Interventing mitochondrial PD-L1 suppressed IFN-γ-induced cancer stemness in hepatocellular carcinoma by sensitizing sorafenib-induced ferroptosis.

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.

Association between leptin receptor polymorphisms and polycystic ovary syndrome risk: a meta-analysis based on 11 studies.

OBJECTIVE: Published evidence indicated that the leptin receptor (LEPR) gene polymorphisms are associated with polycystic ovary syndrome (PCOS) risk. However, studies on the association between the polymorphisms of LEPR gene are inconsistent or even controversial. MATERIAL AND METHODS: We conducted this meta-analysis to explore the more precise relationship between LEPR polymorphisms and PCOS risk. Relevant articles were searched with five online databases up to March 1 2023. Odds ratios (OR) with 95% confidence intervals (CI) were selected to examine the statistical strength of each genetic model. Moreover, RNA secondary structure and variant effects of these loci were examined with in silico analysis. RESULTS: Overall, 11 publications were analyzed, and the pooled results did not present any significant association between rs1137101 A/G polymorphism and PCOS risk in general population and some subgroup analysis. But the significant association were observed in Asian population (AG vs. AA: OR = 0.51, 95%CI = 0.32-0.81, p = .01, I2=0%; AG + GG vs. AA: OR = 0.41, 95%CI = 0.26-0.65, p < .01, I2=25.9%). Moreover, similar positive associations were also observed in rs1805096 polymorphism with PCOS risk. CONCLUSION: In summary, our meta-analysis suggested that the LEPR gene polymorphisms might be associated with PCOS susceptibility. Owing to the limited studies and small sample size in our meta-analysis, more well-designed studies from different races were needed to be conducted to verify the current results.

Predictive value of presepsin and acylcarnitines for severity and biliary drainage in acute cholangitis.

BACKGROUND: Bacteremia, which is a major cause of mortality in patients with acute cholangitis, induces hyperactive immune response and mitochondrial dysfunction. Presepsin is responsible for pathogen recognition by innate immunity. Acylcarnitines are established mitochondrial biomarkers. AIM: To clarify the early predictive value of presepsin and acylcarnitines as biomarkers of severity of acute cholangitis and the need for biliary drainage. METHODS: Of 280 patients with acute cholangitis were included and the severity was stratified according to the Tokyo Guidelines 2018. Blood presepsin and plasma acylcarnitines were tested at enrollment by chemiluminescent enzyme immunoassay and ultra-high-performance liquid chromatography-mass spectrometry, respectively. RESULTS: The concentrations of presepsin, procalcitonin, short- and medium-chain acylcarnitines increased, while long-chain acylcarnitines decreased with the severity of acute cholangitis. The areas under the receiver operating characteristic curves (AUC) of presepsin for diagnosing moderate/severe and severe cholangitis (0.823 and 0.801, respectively) were greater than those of conventional markers. The combination of presepsin, direct bilirubin, alanine aminotransferase, temperature, and butyryl-L-carnitine showed good predictive ability for biliary drainage (AUC: 0.723). Presepsin, procalcitonin, acetyl-L-carnitine, hydroxydodecenoyl-L-carnitine, and temperature were independent predictors of bloodstream infection. After adjusting for severity classification, acetyl-L-carnitine was the only acylcarnitine independently associated with 28-d mortality (hazard ratio 14.396; P < 0.001) (AUC: 0.880). Presepsin concentration showed positive correlation with direct bilirubin or acetyl-L-carnitine. CONCLUSION: Presepsin could serve as a specific biomarker to predict the severity of acute cholangitis and need for biliary drainage. Acetyl-L-carnitine is a potential prognostic factor for patients with acute cholangitis. Innate immune response was associated with mitochondrial metabolic dysfunction in acute cholangitis.

Recent advances in sonodynamic immunotherapy.

Tumor immunotherapy has become an important means of tumor therapy by enhancing the immune response and triggering the activation of immune cells. However, currently, only a small number of patients respond to immunotherapy alone, and patients may experience immune-related adverse events (irAEs) during the course of treatment. Sonodynamic therapy (SDT) can produce cytotoxic substances to tumor tissue, induce apoptosis and enhance immunity. SDT combined with immunotherapy is considered a promising strategy for cancer treatment. In this mini review, we summarize the role of SDT in immunotherapy in recent years, including the application of SDT-triggered immunotherapy and the combination of SDT and immunotherapy.

Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis.

Lipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public database analysis, we found that HBx-expressing hepatocyte-derived prostaglandin E2 (PGE2) induced macrophage polarization imbalance via prostaglandin E2 receptor 4 (EP4) through in vitro, ex vivo, and in vivo models. Here, we revealed that the M1-type polarization of macrophages induced by endoplasmic reticulum oxidoreductase-1-like protein α (ERO1α)-dependent endoplasmic reticulum stress was associated with the HBx-related hepatic NASH phenotype. Mechanistically, HBx promoted Niemann-Pick type C1 (NPC1)/oxysterol-binding protein-related protein 5 (ORP5)-mediated cholesterol transport from the lysosome to the endoplasmic reticulum via mammalian target of rapamycin (mTOR) activation. This study provides a novel basis for screening potential biomarkers in the macrophage mTOR-cholesterol homeostasis-polarization regulatory signaling pathway and evaluating targeted interventions for HBx-associated NASH.

Optimal timing of biliary drainage based on the severity of acute cholangitis: A single-center retrospective cohort study.

BACKGROUND: Biliary decompression is well known to greatly decrease the risks of mortality in acute cholangitis (AC). Although early biliary drainage is recommended by the treatment guidelines for AC, the best time for performing this procedure is yet to be established. Furthermore, since the clinical outcomes of patients with severe AC vary dramatically, screening for patients that could benefit the most from early drainage would be more beneficial than the drainage performed based on the severity grade criteria. AIM: To investigate the optimal drainage timing for AC patients with each disease severity grade and organ dysfunction. METHODS: In this retrospective monocenter cohort analysis, we reviewed 1305 patients who were diagnosed with AC according to the Tokyo guidelines 2018 at a Chinese tertiary hospital between July 2016 and December 2020. Demographic characteristics including age and sex, clinical and laboratory characteristics, and imaging findings of each patient were obtained from electronic medical records. We investigated the all-cause in-hospital mortality (IHM), hospital length of stay (LOS), and hospitalization costs associated with the timing of biliary drainage according to the severity grading and different dysfunctioning organs and predictors [age, white blood cell (WBC) count, total bilirubin, albumin, lactate, malignant obstruction, and Charlton comorbidity index (CCI)]. RESULTS: Biliary drainage within 24 or 48 h in Grade III AC patients could dramatically decrease IHM (3.9% vs 9.0%, P = 0.041; 4% vs 9.9%, P = 0.018, respectively), while increasing LOS and hospitalization costs. Multivariate logistic analysis revealed that neurological, respiratory, renal, and cardiovascular dysfunctions, hypoalbuminemia, and malignant obstruction were significantly associated with IHM (odds ratio = 5.32, 2.541, 6.356, 4.021, 5.655, and 7.522; P < 0.001, P = 0.016, P < 0.001, P = 0.012, P < 0.001, and P < 0.001; respectively). Biliary decompression performed within 12 h of admission significantly decreased the IHM in AC patients with neurological dysfunction (0% vs 17.3%, P = 0.041) or with serum lactate > 2 mmol/L (0% vs 5.4%, P = 0.016). In the subgroup of AC patients with renal dysfunction, abnormal WBC count, hyperbilirubinemia, or hypoalbuminemia, early drainage (< 24 h) reduced the IHM (3.6% vs 33.3%, P = 0.004; 1.9% vs 5.8%, P = 0.031; 1.7% vs 5.0%, P = 0.019; 0% vs 27%, P = 0.026; respectively). The IHM was lower in patients with AC combined with hepatic dysfunction, malignant obstruction, or a CCI > 3 who had undergone biliary drainage within 48 h (2.6% vs 20.5%, P = 0.016; 3.0% vs 13.5%, P = 0.006; 3.4% vs 9.6%, P = 0.021; respectively). CONCLUSION: Biliary drainage within 12 h is beneficial for AC patients with neurological or cardiovascular dysfunction, while complete biliary decompression within 24 h of admission is recommended for treating patients with Grade III AC.

