Distribution of per- and polyfluoroalkyl substances in blood, serum, and urine of patients with liver cancer and associations with liver function biomarkers.

Studies have shown that per- and polyfluoroalkyl substances (PFASs) may be hepatotoxic in animals or humans. However, data on clinical epidemiology are very limited. In this study, 21 PFASs were determined in patients with liver diseases, with the highest median concentrations detected in the serum sample (26.7 ng/mL), followed by blood (10.7 ng/mL) and urine (5.02 ng/mL). Higher total PFAS concentrations were found in hepatocellular carcinoma (HCC) patients compared to non-HCC patients, with significant discrepancies in serum and blood samples. Besides, significant correlations were also found among PFAS concentrations and age, gender, body mass index (BMI), and liver function biomarkers levels. For example, PFAS concentrations are significantly higher in males than in females; Several serum PFASs concentrations increase with age and BMI, while the serum perfluorohexane sulfonic acid (PFHxS) concentrations are negatively correlated with age. In addition, multiple regression models adjusted for age, gender and BMI found that increased serum perfluorobutane sulfonic acid (PFBS), perfluoroheptane sulfonic acid (PFHpS) and perfluorohexylphosphonic acid (PFHxPA) conentrations are correlated with elevated alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alpha-fetoprotein (AFP) (p < 0.05). Our results provide epidemiological support for the future study on the potential clinical hepatotoxicity of PFAS.

Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy.

The COVID-19 pandemic has resulted in a large number of fatalities and, at present, lacks a readily available curative treatment for patients. Here, we demonstrate that unmodified red blood cell-derived extracellular vesicles (RBCEVs) can inhibit SARS-CoV-2 infection in a phosphatidylserine (PS) dependent manner. Using T cell immunoglobulin mucin domain-1 (TIM-1) as an example, we demonstrate that PS receptors on cells can significantly increase the adsorption and infection of authentic and pseudotyped SARS-CoV-2 viruses. RBCEVs competitively inhibit this interaction and block TIM-1-mediated viral entry into cells. We further extend the therapeutic efficacy of this antiviral treatment by loading antisense oligonucleotides (ASOs) designed to target conserved regions of key SARS-CoV-2 genes into RBCEVs. We establish that ASO-loaded RBCEVs are efficiently taken up by cells in vitro and in vivo to suppress SARS-CoV-2 replication. Our findings indicate that this RBCEV-based SARS-CoV-2 therapeutic displays promise as a potential treatment capable of inhibiting SARS-CoV-2 entry and replication.

Time-trends in liver cancer incidence and mortality rates in the U.S. from 1975 to 2017: a study based on the Surveillance, Epidemiology, and End Results database.

Background: A previous study has examined the overall cancer statistics. However, more detailed statistics regarding liver cancer have not been provided. We evaluated the incidence and mortality trends of liver and intrahepatic bile duct cancer in the United States from 1975 to 2017 based on the data in the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Age, gender, race, metastasis, tumor site, and tumor grade of patients were extracted from the SEER database. Codes C22.0 and C22.1 of the International Classification of Disease for Oncology were applied to identify patients with hepatocellular carcinoma (HCC) and/or intrahepatic cholangiocarcinoma (ICC). Age-specified incidence, age-standardized incidence and mortality, 5-year relative survival, race-specific accumulative incidence and mortality, and geographic-specific accumulative mortality were calculated in different groups. Changes in trends of liver cancer incidence and mortality were assessed using Joinpoint regression. Results: The overall incidence increased significantly from 2.641/100,000 person-years in 1975 to 8.657/100,000 person-years in 2017 [average annual percent change (AAPC) =3.42, 95% confidence interval (CI): 3.28-3.62, P<0.001]. The steepest incidence rate increase was observed in the 60-69-year-old age group (AAPC =4.40, 95% CI: 4.10-4.70, P<0.001). Males exhibited a more rapid increase in cancer incidence, from 3.928/100,000 to 13.128/100,000 person-years (AAPC =3.41, 95% CI: 3.21-3.61, P<0.001), than females [from 1.642/100,000 to 4.783/100,000 person-years (AAPC =3.03, 95% CI: 2.91-3.21, P=0.001)]. The overall mortality rate increased from 2.808/100,000 person-years in 1975 to 6.648/100,000 person-years in 2017 (AAPC =2.41, 95% CI: 2.29-2.51, P<0.001). The highest mortality rate was observed in Hawaii (6.996/100,000 person-years). Conclusions: The incidence and mortality rates of HCC and ICC increased from 1975 to 2017, especially in males, non-Hispanic Blacks and older individuals. Comprehensive policy and control measures should be implemented to reduce the burden of disease, particularly through health monitoring and intervention for high-risk groups.

Single-cell RNA-sequencing technology demonstrates the heterogeneity between aged prostate peripheral and transitional zone.

