Fabrication of close-contact S-scheme Cr2Bi3O11-Bi2O3/Fe3O4@porous carbon microspheres based on in-situ reaction: Enhanced photo-Fenton wastewater treatment.

Low photo-induced carrier recombination rate, exceptional light absorption, and advantageous recycling performance are crucial attributes of semiconductor photocatalyst for wastewater purification. Herein, based on in-situ reaction, close-contact S-scheme bismuth chromate/bismuth oxide/ferroferric oxide@porous carbon microspheres (Cr2Bi3O11-Bi2O3/Fe3O4@PCs) (F-CBFP) was fabricated using alginates as precursor. Due to the abundance of functional groups on the porous carbon (PCs), Bi2O3 and Cr2Bi3O11 nanoparticles (NPs) are in situ deposited onto the highly conductive 3D magnetic porous Fe3O4@PCs microsphere surface, which not only form tight interfacial contacts and reduces interfacial potential barriers but also prevent agglomeration or shedding of the NPs during photocatalytic reactions. Moreover, density functional theory (DFT) calculations further confirm that the formation of a robust built-in electric field (BIEF) within F-CBFP prompts photo-induced electrons in the conduction band (CB) of Bi2O3 to combine with holes in the valence band (VB) of Cr2Bi3O11, effectively constructing a S-scheme heterojunction system. Also, Fe3O4 can act as a Fenton catalyst, activating the H2O2 generated by Cr2Bi3O11 under illumination. In wastewater treatment, the obtained F-CBFP shows remarkable photo-Fenton degradation (towards methyl orange (97.8 %, 60 min) and tetracycline hydrochloride (95.3 %, 100 min)) and disinfection performance (100 % E. coli inactivation), and exceptional cyclic stability.

Apatinib remodels the immunosuppressive tumor ecosystem of gastric cancer enhancing anti-PD-1 immunotherapy.

Apatinib has been shown to clinically enhance anti-PD-1 immunotherapy for advanced gastric cancer (GC). However, the complexity of GC immunosuppression remains a challenge for precision immunotherapy. Here, we profile the transcriptomes of 34,182 single cells from GC patient-derived xenografts of humanized mouse models treated with vehicle, nivolumab, or nivolumab plus apatinib. Notably, excessive expression of CXCL5 in the CellCycle malignant epithelium, induced by anti-PD-1 immunotherapy and blocked by combined apatinib treatment, is found to be a key driver of tumor-associated neutrophil (TAN) recruitment in the tumor microenvironment through the CXCL5/CXCR2 axis. We further show that the protumor TAN signature is associated with anti-PD-1 immunotherapy-related progressive disease and poor cancer prognosis. Molecular and functional analyses in cell-derived xenograft models confirm the positive in vivo therapeutic effect of targeting the CXCL5/CXCR2 axis during anti-PD-1 immunotherapy. Altogether, our study elucidates the GC immunosuppressive landscape in anti-PD-1 immunotherapy and highlights potential targets for overcoming checkpoint immunotherapy resistance.

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients.

BACKGROUND: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. METHODS: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). RESULTS: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment. CONCLUSIONS: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.

Case Report: Prenatal Diagnosis and Treatment of Fetal Autoimmune-Associated First-Degree Atrioventricular Block: First Report From China.

Background: The rapid progression from fetal first-degree atrioventricular block (AVB) to third-degree AVB had been reported. However, how to define fetal first-degree AVB with proper technique and the necessity of the treatment in utero for fetal autoimmune-associated first-degree AVB are still controversial. Purpose: To explore the diagnosis and the effect of treatment for fetal first-degree AVB. Cases Presentation: Four pregnant women with positive autoantibodies anti-SSA/Ro were admitted into our hospital with complaints of rapid prolonged atrioventricular (AV) intervals of their fetuses. Fetal AV intervals were re-measured by tissue Doppler imaging (TDI) from the onset of atrial contraction to ventricular systole (Aa-Sa), which were 170 ms (case 1-twin A), 160 ms (case 1-twin B), 163 ms (case 2) and 172 ms (case 3) and 170 ms (case 4), respectively. The histories of medication usage or infection during gestation were denied. Amniotic fluid genetic screenings and virological tests were negative in all cases. No structural cardiac disorders were found and the cardiovascular profile scores were 10 for each fetus. Oral dexamethasone (initial dose of 4.5 mg daily) and hydroxychloroquine (200 mg bid) plus weekly follow-up surveillance were suggested. The dosage of dexamethasone was adjusted according to the changes of the AV intervals and fetal development of biparietal diameters (BPD) and femur lengths (FL). All fetal AV intervals were controlled well. Maternal and fetal adverse effects were noted as diabetes in 1 mother and growth retardation in all fetuses. All fetuses were delivered via cesarean section at 35+4, 37, 38, and 37+1 gestational weeks, with 10 scores of Apgar score. Postnatally, positive anti-SSA/Ro was found in all neonates. However, there were no clinical or laboratory evidence of neonatal lupus syndrome. No abnormal signs were found on postnatal electrocardiogram and echocardiography for all neonates. With a follow-up of 8-53 months, there was no progression of disease and all infants demonstrated normal physical, mental, and motor development. Conclusion: Prenatal treatment for fetal autoimmune-associated first-degree AVB could be an alternative. Strict surveillance and timely adjustment of the treatment according to the conditions of the mother and the fetus are indicated. Further studies are necessary to prove our concept.

