Marine anoxia linked to abrupt global warming during Earth's penultimate icehouse.

Piecing together the history of carbon (C) perturbation events throughout Earth's history has provided key insights into how the Earth system responds to abrupt warming. Previous studies, however, focused on short-term warming events that were superimposed on longer-term greenhouse climate states. Here, we present an integrated proxy (C and uranium [U] isotopes and paleo CO2) and multicomponent modeling approach to investigate an abrupt C perturbation and global warming event (∼304 Ma) that occurred during a paleo-glacial state. We report pronounced negative C and U isotopic excursions coincident with a doubling of atmospheric CO2 partial pressure and a biodiversity nadir. The isotopic excursions can be linked to an injection of ∼9,000 Gt of organic matter­derived C over ∼300 kyr and to near 20% of areal extent of seafloor anoxia. Earth system modeling indicates that widespread anoxic conditions can be linked to enhanced thermocline stratification and increased nutrient fluxes during this global warming within an icehouse.

Aneurysmal Subarachnoid Hemorrhage and Sex Differences: Analysis of Epidemiology, Outcomes, and Risk Factors.

BACKGROUND: The differences in outcomes after aneurysmal subarachnoid hemorrhage (aSAH) between the sexes have not been concretely determined. This study aimed to evaluate the differences in epidemiology, outcomes, and risk factors between male and female patients with aSAH. METHODS: We performed a multicenter, retrospective study of patients with aSAH from 2017 to 2020. We investigated the epidemiological differences between the two sexes. Propensity score matching (PSM) was used to compare short-term outcomes between the sexes. Binary logarithmic regression was performed to investigate the odds ratio (OR) for dependent survival in patients of different sexes. RESULTS: A total of 5,407 consecutive patients with aSAH were included in this study, and the female-to-male ratio was 1.8:1. The peak incidence of aSAH occurred in the 6th and 7th decades in males and females, respectively. There were more female patients with internal carotid artery or posterior communicating artery aneurysms (53.2%), and there were more male patients with anterior cerebral artery or anterior communicating artery aneurysms (43.2%). The incidence of multiple aneurysms was greater in female patients (21.5% vs. 14.2%, P < 0.001). There was no significant difference in outcomes before and after PSM at discharge. The dependent survival risk was related only to the clinical condition on admission in women. In addition, age > 50 years (OR 1.88, 95% confidence interval 1.17-3.02; P = 0.01) and hypertension (OR 1.81, 95% confidence interval 1.25-2.61; P = 0.002) were also risk factors for male patients. CONCLUSIONS: There were more female patients with aneurysms than male patients in this study. Most aneurysm locations were different between the two groups. There was no significant difference in discharge outcomes before and after PSM. The risk factors for dependent survival were different between female and male patients.

The association of carbohydrate antigen 19-9 response with radiologic response and survival in intrahepatic cholangiocarcinoma: A prospective cohort study.

BACKGROUND: The role of carbohydrate antigen 19-9 (CA 19-9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of the CA 19-9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA. METHODS: A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19-9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19-9 response and the radiologic response was performed. The associations between CA 19-9 response and imaging response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Two hundred sixty-seven patients (63.3%) had a CA 19-9 response. A CA 19-9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19-9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio [HR], 4.8 months; 95% confidence interval [CI], 3.8-6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2-6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19-9 nonresponder status, and radiologic nonresponder status in multivariable analysis. CONCLUSIONS: CA 19-9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19-9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies. PLAIN LANGUAGE SUMMARY: A decline in carbohydrate antigen 19-9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies.

Microfluidic platforms in diagnostic of ovarian cancer.

The most important reason for death from ovarian cancer is the late diagnosis of this disease. The standard treatment of ovarian cancer includes surgery and chemotherapy based on platinum, which is associated with side effects for the body. Due to the nonspecific nature of clinical symptoms, developing a platform for early detection of this disease is needed. In recent decades, the advancements of microfluidic devices and systems have provided several advantages for diagnosing ovarian cancer. Designing and manufacturing new platforms using specialized technologies can be a big step toward improving the prevention, diagnosis, and treatment of this group of diseases. Organ-on-a-chip microfluidic devices are increasingly used as a promising platform in cancer research, with a focus on specific biological aspects of the disease. This review focusing on ovarian cancer and microfluidic application technologies in its diagnosis. Additionally, it discusses microfluidic platforms and their potential future perspectives in advancing ovarian cancer diagnosis.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

ß-Cryptoxanthin Attenuates Cigarette-Smoke-Induced Lung Lesions in the Absence of Carotenoid Cleavage Enzymes (BCO1/BCO2) in Mice.