BACKGROUND: Identifying cellular and functional heterogeneity within aged prostate is critical for understanding the spatial distribution of prostate diseases. METHODS: Aged human prostate peripheral zone (PZ) and transitional zone (TZ) tissues were used for single-cell RNA-sequencing. Results were validated by immunofluorescence staining. RESULTS: We found that club/hillock epithelial cells, compared with other epithelial cells, had significantly higher NOTCH signaling activity and expressed higher levels of neuro-stems but lower androgen-related genes. These cells were primarily found in the TZ and provided a stem-like niche around the proximal prostate ducts. Significant heterogeneity was observed in the aged luminal population. A novel TFF3+ luminal subtype with elevated MYC and E2F pathway activities was observed, primarily in the PZ. Further analysis revealed that epithelial cells in the TZ had higher levels of stem- and inflammation-related pathway activities but lower androgen/lineage-related pathway activities than those in the PZ. Notably, the activation of MYC, E2F and DNA repair pathways significantly increased in PZ luminal cells. In the immune landscape, we found that the immune microenvironment in the TZ is more complex and disordered with more infiltration of NK and Treg cells. CD8 T cell and macrophage in the TZ exhibit both inflammation activation and suppression phenotypes. In the stroma, the TZ had a higher fibroblast density, and fibroblasts in the TZ exhibited stronger transcriptome activity in immunity and proliferation. Ligand-receptor interaction analysis revealed that fibroblasts could contribute to a NOTCH signaling niche for club/hillock cells in the TZ and balance the prostate immune microenvironment. The activation of stem properties, inflammatory infiltration and loss of androgen/lineage activity are prominent features distinguishing the TZ from PZ. CONCLUSIONS: Our study explains the heterogeneity between the TZ and PZ of aged prostate, which may help understand the spatial distribution of prostate diseases and establish a foundation for novel target discovery.

Bone marrow mesenchymal stem cells inhibit hepatic fibrosis via the AABR07028795.2/rno-miR-667-5p axis.

BACKGROUND: The mechanism of bone marrow mesenchymal stem cells (BMSCs) in treating hepatic fibrosis remains unclear. METHODS: TGF-ß1-induced hepatic stellate cell (HSC)-T6 and CCl4-induced hepatic fibrosis rats were treated with BMSCs. HSC-T6 cell activity was determined using the cell counting kit-8 assay, and the histology change was evaluated using hematoxylin and eosin and Masson staining. The expression of fibrosis markers was determined using real-time quantitative PCR, Western blotting, and immunocytochemistry. RNA sequencing (RNA-seq) was used to screen the lncRNAs involved in the effect of BMSCs in fibrosis, and the function of fibrosis-associated lncRNA in fibrosis histology change and fibrosis marker expression was investigated. The potential miRNA target of lncRNA was predicted using R software. The interaction between lncRNA and miRNA was verified using luciferase report system and RNA immunoprecipitation (RIP) in 293T and HSC-T6 cells. RESULTS: BMSC attenuated TGF-ß1-induced HSC-T6 activation and suppressed the expression of fibrosis-associated gene (MMP2, Collagen I, and αSMA) expression at the transcription and translation levels. BMSC treatment also improves hepatic fibrosis in rats with CCl4-induced fibrosis by decreasing the expression of fibrosis-associated genes and suppressing collagen deposition in the liver. RNA-seq revealed that AABR07028795.2 (lnc-BIHAA1) was downregulated in the TGF-ß1-induced HSC-T6 after treatment with BMSCs as compared with those in TGF-ß1-induced HSC-T6, and subsequently, functional analysis showed that lnc-BIHAA1 plays a beneficial role in suppressing hepatic fibrosis. Luciferase activity assay and RIP revealed that lnc-BIHAA1 interacted with the miRNA, rno-miR-667-5p, functioning as a fibrosis phenotype suppressor in TGF-ß1-induced HSC-T6. Moreover, overexpression of rno-miR-667-5p significantly reverses the effect of lnc-BIHAA1 on HSC-T6. CONCLUSIONS: BMSC treatment suppresses hepatic fibrosis by downregulating the lnc-BIHAA1/rno-miR-667-5p signaling pathway in HSCs. Our results provide a scientific basis for establishing BMSCs as a biological treatment method for liver fibrosis.

Efficient ammonia synthesis via electroreduction of nitrite using single-atom Ru-doped Cu nanowire arrays.

Here, we report the highly active and selective electrocatalytic reduction of NO2- ions to value-added NH3 over a single-atom Ru-modified Cu nanowire array on three-dimensional copper foam (Ru-Cu NW/CF) under ambient conditions. The obtained Ru-Cu NW/CF catalyst exhibited a maximum faradaic efficiency of 94.1% and an NH3 yield up to 211.73 mg h-1 cm-2 (0.732 mmol h-1 cm-2), which was approximately five times higher than that of the Cu NW/CF catalyst.