Inhibition of Bcl6b promotes gastric cancer by amplifying inflammation in mice.

BACKGROUND: Chronic gastritis has been demonstrated to be a key cause of gastric cancer (GC), and control of gastric inflammation is regarded as an effective treatment for the clinical prevention of gastric carcinogenesis. However, there remains an unmet need to identify the dominant regulators of gastric oncogenesis-associated inflammation in vivo. METHODS: The mouse model for the study of inflammation-associated GC was induced by Benzo[a]pyrene (BaP) intragastric administration in Bcl6b-/- and wildtype mice on a C57BL/6 background. 5-Aza-2'-deoxycytidine (5-Aza), the demethylation drug, was intraperitoneally injected to restore Bcl6b expression. Human GC tissue array was used to analyse patient survival based on BCL6B and CD3 protein expression. RESULTS: Bcl6b was gradually downregulated by its own promoter hypermethylation in parallel to an increasing inflammatory response during the progression of BaP-induced gastric carcinogenesis in mice. Moreover, knockout of Bcl6b dramatically worsened the severity of gastric cancer and aggravated the inflammatory response in the BaP-induced mice GC model. Re-activation of Bcl6b by 5-Aza impeded inflammatory amplification and BaP-induced GC development, prolonging survival time in wildtype mice, whereas no notable curative effect occurred in Bcl6b-/- mice with 5-Aza treatment. Finally, significant negative correlations were detected between the mRNA levels of BCL6B and inflammatory cytokines in human GC tissues; patients harbouring BCL6B-negetive and severe-inflammation GC tumours were found to exhibit the shortest survival time. CONCLUSIONS: Epigenetic inactivation of Bcl6b promotes gastric cancer through amplification of the gastric inflammatory response in vivo and offers a new approach for GC treatment and regenerative medicine.

A Novel c.676_677insG PHOX2B Mutation in Congenital Central Hypoventilation Syndrome.

ABSTRACT: Paired-like homeobox (PHOX)2B is considered to be the causative gene of congenital central hypoventilation syndrome (CCHS), a dominant genetic disorder that results in abnormal central respiratory control with resulting hypoventilation during sleep. In this study, we report a novel c.676_677insG (p.Ala226fs) mutation in a patient with severe CCHS, and we evaluated the function of this mutation. The mutation reduced the translation of the mutant PHOX2B protein and impaired its ability to activate the PHOX2A promoter, due to a haploinsufficiency effect. The mutant PHOX2B was able to interact with wildtype PHOX2B, resulting in retention of PHOX2B on the nuclear membrane, which may impair the normal function of the nuclear membrane, and leading to cellular morbidity. Our study provides useful information for the functional studies of PHOX2B and understanding the pathogenesis of CCHS, and thus is beneficial for the prognosis of, genetic counseling for, and development of pharmaceuticals for PHOX2B-associated diseases.

Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/ß-catenin-Lin28/let7-PDK1 cascade.

BACKGROUND: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. METHODS: Gene expression pattern of NPC cells were used to test associations between Chibby and ß-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, ß-Catenin, and PDK1 by immunostaining. RESULTS: We observed that Chibby, a ß-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/ß-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/ß-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/ß-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/ß-Catenin signaling and PDK1. CONCLUSIONS: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/ß-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment.

Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer.

Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.

Aldose reductase interacts with AKT1 to augment hepatic AKT/mTOR signaling and promote hepatocarcinogenesis.

Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis. Conversely, AR knockdown suppressed lactate formation and inflammation. Using cultured liver cancer cells, we also demonstrated that AKT1 was essential for AR-induced dysregulation of AKT/mTOR signaling, metabolic reprogramming, antioxidant defense, and inflammatory responses. These findings suggest that aberrantly overexpressed/over-activated hepatic AR promotes HCC development at least in part by interacting with oncogenic AKT1 to augment AKT/mTOR signaling. Inhibition of AR and/or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.