Hepatocytes direct the formation of a pro-metastatic niche in the liver.

The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Tgfb1 deficiency impairs the self-renewal capacity of murine hematopoietic stem/progenitor cells in vivo.

Transforming growth factor ß1 (TGFB1) refers to a pleiotropic cytokine exerting contrasting roles in hematopoietic stem cells (HSCs) functions in vitro and in vivo. However, the understanding of hematopoiesis in vivo, when TGFB1 is constantly deactivated, is still unclear, mainly due to significant embryonic lethality and the emergence of a fatal inflammatory condition, which makes doing these investigations challenging. Our study aims to find the specific role of TGFB1 in regulating hematopoiesis in vivo. We engineered mice strains (Vav1 or Mx1 promoter-driven TGFB1 knockout) with conditional knockout of TGFB1 to study its role in hematopoiesis in vivo. In fetal and adult hematopoiesis, TGFB1 KO mice displayed deficiency and decreased self-renewal capacity of HSCs with myeloid-biased differentiation. The results were different from the regulating role of TGFB1 in vitro. Additionally, our results showed that TGFB1 deficiency from fetal hematopoiesis stage caused more severe defect of HSCs than in the adult stage. Mechanistically, our findings identified TGFB1-SOX9-FOS/JUNB/TWIST1 signal axis as an essential regulating pathway in HSCs homeostasis. Our study may provide a scientific basis for clinical HSC transplantation and expansion.

PHF6 loss reduces leukemia stem cell activity in an acute myeloid leukemia mouse model.

Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.

Largely Pseudocapacitive Two-Dimensional Conjugated Metal-Organic Framework Anodes with Lowest Unoccupied Molecular Orbital Localized in Nickel-bis(dithiolene) Linkages.

Although two-dimensional conjugated metal-organic frameworks (2D c-MOFs) provide an ideal platform for precise tailoring of capacitive electrode materials, high-capacitance 2D c-MOFs for non-aqueous supercapacitors remain to be further explored. Herein, we report a novel phthalocyanine-based nickel-bis(dithiolene) (NiS4)-linked 2D c-MOF (denoted as Ni2[CuPcS8]) with outstanding pseudocapacitive properties in 1 M TEABF4/acetonitrile. Each NiS4 linkage is disclosed to reversibly accommodate two electrons, conferring the Ni2[CuPcS8] electrode a two-step Faradic reaction with a record-high specific capacitance among the reported 2D c-MOFs in non-aqueous electrolytes (312 F g-1) and remarkable cycling stability (93.5% after 10,000 cycles). Multiple analyses unveil that the unique electron-storage capability of Ni2[CuPcS8] originates from its localized lowest unoccupied molecular orbital (LUMO) over the nickel-bis(dithiolene) linkage, which allows the efficient delocalization of the injected electrons throughout the conjugated linkage units without inducing apparent bonding stress. The Ni2[CuPcS8] anode is used to demonstrate an asymmetric supercapacitor device that delivers a high operating voltage of 2.3 V, a maximum energy density of 57.4 Wh kg-1, and ultralong stability over 5000 cycles.

Extracellular Vesicles Derived from Human Umbilical Cord MSC Improve Vascular Endothelial Function in In Vitro and In Vivo Models of Preeclampsia through Activating Arginine Metabolism.

Endothelial cell damage is an important feature of preeclampsia (PE). Human umbilical mesenchymal stem-cell-derived extracellular vesicles (HUMSCs-derived EVs) have been shown to have therapeutic effects on a variety of diseases and tissue damage. However, the therapeutic effect of HUMSCs-derived EVs on endothelial injury in PE remains unclear. This study explored the possible mechanism of HUMSCs-derived EVs in the treatment of endothelial cell injury. Tumor necrosis factor α- and lipopolysaccharide-induced endothelial dysfunction models were used to evaluate the therapeutic effect of HUMSCs-derived EVs on endothelial injury. We further constructed PE mouse models to explore the function of HUMSCs-derived EVs in vivo. The changes of metabolites in endothelial cells after HUMSCs-derived EVs treatment were analyzed by metabolomics analysis and further validated by cell experiments. HUMSCs-derived EVs treatment can alleviate endothelial cell injury in PE, involving cell proliferation, migration, angiogenesis, and anti-inflammatory. Importantly, administration of HUMSCs-derived EVs improves hypertension and proteinuria in PE mice, alleviates kidney damage, and promotes vascularization in the placenta. Furthermore, metabolomics analysis found that the arginine metabolic pathway is activated after HUMSCs-derived EVs treatment. We also observed increased arginine level, nitric oxide content, and nitric oxide synthase activity, and further experiments proved that activating the arginine metabolic pathway could alleviate endothelial dysfunction. Our results reveal that HUMSCs-derived EVs could ameliorate PE endothelial dysfunction by activating the arginine metabolic pathway and may serve as a therapeutic method for treating PE.

Berberine alleviates intestinal barrier dysfunction in glucolipid metabolism disorder hamsters by modulating gut microbiota and gut-microbiota-related tryptophan metabolites.