High dietary intake of ß-cryptoxanthin (BCX, an oxygenated provitamin A carotenoid) is associated with a lower risk of lung disease in smokers. BCX can be cleaved by ß-carotene-15,15'-oxygenase (BCO1) and ß-carotene-9',10'-oxygenase (BCO2) to produce retinol and apo-10'-carotenoids. We investigated whether BCX has protective effects against cigarette smoke (CS)-induced lung injury, dependent or independent of BCO1/BCO2 and their metabolites. Both BCO1-/-/BCO2-/- double knockout mice (DKO) and wild type (WT) littermates were supplemented with BCX 14 days and then exposed to CS for an additional 14 days. CS exposure significantly induced macrophage and neutrophil infiltration in the lung tissues of mice, regardless of genotypes, compared to the non-exposed littermates. BCX treatment significantly inhibited CS-induced inflammatory cell infiltration, hyperplasia in the bronchial epithelium, and enlarged alveolar airspaces in both WT and DKO mice, regardless of sex. The protective effects of BCX were associated with lower expression of IL-6, TNF-α, and matrix metalloproteinases-2 and -9. BCX treatment led to a significant increase in hepatic BCX levels in DKO mice, but not in WT mice, which had significant increase in hepatic retinol concentration. No apo-10'-carotenoids were detected in any of the groups. In vitro BCX, at comparable doses of 3-OH-ß-apo-10'-carotenal, was effective at inhibiting the lipopolysaccharide-induced inflammatory response in a human bronchial epithelial cell line. These data indicate that BCX can serve as an effective protective agent against CS-induced lung lesions in the absence of carotenoid cleavage enzymes.

Comparison of the Therapeutic Effects of Iodine-125 Seed Implantation and Conventional Radiochemotherapy for Advanced Esophageal Cancer.

BACKGROUND: The purpose of this study was to explore the feasibility, safety and efficacy of iodine-125 seed implantation in the treatment of dysphagia of advanced esophageal cancer. METHODS: We retrospectively analyzed patients with advanced esophageal cancer who underwent EUS-guided iodine-125 seed implantation or conventional chemoradiotherapy in our hospital. The propensity score match was used to reduce the baseline differences. RESULTS: A total of 127 patients were enrolled, 17 patients received EUS-guided iodine 125 seed implantation (Group A), 31 patients received radiotherapy (Group B), 38 patients received chemotherapy (Group C) and 41 patients received chemotherapy combined with radiotherapy (Group D). At half month postoperatively, the dysphagia remission rate in Group A (100%) was better than that in Groups B (39.3%), C (20%), D (15.8%), respectively, in the original cohort (P < 0.01); At 1 month postoperatively, the dysphagia remission rate in Group A (86.7%) was better than that in Group B (57.1%) (P > 0.05), Group C (25.7%) (P < 0.05) and Group D (34.2%) (P < 0.05), respectively, in the original cohort. There was no statistically significant difference in median overall survival (OS) between Group A (16 months) and Group B (37 months) (P = 0.149), and between Group A (16months) and Group C (16 months) (P = 0.918) in the original cohort. The mean OS of Group D (54 months) was better than that of Group A (20 months) in the original cohort (P = 0.031). The incidences of grade ≥2 myelosuppression in Groups B, C, and D were 12.9%, 28.9%, and 43.9%, respectively; the incidence of grade ≥2 gastrointestinal adverse events in Groups B, C, and D were 12.9%, 15.8%, 12.2%, respectively. No serious adverse events were found in Group A. The radiation dose around the patient was reduced to a safe range after the distance from the implantation site was more than 1 m (4.2 ± 2.6 µSv/h) or with lead clothing (0.1 ± 0.07 µSv/h). CONCLUSIONS: Compared with conventional radiotherapy or chemotherapy alone, iodine-125 seed implantation might improve dysphagia more quickly and safely, further clinical data is needed to verify whether it could effectively prolong the OS of patients.