Familial left cervical neurofibromatosis 1 with scoliosis: A case report.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder affecting many parts of the body with café au lait spots, skeletal deformity, and scoliosis. A familial case of NF1 with scoliosis and a painless mass had not yet been reported. CASE SUMMARY: We describe the case of a 15-year-old male patient with a painless lump on the left side of his neck for 10 years and scoliosis. His right shoulder was about 5 cm lower than the left, the left side of his face was deformed, and the left submandibular skin was relaxed. The folding and drooping were obvious and movement was poor. Computed tomography revealed the involvement of the neck, upper chest wall, and surrounding left shoulder, accompanied by bone changes and scoliosis. Histological evaluation showed subepidermal pale blue mucoid degeneration, fibrous fusiform cells in the dermis in a fascicular, woven arrangement. His mother had the same medical history. The diagnosis was neurofibromatosis of the left neck. Various parts of the tumor tissue were serially resected during several visits. Eight months after surgery, there was a slight tendency to regrow. CONCLUSION: This case of slow-progressing NF1 highlights the importance of early diagnosis and treatment to reduce its impact on the patient's growth and development.

Case Report: Disseminated Cysticercosis due to Intentional Ingestion of Parasitic Worm Eggs for Weight Loss.

A 20-year-old female resident of Beijing intended to consume the eggs of the parasitic worm, Taenia saginata, for weight loss; however, she apparently inadvertently ingested Taenia solium (pork tapeworm) eggs, which resulted in disseminated cysticercosis. Cysticerci developed in the brain, tongue, muscles, liver, peritoneum, and subcutaneous tissues. She was administered oral albendazole and praziquantel. After four 10-day courses of treatment, most of the cysts disappeared and she recovered. After 3 years, the patient remains in good health.

Intestinal Mucosal Barrier Is Regulated by Intestinal Tract Neuro-Immune Interplay.

Inflammatory bowel disease, irritable bowel syndrome and severe central nervous system injury can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases. Hence, repairing the intestinal barrier represents a potential therapeutic target for many diseases. Enteral afferent nerves, efferent nerves and the intrinsic enteric nervous system (ENS) play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors. In addition, intestinal microorganisms and their metabolites play a regulatory role in the intestinal mucosal barrier. This paper primarily discusses the interactions between norepinephrine and ß-adrenergic receptors, cholinergic anti-inflammatory pathways, nociceptive receptors, complex ENS networks, gut microbes and various immune cells with their secreted cytokines to summarize the key roles in regulating intestinal inflammation and improving mucosal barrier function.

Mucoepidermoid carcinoma in the infratemporal fossa: A case report.

BACKGROUND: Mucoepidermoid carcinoma is the most common primary epithelial salivary gland malignancy. It mostly occurs in the major or intraoral minor salivary glands but rarely in the infratemporal fossa. Here, we present a case of aggressive mucoepidermoid carcinoma in the infratemporal fossa with neck lymph node metastasis and also discuss diagnostic and treatment strategies. CASE SUMMARY: A 39-year-old woman with a mass located in the right submandibular area presented to our department. Physical examination revealed lymphadenopathy on the right submandibular side measuring 2.5 cm × 3 cm that was hard and had poor mobility. Results of nasal endoscopy were unremarkable. Ultrasound examination revealed an enlarged lymph node at level II of the right side. Fine needle aspiration cytology of the metastatic lymph node revealed malignant cells with infection. Contrast-enhanced computed tomography revealed an enhancing ill-defined soft tissue mass in the right infratemporal region. Positron emission tomography/computed tomography revealed hyperintensity in the right infratemporal fossa along with lymphadenopathy at level II of the right-side lymph node. The patient underwent extended resection of the primary tumor, and ipsilateral radical neck dissection was also completed. Hematoxylin-eosin staining and immunohistochemistry revealed a high-grade mucoepidermoid carcinoma. No signs and symptoms of recurrence of the neoplasm were present after 20 mo of follow-up. CONCLUSION: Positron emission tomography/computed tomography play a key role in primary tumor localization. Furthermore, histopathology and immunohistochemistry play pivotal roles in disease diagnosis.

Prognostic significance of contactin 3 expression and associated genes in glioblastoma multiforme.