BACKGROUND: Barberry plants can be considered as useful additives and functional compounds in various industries, especially in the food industry. Berberine (BBR), the most important functional compound in the barberry roots, has recently been used to treat obesity, diabetes, and atherosclerosis. Gut microbiota and the intestinal barrier play an important role in the development of glucolipid metabolism disorders (GLMDs). However, the association of gut microbiota metabolism disorder and the intestinal barrier dysfunction effect of BBR in GLMDs remains elusive. RESULTS: The results showed that administration of BBR could increase the number of colonic glands and goblet cell mucus secretion, improve the intestinal barrier function, and reduce the serum glycolipid level in GLMD hamsters. Interestingly, BBR was metabolized into 12 metabolites by gut microbiota, and the main metabolic pathways were oxidation, demethylation, and hydrogenation. In addition, BBR significantly improved the species diversity and uniformity of gut microbiota and promoted the proliferation of beneficial microbiota. Furthermore, the levels of tryptophan metabolites, such as indole, indole-3-acetamide, indole-3-acetaldehyde, indole-3-pyruvic acid, and indole-3-acetic acid were significantly altered by BBR. Both the intestinal tight junction proteins and intestinal immune factors were altered by BBR. CONCLUSION: BBR could alleviate intestinal barrier dysfunction of GLMDs by modulating gut microbiota and gut-microbiota-related tryptophan metabolites, which may be one of the pharmacological mechanisms for the treatment of GLMDs. © 2022 Society of Chemical Industry.

The effects of evidence-based nursing interventions on pressure ulcers in patients with stroke: a meta-analysis.

This meta-analysis evaluated the role of evidence-based nursing interventions in preventing pressure ulcers in patients with stroke. Computer systems were used to retrieve randomised controlled trials (RCTs) on evidence-based nursing interventions for patients with stroke and comorbid pressure ulcers from PubMed, EMBASE, Scopus, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Data from database inception until April 2023. Two researchers independently screened the literature, extracted the data and evaluated the quality of the included studies according to the inclusion and exclusion criteria. RevMan 5.4 software was used for the meta-analysis. A total of 23 articles with results on 2035 patients were included, with 1015 patients in the evidence-based nursing group and 1020 patients in the routine nursing group. The meta-analysis results showed that evidence-based nursing interventions significantly reduced the incidence of pressure ulcers in patients with stroke (5.22% vs. 22.84%, odds ratio [OR]: 0.18, 95% confidence interval [CI]: 0.13-0.24, p < 0.001), delayed the onset of pressure ulcers (standardised mean difference [SMD]: 3.41, 95% CI: 1.40-5.42, p < 0.001) and improved patient quality of life (SMD: 2.95, 95% CI: 2.35-3.56, p < 0.001). Evidence-based nursing interventions are effective at preventing pressure ulcers in patients with stroke, delaying the onset of pressure ulcers and improving their quality of life. Evidence-based nursing should be promoted for patients with stroke. However, owing to differences in sample size between studies and the methodological inadequacies of some studies, these results should be verified by large, high-quality RCTs.

Effects of bundle-care interventions on pressure ulcers in patients with stroke: A meta-analysis.

We conducted a meta-analysis to assess the effects of bundle-care interventions on pressure ulcers in patients with stroke to provide a basis for clinical work. Randomised controlled trials on the effects of bundle-care interventions in patients with stroke were identified using computerised searches of the PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, VIP and Wanfang databases, from the time of inception of each database to July 2023, supplemented by manual literature searches. Two researchers independently retrieved and screened the articles, extracted the data and evaluated the quality of the included studies. After reaching consensus, meta-analysis was performed using RevMan 5.4. Twenty-four papers were included, involving 3330 patients of whom 1679 were in the intervention group and 1651 were in the control group. The results showed that, compared with standard care, bundle-care interventions significantly reduced the incidence of pressure ulcers (3.28% vs. 14.84%, odds ratio [OR]: 0.19, 95% confidence interval [CI]: 0.14-0.26, p < 0.001), and aspiration (5.60% vs. 18.84%, OR: 0.25, 95% CI: 0.17-0.39, p < 0.001), and improved patient satisfaction with nursing care (96.59% vs. 84.43%, OR. 5.45, 95% CI: 3.76-7.90, p < 0.001). Current evidence suggests that care bundles are significantly better than conventional nursing measures in preventing pressure ulcers and aspiration, and improving patient satisfaction with nursing care in patients with stroke, and are worthy of clinical promotion and application.

GPAT3 deficiency alleviates insulin resistance and hepatic steatosis in a mouse model of severe congenital generalized lipodystrophy.