Analysis of risk factors for post-endoscopic papillectomy bleeding.

BACKGROUND: Endoscopic papillectomy (EP) is an effective treatment for ampullary lesions but technically challenging because of anatomical specificities concerning the high rate of adverse events. Bleeding is one of the most feared complications and can be potentially life-threatening. AIM: To study the risk factors for bleeding after EP are presented with the goal of establishing preventive measures. METHODS: A total of 173 consecutive patients with ampullary lesions undergone EP from January 2006 to October 2020 were enrolled in this study. They were divided into a bleeding group and a non-bleeding group depending on whether postoperative bleeding occurred. Related factors were analyzed by univariate and multivariate logistics regression. RESULTS: Postoperative bleeding was experienced in 33 patients (19.07%). Multivariate analysis also identified intraoperative bleeding (OR: 4.38, 95% CI: 1.87-11.15, p = .001) and endoscopic closure (OR: 0.25, 95% CI: 0.10-0.58, p = .001) as independent factors significantly associated with bleeding after EP. Lesion size (≥3 cm) was shown as an independent factor significantly associated with intraoperative bleeding (OR: 4.25, 95% CI: 1.21-16.44, p = .028). CONCLUSIONS: This retrospective evaluation found that endoscopic closure was associated with reduced risk and intraoperative bleeding with increased risk of bleeding after EP. Lesion size may indirectly influence the risk of postoperative bleeding by increasing the risk of intraoperative bleeding.

NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic ß-cells for protection.

Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic ß-cells. ER stress or ROS causes c-Jun N-terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi-stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual-luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in ß-cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p-JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome-dependent manner. We found that NR4A1 increased the expression of cbl-b (an E3 ligase); knocking down cbl-b expression increased MKK4 and p-JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl-b promoter by physical association. We further confirmed that cbl-b expression in ß-cells was reduced in NR4A1-knockout mice compared with WT mice. NR4A1 down-regulates JNK activation by ER stress or ROS in ß-cells via enhancing cbl-b expression.

Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.

BACKGROUND & AIMS: The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS: We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. RESULTS: IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). CONCLUSION: Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. LAY SUMMARY: Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.

Role of lycopene in smoke-promoted chronic obstructive pulmonary disease and lung carcinogenesis.

Chronic obstructive pulmonary disease (COPD) and lung cancer are a major cause of morbidity and mortality worldwide, with cigarette smoking being the single most important risk factor for both. Emerging evidence indicates alterations in reverse cholesterol transport-mediated removal of excess cholesterol from lung, and intracellular cholesterol overload to be involved in smoke-promoted COPD and lung cancer development. Since there are currently few effective treatments for COPD and lung cancer, it is important to identify food-derived, biologically active compounds, which can protect against COPD and lung cancer development. High intake of the carotenoid lycopene, as one of phytochemicals, is associated with a decreased risk of chronic lung lesions. This review article summarizes and discusses epidemiologic evidence, in vitro and in vivo studies regarding the prevention of smoke-promoted COPD and lung carcinogenesis through dietary lycopene as an effective intervention strategy. We focus on the recent research implying that lycopene preventive effect is through targeting the main genes involved in reverse cholesterol transport. This review also indicates gaps in knowledge about the function of lycopene against COPD and lung cancer, offering directions for further research.

Concentrations of Circulating Phylloquinone, but Not Cerebral Menaquinone-4, Are Positively Correlated with a Wide Range of Cognitive Measures: Exploratory Findings in Centenarians.

