursodeoxycholic acid intervention.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an accurate diagnostic method for choledocholithiasis and treatment option for stone removal. Additionally, ursodeoxycholic acid (UDCA) can dissolve cholesterol stones and prevent their development and reappearance by lowering the cholesterol concentration in bile. Despite these treatment options, there are still patients who experience stone recurrence. AIM: To analyze the risk factors for choledocholithiasis recurrence after ERCP retrograde cholangiopancreatography and the effect of UDCA intervention. METHODS: The clinical data of 100 patients with choledochal stones who were hospitalized at the Yixing People's Hospital and underwent ERCP for successful stone extraction between June 2020 and December 2022 were retrospectively collected. According to the post-ERCP treatment plan, 100 patients were classified into UDCA (n = 47) and control (n = 53) groups. We aimed to assess the clinical efficacy and rate of relapse in the two patient populations. We then collected information (basic demographic data, clinical characteristics, and serum biochemical indicators) and determined the factors contributing to relapse using logistic regression analysis. Our secondary goal was to determine the effects of UDCA on liver function after ERCP. RESULTS: Compared to the control group, the UDCA group demonstrated a higher clinical effectiveness rate of 92.45% vs 78.72% (P < 0.05). No significant differences were observed in liver function indices, including total bilirubin, direct bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase, between the two groups before treatment. After treatment, all liver function indices were significantly reduced. Comparing the control vs UDCA groups, the UDCA group exhibited significantly lower levels of all indices (55.39 ± 6.53 vs 77.31 ± 8.52, 32.10 ± 4.62 vs 45.39 ± 5.69, 142.32 ± 14.21 vs 189.63 ± 16.87, 112.52 ± 14.25 vs 149.36 ± 15.36, 122.61 ± 16.00 vs 171.33 ± 22.09, 96.98 ± 10.44 vs 121.35 ± 11.57, respectively, all P < 0.05). The stone recurrence rate was lower in the UDCA group (13.21%) in contrast with the control group (44.68%). Periampullary diverticula (OR: 6.00, 95%CI: 1.69-21.30), maximum stone diameter (OR: 1.69, 95%CI: 1.01-2.85), stone quantity >3 (OR: 4.23, 95%CI: 1.17-15.26), and positive bile culture (OR: 7.61, 95%CI: 2.07-27.91) were independent factors that influenced the relapse of common bile duct stones after ERCP (P < 0.05). Furthermore, postoperative UDCA was identified as a preventive factor (OR: 0.07; 95%CI: 0.08-0.09). CONCLUSION: The intervention effect of UDCA after ERCP for common bile duct stones is adequate, providing new research directions and references for the prevention and treatment of stone recurrence.

Inflammatory cell death PANoptosis is induced by the anti-cancer curaxin CBL0137 via eliciting the assembly of ZBP1-associated PANoptosome.

OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.

Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity.

Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs' contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment.

Gene Expression in Synovium of Rotator Cuff Tear Patients Determined by RNA Sequencing.

Rotator cuff tear (RCT) is a common shoulder disorder related to pain and dysfunction. However, the pathological mechanism of RCT remains unclear. Thus, this study aims to investigate the molecular events in RCT synovium and identify possible target genes and pathways as determined by RNA sequencing (RNA-Seq). The synovial tissue was biopsied from 3 patients with RCT (RCT group) and 3 patients with shoulder instability (Control group) during arthroscopic surgery. Then, differentially expressed (DE) mRNAs, long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) were comprehensively profiled by RNA-Seq. Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analysis were performed to identify the potential functions of these DE genes. 447 mRNAs, 103 lncRNAs and 15 miRNAs were identified differentially expressed. The DE mRNAs were highlighted in inflammatory pathway including up-regulated T cell costimulation, positive regulation of T cell activation, and T cell receptor signaling. Down-regulated fatty acid degradation pathway and 5'-AMP-activated protein kinase (AMPK) signaling in RCT group are also enriched. Validation assay showed that the expression of pro-inflammatory molecules including IL21R, CCR5, TNFSF11, and MMP11 was significantly increased in RCT group compared with Control group. CeRNA analysis further revealed lncRNA-miRNA-mRNA regulatory networks involving IL21R and TNFSF11 in RCT. Activated synovial inflammation is the remarkable event of RCT. Importantly, increased T cell activation and disordered fatty acid metabolism signaling might play a significant role. ceRNA networks involving IL21R and TNFSF11 identified could potentially control the progression of RCT. In conclusion, our findings could provide new evidence for the molecular mechanisms of RCT and might identify new therapeutic targets.

Variability of somatosensory evoked potential and motor evoked potential change criteria in thoracic spinal decompression surgery based on preoperative motor status.

BACKGROUND CONTEXT: Combined somatosensory- and motor-evoked potential (SSEP and MEP) changes for predicting prognosis in thoracic spinal surgery have been variably reported. PURPOSE: We aimed to explore the validity of combined SSEP and MEP for predicting postoperative motor deficits (PMDs) in thoracic spinal decompression surgery (TSDS) and identify a relatively optimal neurophysiological predictor of PMDs in patients based on preoperative motor status. STUDY SETTING: Retrospective study. PATIENT SAMPLE: A total of 475 patients were analyzed. OUTCOME MEASURES: A reduction in muscle strength by more than or equal to one manual muscle testing (MMT) grade postoperatively compared with the preoperative MMT grade was identified as PMDs. Postoperative motor deficits were detected by comparing the preoperative and postoperative physical examination findings in short- and long-term follow-up visits. METHODS: All patients were divided into two subgroups according to preoperative motor status. The following data were collected: (1) demographic data; (2) IONM (intraoperative neuromonitoring) data; and (3) postoperative motor outcomes. Binary logistic regression analysis was performed to assess the efficacy of IONM change to predict PMDs. A receiver operating characteristic curve (ROC) was used to establish optimal IONM warning criteria. RESULTS: Ninety-eight patients had severe preoperative motor deficits (Group S), and 377 patients did not (Group N). MEP and SSEP change was effective for predicting PMDs in the short term (p<.01) and long term (p<.01) for TSDS patients. In Group N, the cutoff values for predicting PMDs in the short term were a decrease of 65% in SSEP amplitude and 89.5% in MEP amplitude of the baseline value. Furthermore, the cutoff values for predicting PMDs in the short term were durations of change of 24.5 minutes for SSEP and 32.5 minutes for MEP. In Group S, however, the cutoff values for predicting PMDs in the short term were a decrease of 36.5% in SSEP amplitude and 59.5% in MEP amplitude of the baseline value. Moreover, the critical values for predicting short-term PMDs were durations of change of 16.5 minutes for SSEP and 17.5 minutes for MEP. CONCLUSIONS: The optimal IONM changes for prediction vary depending on preoperative motor status. Combined SSEP and MEP are excellent for predicting PMDs in TSDS.