Contactin 3 (CNTN3) is a member of the contactin family that is primarily expressed in the nervous system. However, to the best of our knowledge, expression of contactin and its role in the development and progression of brain tumours has not been studied. Although glioblastoma multiforme (GBM) is the most common malignant brain tumour, advances in therapeutic options for patients with GBM have been modest due to an incomplete understanding of the molecular mechanisms underlying development and progression. The aim of the present study was to examine the correlation between CNTN3 and its associated genes and the clinical outcome in patients with GBM. CNTN3 and the expression levels of associated genes were analysed in GBM datasets obtained from the SAGE Anatomical viewer website, Gene Expression Omnibus, Oncomine and The Cancer Genome Atlas. CNTN3 was significantly downregulated in patients with GBM. Subsequently, the expression of CNTN3 was further validated using immunohistochemistry in a cohort of GBM specimens. The immunohistochemistry results were consistent with the in silico analyses. Kaplan-Meier analysis indicated that patients with lower expression levels of CNTN3 had a significantly shorter overall survival (OS) time compared with patients with higher levels of CNTN3 expression. Univariate and multivariate Cox regression analyses demonstrated that CNTN3 expression was an independent prognostic indicator in patients with GBM. Furthermore, gene set enrichment analysis revealed that CNTN3 was associated with the receptor tyrosine-protein kinase (ErbB) signalling pathway. In the ErbB signalling pathway, epidermal growth factor receptor (EGFR) was negatively correlated with CNTN3. Taken together, these data suggest that lower expression levels of CNTN3 may be an independent biomarker that predicts poor OS time in patients with GBM, and that EGFR expression in the ErbB pathway may be associated with CNTN3 expression.

Effect of Blumgart anastomosis in reducing the incidence rate of pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Pancreatic fistula is one of the most serious complications after pancreatoduodenectomy for treating any lesions at the pancreatic head. For years, surgeons have tried various methods to reduce its incidence. AIM: To investigate and emphasize the clinical outcomes of Blumgart anastomosis compared with traditional anastomosis in reducing postoperative pancreatic fistula. METHODS: In this observational study, a retrospective analysis of 291 patients who underwent pancreatoduodenectomy, including Blumgart anastomosis (201 patients) and traditional embedded pancreaticojejunostomy (90 patients), was performed in our hospital. The preoperative and perioperative courses and long-term follow-up status were analyzed to compare the advantages and disadvantages of the two methods. Moreover, 291 patients were then separated by the severity of postoperative pancreatic fistula, and two methods of pancreaticojejunostomy were compared to detect the features of different anastomosis. Six experienced surgeons were involved and all of them were proficient in both surgical techniques. RESULTS: The characteristics of the patients in the two groups showed no significant differences, nor the preoperative information and pathological diagnoses. The operative time was significantly shorter in the Blumgart group (343.5 ± 23.0 vs 450.0 ± 40.1 min, P = 0.028), as well as the duration of pancreaticojejunostomy drainage tube placement and postoperative hospital stay (12.7 ± 0.9 d vs 17.4 ± 1.8 d, P = 0.031; and 21.9 ± 1.3 d vs 28.9 ± 1.3 d, P = 0.020, respectively). The overall complications after surgery were much less in the Blumgart group than in the embedded group (11.9% vs 26.7%, P = 0.002). Patients who underwent Blumgart anastomosis would suffer less from severe pancreatic fistula (71.9% vs 50.0%, P = 0.006), and this pancreaticojejunostomy procedure did not have worse influences on long-term complications and life quality. Thus, Blumgart anastomosis is a feasible pancreaticojejunostomy procedure in pancreatoduodenectomy surgery. It is safe in causing less postoperative complications, especially pancreatic fistula, and thus shortens the hospitalization duration. CONCLUSION: Surgical method should be a key factor in reducing pancreatic fistula, and Blumgart anastomosis needs further promotion.

Disseminated cysticercosis in China with complex and variable clinical manifestations: a case series.