BACKGROUND: Vitamin K (VK) exists in the form of phylloquinone (PK) and menaquinones (MKs). Roles of VK on cognitive health in the elderly are emerging, but there is limited evidence on VK uptake and metabolism in human brain. OBJECTIVES: The primary objective of this study was to characterize VK distribution in brains of an elderly population with varied cognitive function. In addition, associations among circulating (a biomarker of VK intake) and cerebral VK concentrations and cognition were investigated. METHODS: Serum or plasma (n = 27) and brain samples from the frontal cortex (FC; n = 46) and the temporal cortex (TC; n = 33) were acquired from 48 decedents (aged 98-107 y; 25 demented and 23 nondemented) enrolled in the Georgia Centenarian Study. Both circulating and brain VK concentrations were measured using HPLC with fluorescence detection. Cognitive assessment was performed within 1 y prior to mortality. Partial correlations between serum/plasma or cerebral VK concentrations and cognitive function were performed, adjusting for covariates and separating by dementia and antithrombotic use. RESULTS: MK-4 was the predominant vitamer in both FC (mean ± SD = 4.92 ± 2.31 pmol/g, ≥89.15% ± 5.09% of total VK) and TC (4.60 ± 2.11 pmol/g, ≥89.71% ± 4.43% of total VK) regardless of cognitive status. Antithrombotic users had 34.0% and 53.9% lower MK-4 concentrations in FC (P < 0.05) and TC (P < 0.001), respectively. Circulating PK was not correlated with cerebral MK-4 or total VK concentrations. Circulating PK concentrations were significantly associated with a wide range of cognitive measures in nondemented centenarians (P < 0.05). In contrast, cerebral MK-4 concentrations were not associated with cognitive performance, either before or after exclusion of antithrombotic users. CONCLUSIONS: Circulating VK concentrations are not related to cerebral MK-4 concentrations in centenarians. Cerebral MK-4 concentrations are tightly regulated over a range of VK intakes and cognitive function. Circulating PK may reflect intake of VK-rich foods containing other dietary components beneficial to cognitive health. Further investigation of VK uptake and metabolism in the brain is warranted.

Lycopene in protection against obesity and diabetes: A mechanistic review.

Lycopene, a natural pigment that mainly exists in the mature fruit of tomatoes, has gained increasing attention due to its protective effects against obesity and diabetes. The aim of this review is to summarize the potential mechanisms in which lycopene exerts protection against obesity and diabetes, along with highlighting its bioavailability, synthesis and safety. Literature sources used in this review were from the PubMed Database, China Knowledge Resource Integrated Database, China Science and Technology Journal Database, National Science and Technology Library, Wanfang Data, and the Web of Science. For the inquiries, keywords such as lycopene, properties, synthesis, diabetes, obesity, and safety were used in various combinations. About 200 articles and reviews were evaluated. Lycopene exhibits anti-obesity and anti-diabetic activities in different organs and/or tissues, including adipose tissue, liver, kidney, pancreas, brain, ovaries, intestine, and eyes. The underlying mechanism may be attributed to its anti-oxidant and anti-inflammatory properties and through its ability to regulate of AGE/RAGE, JNK/MAPK, PI3K/Akt, SIRT1/FoxO1/PPARγ signaling pathways and AchE activity. The epidemiological investigations support that lycopene consumption may contribute to lowering the risk of obesity and diabetes. The cis-isomers of lycopene are more bioavailable and better absorbed than trans-lycopene, and mainly distribute in liver and adipose tissue. Lycopene exhibits a good margin of safety and can be obtained by plant extraction, chemical synthesis and microbial fermentation. In summary, lycopene consumption beneficially contributes to protecting against diabetes and obesity in animal studies and epidemiological investigations, which supports the potential of this compound as a preventive/therapeutic agent against these disorders. Well-designed, prospective clinical studies are warranted to evaluate the potential therapeutic effect of lycopene against common metabolic diseases.

Dietary ß-Cryptoxanthin Inhibits High-Refined Carbohydrate Diet-Induced Fatty Liver via Differential Protective Mechanisms Depending on Carotenoid Cleavage Enzymes in Male Mice.