Deep venous thrombosis in an individual with statin-exposed anti-SRP myopathy: case report and review of literature.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal muscle weakness, elvated serum muscle enzyme levels, myopathic electromyography findings, and necrotic muscle fiber with few inflammatory cell infiltration in muscle biopsies. Statins, the first line drug to lower triglyceride and cholesterol level in blood, have been reported to be associated with statins-induced necrotizing autoimmune myopathy (SINAM). Although anti-3-hydroxy-3-methylglutarylcoenzyme-A reductase (anti-HMGCR) myopathy is considered as the leading myopathy related to the statins medication, anti-signal recognition particle (SRP) myopathy were also identified in several cases with statin exposure. The risk of deep venous thrombosis (DVT) is substantially high in individuals with autoimmune inflammatory diseases. But few studies have reported the occurrence and recommendation for treatment of DVT in patients with anti-SRP myopathy. Here, we reported a statin-exposed anti-SRP myopathy individual developed DVT who was successfully treated with catheter-directed thrombolysis (CDT) and systemic anticoagulants therapy. CASE PRESENTATION: A 56-year-old Chinese female came to the outpatient room with gradually progressive bilateral lower-extremity weakness. Magnetic resonance imaging revealed myopathy in bilateral thighs. Serum anti-SRP antibody was positive. She was diagnosed with anti-SRP myopathy. When treated with corticosteroids and immunosuppressants, the patient developed mild edema and pain of left lower extremity. Angiography and ultrasound revealed diffuse venous thrombosis of left lower extremity. Therapy was initiated with CDT and lower molecular weight heparin, then switched to once daily oral rivaroxaban. Meanwhile, steroids combined with tacrolimus were also carried on while simvastatin was discontinued. One month later, patient's symptoms were resolved and only partial thrombosis in left femoral vein was remained. CONCLUSION: The prevalence of DVT in patient with anti-SRP myopathy was rare. No well-established treatment strategy is available to manage the IMNM and DVT at the same time. The systemic anticoagulants therapy combined CDT can be an effective therapeutic approach to address extensive DVT in patient with anti-SRP myopathy.

Occurrence and distribution of per- and polyfluoroalkyl substances (PFASs) in human livers with liver cancer.

Per- and polyfluoroalkyl substances (PFASs) are anthropogenic compounds that are widely accumulated in human tissues, and the liver is considered a primary target organ for PFASs exposure. The occurrence and distribution of 21 PFASs in liver tissues with tumors (n = 55) and without tumors (n = 55) are investigated in this study. Eleven perfluorinated carboxylic acids (PFCAs) and five perfluorinated sulfonic acids (PFSAs) were detected at high frequencies (45.5%-100 %), while the detection frequencies of five perfluoroalkyl phosphate (PFPAs) were relatively lower (≤29.1 %). PFSAs and PFCAs accounted for up to 82.5%-92.7 % of the total PFASs. Although it was not found to be statistically significant, the concentrations of the total PFASs were slightly higher in the tumor liver samples (mean 64.3, range 5.70-303 ng/g) than those in the non-tumor liver samples (mean 62.7, range 4.08-240 ng/g).The perfluorooctanoic acid (PFOA), perfluorotridecanoic acid (PFTrDA), and perfluorobutanesulphonate (PFBS) showed significant differences (p < 0.05) between the tumor and non-tumor liver samples, and the different distribution levels of these three PFASs may have been a consequence of oxidative stress. The total concentrations of PFASs in the three age groups were in the decreasing order of middle-aged people (45-60) > old people (>60) > young people (<45). The PFASs in females were generally lower than in males, which may have been related to women's special excretion methods (such as childbirth and breastfeeding). The results should be valuable for further mechanistic studies regarding the toxic effects of PFASs in human livers.

Stigma, Structural Vulnerability, and "What Matters Most" Among Women Living With HIV in Botswana, 2017.

Objectives. To explore whether beneficial health care policies, when implemented in the context of gender inequality, yield unintended structural consequences that stigmatize and ostracize women with HIV from "what matters most" in local culture. Methods. We conducted 46 in-depth interviews and 5 focus groups (38 individuals) with men and women living with and without HIV in Gaborone, Botswana, in 2017. Results. Cultural imperatives to bear children bring pregnant women into contact with free antenatal services including routine HIV testing, where their HIV status is discovered before their male partners'. National HIV policies have therefore unintentionally reinforced disadvantage among women with HIV, whereby men delay or avoid testing by using their partner's status as a proxy for their own, thus facilitating blame toward women diagnosed with HIV. Gossip then defines these women as "promiscuous" and as violating the essence of womanhood. We identified cultural and structural ways to resist stigma for these women. Conclusions. Necessary HIV testing during antenatal care has inadvertently perpetuated a structural vulnerability that propagates stigma toward women. Individual- and structural-level interventions can address stigma unintentionally reinforced by health care policies.