BACKGROUND: Cysticercosis is an emerging and neglected tropical disease (NTD) that poses a serious public health concern worldwide. Disseminated cysticercosis (DCC) is an uncommon manifestation of cysticercosis, also found in China. CASE PRESENTATION: We report three cases of DCC in patients living in China, with different clinical and radiological presentations. All three patients had DCC with active ocular cysticercosis, including one patient with widespread DCC caused by direct ingestion of Taenia solium eggs. The intravitreal cysticercus cyst in this patient was completely extracted entirely by 23-gauge pars plana vitrectomy, and the cyst was oval in shape on the flat mount preparation. CONCLUSION: The clinical presentation of DCC is highly sophisticated. The diagnosis depended on the typical radiological presentations, biopsy and flat mount preparations of the cyst.

Effect of joint mobilization techniques for primary total knee arthroplasty: Study protocol for a randomized controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) has become the most preferred procedure by patients for the relief of pain caused by knee osteoarthritis. TKA patients aim a speedy recovery after the surgery. Joint mobilization techniques for rehabilitation have been widely used to relieve pain and improve joint mobility. However, relevant randomized controlled trials showing the curative effect of these techniques remain lacking to date. Accordingly, this study aims to investigate whether joint mobilization techniques are valid for primary TKA. METHODS/DESIGN: We will manage a single-blind, prospective, randomized, controlled trial of 120 patients with unilateral TKA. Patients will be randomized into an intervention group, a physical modality therapy group, and a usual care group. The intervention group will undergo joint mobilization manipulation treatment once a day and regular training twice a day for a month. The physical modality therapy group will undergo physical therapy once a day and regular training twice a day for a month. The usual care group will perform regular training twice a day for a month. Primary outcome measures will be based on the visual analog scale, the knee joint Hospital for Special Surgery score, range of motion, surrounded degree, and adverse effect. Secondary indicators will include manual muscle testing, 36-Item Short Form Health Survey, Berg Balance Scale function evaluation, Pittsburgh Sleep Quality Index, proprioception, and muscle morphology. We will direct intention-to-treat analysis if a subject withdraws from the trial. DISCUSSION: The important features of this trial for joint mobilization techniques in primary TKA are randomization procedures, single-blind, large sample size, and standardized protocol. This study aims to investigate whether joint mobilization techniques are effective for early TKA patients. The result of this study may serve as a guide for TKA patients, medical personnel, and healthcare decision makers. TRIAL REGISTRATION: It has been registered at http://www.chictr.org.cn/showproj.aspx?proj=15262 (Identifier:ChiCTR-IOR-16009192), Registered 11 September 2016. We also could provide the correct URL of the online registry in the WHO Trial Registration. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-IOR-16009192.

Chemical Composition, Antioxidant, Antimicrobial and Cytotoxic Activities of Essential Oil from Premna microphylla Turczaninow.

Premna microphylla Turczaninow, an erect shrub, was widely used in Chinese traditional medicine to treat dysentery, appendicitis, and infections. In this study, the essential oil from P. microphylla Turcz. was obtained by hydrodistillation and analyzed by GC (Gas Chromatography) and GC-MS (Gas Chromatography-Mass Spectrometer). Fifty-six compounds were identified in the oil which comprised about 97.2% of the total composition of the oil. Major components of the oil were blumenol C (49.7%), ß-cedrene (6.1%), limonene (3.8%), α-guaiene (3.3%), cryptone (3.1%), and α-cyperone (2.7%). Furthermore, we assessed the in vitro biological activities displayed by the oil obtained from the aerial parts of P. microphylla, namely the antioxidant, antimicrobial, and cytotoxic activities. The antioxidant activity of the essential oil was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. For this, the IC50 value was estimated to be 0.451 mg/mL. The essential oil of P. microphylla exhibited considerable antibacterial capacity against Escherichia coli with an MIC (Minimum Inhibitory Concentration) value of 0.15 mg/mL, along with noticeable antibacterial ability against Bacillus subtilis and Staphylococcus aureus with an MIC value of 0.27 mg/mL. However, the essential oil did not show significant activity against fungus. The oil was tested for its cytotoxic activity towards HepG2 (liver hepatocellular cells) and MCF-7 Cells (human breast adenocarcinoma cell line) using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, and exerted cytotoxic activity with an IC50 of 0.072 and 0.188 mg/mL for 72 h. In conclusion, the essential oil from P. microphylla is an inexpensive but favorable resource with strong antibacterial capacity as well as cytotoxic activity. Thus, it has the potential for utilization in the cosmetics and pharmaceutical industries.