BACKGROUND: ß-Cryptoxanthin (BCX), a provitamin A carotenoid shown to protect against nonalcoholic fatty liver disease (NAFLD), can be cleaved by ß-carotene-15,15'-oxygenase (BCO1) to generate vitamin A, and by ß-carotene-9',10'-oxygenase (BCO2) to produce bioactive apo-carotenoids. BCO1/BCO2 polymorphisms have been associated with variations in plasma carotenoid amounts in both humans and animals. OBJECTIVES: We investigated whether BCX feeding inhibits high refined-carbohydrate diet (HRCD)-induced NAFLD, dependent or independent of BCO1/BCO2. METHODS: Six-week-old male wild-type (WT) and BCO1-/-/BCO2-/- double knockout (DKO) mice were randomly fed HRCD (66.5% of energy from carbohydrate) with or without BCX (10 mg/kg diet) for 24 wk. Pathological and biochemical variables were analyzed in the liver and mesenteric adipose tissues (MATs). Data were analyzed by 2-factor ANOVA. RESULTS: Compared to their respective HRCD controls, BCX reduced hepatic steatosis severity by 33‒43% and hepatic total cholesterol by 43‒70% in both WT and DKO mice (P < 0.01). Hepatic concentrations of BCX, but not retinol and retinyl palmitate, were 33-fold higher in DKO mice than in WT mice (P < 0.001). BCX feeding increased the hepatic fatty acid oxidation protein peroxisome proliferator-activated receptor-α, and the cholesterol efflux gene ATP-binding cassette transporter5, and suppressed the lipogenesis gene acetyl-CoA carboxylase 1 (Acc1) in the MAT of WT mice but not DKO mice (P < 0.05). BCX feeding decreased the hepatic lipogenesis proteins ACC and stearoyl-CoA desaturase-1 (3-fold and 5-fold) and the cholesterol synthesis genes 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and HMG-CoA synthase 1 (2.7-fold and 1.8-fold) and increased the cholesterol catabolism gene cholesterol 7α-hydroxylase (1.9-fold) in the DKO but not WT mice (P < 0.05). BCX feeding increased hepatic protein sirtuin1 (2.5-fold) and AMP-activated protein kinase (9-fold) and decreased hepatic farnesoid X receptor protein (80%) and the inflammatory cytokine gene Il6 (6-fold) in the MAT of DKO mice but not WT mice (P < 0.05). CONCLUSION: BCX feeding mitigates HRCD-induced NAFLD in both WT and DKO mice through different mechanisms in the liver-MAT axis, depending on the presence or absence of BCO1/BCO2.

Favus of Scrotum Due to Trichophyton rubrum in Immunocompetent Patients: A Clinical, Mycological and Ultrastructural Study.

PURPOSE: To characterize the clinical and mycological features of favus of scrotum due to Trichophyton rubrum. METHODS: A single-site prospective study was carried out in an outpatient dermatology clinic. Microscopic examination and fungal culture were done using skin scrapings. Scales on the scrotum were stained with PAS and visualized by microscopy, including in vivo reflectance confocal microscopy (RCM). Two strains were analyzed by RAPD typing. Scutular lesions were fixed for scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: Cultures of the scale from the scrotum and/or groin in all patients showed a growth of T. rubrum. T. rubrum strains from scrotum and groins in one patient were demonstrated as the same strain by RAPD typing. The average age of patients was 34.1 ± 12.78 years. The mean course was 8.2 ± 5.07 days. All the patients received only topical treatment for 2 weeks without recurrence. Direct smear, calcofluor-white staining and in vivo RCM study of the scrotal favus in patients showed a massive number of septate branching hyphae, while fewer septate hyphae in scales in the groin. Abundant hyphae were found only in the outer layer of the stratum corneum of the scrotum under SEM and TEM with intact bilateral cell walls, and normal nucleus, liposomes and reticulum. Few distorted hyphae structures, cell wall degeneration, degenerated cytoplasm and the autophagy phenomenon could be seen in scales from groin under TEM. CONCLUSIONS: Scrotal favus due to T. rubrum is still a true infection, which most often occurred in immunocompetent patients.

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression.

Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor with diverse functions. It has been reported that NR4A1, as a transcriptional activator, is implicated in glucose and lipid metabolism. The aim of this study was to investigate the regulatory role of NR4A1 in adipogenesis and explore the underlying mechanisms. Quantitative real-time PCR and Western blotting were used to analyse the expression of genes involved in synthesis and mobilization of fats in vivo and in vitro. Dual-luciferase reporter assay was conducted to study the regulatory mechanisms of NR4A1. Our data from in vivo study confirmed that NR4A1 knockout (KO) mice fed with high-fat diet were more prone to obesity, and gene expression levels of PPARγ and FAS were increased in KO mice compared to controls; our data from in vitro study showed that NR4A1 overexpression in 3T3-L1 pre-adipocytes inhibited adipogenesis. Moreover, NR4A1 enhanced GATA binding protein 2 (GATA2) expression, which in turn inhibited peroxisome proliferator-activated receptor γ (PPARγ); NR4A1 inhibited sterol regulatory element binding transcription factor 1 (SREBP1) and its downstream gene fatty acid synthase (FAS) by up-regulating p53. NR4A1 inhibits the differentiation and lipid accumulation of adipocytes by enhancing the expression of GATA2 and p53.

Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway.

ß-Carotene-15, 15'-oxygenase (BCO1) and ß-carotene-9', 10'-oxygenase (BCO2) are essential enzymes in carotenoid metabolism. While BCO1/BCO2 polymorphisms have been associated with alterations to human and animal carotenoid levels, experimental studies have suggested that BCO1 and BCO2 may have specific physiological functions beyond the cleavage of carotenoids. In the present study, we investigated the effect of ablation of both BCO1/BCO2 in the development of non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism(s). BCO1/BCO2 double knock out (DKO) mice developed hepatic steatosis (8/8) and had significantly higher levels of hepatic and plasma triglyceride and total cholesterol compared to WT (0/8). Hepatic changes in the BCO1/BCO2 DKO mice were associated with significant: 1) increases in lipogenesis markers, and decreases in fatty acid ß-oxidation markers; 2) upregulation of cholesterol metabolism markers; 3) alterations to microRNAs related to TG accumulation and cholesterol metabolism; 4) increases in an hepatic oxidative stress marker (HO-1) but decreases in anti-oxidant enzymes; and 5) decreases in farnesoid X receptor (FXR), small heterodimer partner (SHP), and sirtuin 1 (SIRT1). The present study provided novel experimental evidence that BCO1 and BCO2 could play a significant role in maintaining normal hepatic lipid and cholesterol homeostasis, potentially through the regulation of the FXR/miR-34a/SIRT1 pathway.

The microbiology of chronic rhinosinusitis with and without nasal polyps.

OBJECTIVE: To compare the microbiological features in middle meatus samples from chronic rhinosinusitis (CRS) patients with nasal polyps (CRSwNP) and those without nasal polyps (CRSsNP), and control subjects. METHODS: A total of 136 CRSwNP patients, 66 CRSsNP patients, and 49 control subjects who underwent endoscopic surgery in Beijing TongRen Hospital were enrolled between January 2014 and January 2016. Swab samples were obtained from the middle meatus during surgery and processed for the presence of aerobic and non-aerobic bacteria and fungi. Information on the allergic rhinitis, asthma, the percentage of eosinophils in peripheral blood, and the history of smoking and surgery was collected. RESULTS: The overall isolation rate for bacteria was 81.3% for the three groups, with the lowest in the CRSsNP group (77.3%) and the highest in the CRSwNP group (88.4%). There were no significant differences in isolation rates among the three groups (P = 0.349). The three most common bacterial species were: Coagulase-negative Staphylococcus (24.3%), Corynebacterium (19.9%), and Staphylococcus epidermidis (19.1%) in the CRSwNP group; S. epidermidis (21.2%), Corynebacterium (21.2%), Coagulase-negative staphylococcus (18.2%), and Staphylococcus aureus (13.6%) in the CRSsNP group; S. epidermidis (30.6%), Coagulase-negative Staphylococcus (28.6%), and S. aureus (14.3%) in the control group. For the bacterial species with high isolation rates, no significant difference in the microbial cultures was observed among the three groups; whereas in the CRSwNP group, a relatively high proportion of Citrobacter (5.9%, a bacterium with low isolation rate) was observed compared with the CRSsNP and control groups (all 0.0%). Furthermore, when samples were categorized into subgroups according to the percentage of eosinophils, some bacterial species showed different rates in the CRSwNP group (e.g., S. aureus, 3.3% in the subgroup with normal percentage of eosinophils, 17.2% in the subgroup with increased percentage of eosinophils, P = 0.011). CONCLUSIONS: There were no significant differences in the microbiological features (except Citrobacter) in middle meatus samples from CRSwNP patients, CRSsNP patients, and control subjects. S. aureus may promote eosinophilic inflammatory response, while S. epidermidis may promote non-eosinophilic inflammatory response.