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy and is caused by loss-of-function mutations in the BSCL2/seipin gene. Exactly how seipin may regulate adipogenesis remains unclear. A recent study in vitro suggested that seipin may function to inhibit the activity of glycerol-3-phosphate acyltransferases (GPATs), and increased GPAT activity may be responsible for the defective adipogenesis under seipin deficiency. Here we generated Seipin-/-Gpat3-/- mice, which had mild but significant recovery of white adipose tissue mass over Seipin-/- mice. The mass of brown adipose tissue (BAT) of the Seipin-/-Gpat3-/- mice was almost completely restored to normal level. Importantly, the Seipin-/-Gpat3-/- mice showed significant improvement in liver steatosis and insulin sensitivity over Seipin-/- mice, which is attributable to the increased BAT mass and to the enhanced browning of the subcutaneous fat of the Seipin-/-Gpat3-/- mice. Together, our results establish a functional link between seipin and GPAT3 in vivo and suggest that GPAT inhibitors may have beneficial effects on BSCL2 patients.

Integrated lipidomics and network pharmacology analysis to reveal the mechanisms of berberine in the treatment of hyperlipidemia.

BACKGROUND: Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma Coptis, is widely used in the treatment of hyperlipidemia (HLP) in China. At present, the efficacy of BBR against HLP is relatively clear, but there are few researches on its mechanism. The purpose of this study was to evaluate the potentially beneficial role of BBR in HLP hamster models, as well as investigate its possible mechanisms and potential lipid biomarkers in combination with network pharmacology. METHODS: HLP hamster model was induced by high-fat diet. Hematoxylin-eosin (HE) staining was used to determine the degree of hepatic pathological injury. Liquid chromatography-mass spectrometry was used to analyze lipid metabolism profiles of liver samples, and multiple statistical analysis methods were used to screen and identify lipid biomarkers. The possible molecular mechanism was unraveled by network pharmacology. RESULTS: The results showed that 13 metabolites, including CE (16:1), HexCer (D18:1/19:0) and LPC (O-22:0) were biomarkers of BBR regulation. CHPT1, PLA2G4A, LCAT and UGCG were predicted as the lipid-linked targets of BBR against HLP, whilst glycerophospholipid and sphingolipid metabolism were the key pathways of BBR against HLP. CONCLUSIONS: In summary, this study provides new insights into the protective mechanism of BBR against HLP through network pharmacology and lipidomic approaches.

Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.

[Figure: see text].

Characterization and Genomic Analysis of Bacteriophage vB_KpnM_IME346 Targeting Clinical Klebsiella pneumoniae Strain of the K63 Capsular Type.

A Klebsiella pneumoniae bacteriophage (vB_KpnM_IME346) was isolated from a hospital sewage sample. This bacteriophage specifically infects a clinical K. pneumoniae strain with a K63 capsular polysaccharide structure. The phage genome was evaluated by next-generation sequencing, which revealed a linear double-stranded DNA genome consisting of 49,482 base pairs with a G+C content of 49.1%. The latent period of vB_KpnM_IME346 was shown to be 20 min, and the burst size was 25-30 pfu (plaque-forming units)/infected cell. Transmission electron microscopy and phylogenetic analysis showed that the JD001-like phage belongs to the genus Jedunavirus of the family Myoviridae. The newly isolated vB_KpnM_IME346 shows infectivity in the clinical host K. pneumoniae KP576 strain, indicating that it is a promising alternative to antibacterial agents for removing K. pneumoniae from patients.

DSCMF: prediction of LncRNA-disease associations based on dual sparse collaborative matrix factorization.

BACKGROUND: In the development of science and technology, there are increasing evidences that there are some associations between lncRNAs and human diseases. Therefore, finding these associations between them will have a huge impact on our treatment and prevention of some diseases. However, the process of finding the associations between them is very difficult and requires a lot of time and effort. Therefore, it is particularly important to find some good methods for predicting lncRNA-disease associations (LDAs). RESULTS: In this paper, we propose a method based on dual sparse collaborative matrix factorization (DSCMF) to predict LDAs. The DSCMF method is improved on the traditional collaborative matrix factorization method. To increase the sparsity, the L2,1-norm is added in our method. At the same time, Gaussian interaction profile kernel is added to our method, which increase the network similarity between lncRNA and disease. Finally, the AUC value obtained by the experiment is used to evaluate the quality of our method, and the AUC value is obtained by the ten-fold cross-validation method. CONCLUSIONS: The AUC value obtained by the DSCMF method is 0.8523. At the end of the paper, simulation experiment is carried out, and the experimental results of prostate cancer, breast cancer, ovarian cancer and colorectal cancer are analyzed in detail. The DSCMF method is expected to bring some help to lncRNA-disease associations research. The code can access the https://github.com/Ming-0113/DSCMF website.

Combination of optimized tissue engineering bone implantation with heel-strike like mechanical loading to repair segmental bone defect in New Zealand rabbits.

In this study, effects of combining optimized tissue engineering bone (TEB) implantation with heel-strike like mechanical loading to repair segmental bone defect in New Zealand rabbits were investigated. Physiological characteristics of bone marrow mesenchymal stem cells (BMMSCs), compact bone cells (CBCs), and bone marrow and compact bone coculture cells (BMMSC-CBCs) were compared to select the optimal seed cells for optimized TEB construction. Rabbits with segmental bone defects were treated in different ways (cancellous bone scaffold for group A, cancellous bone scaffold and mechanical loading for group B, optimized TEB for group C, optimized TEB and mechanical loading for group D, n = 4), and the bone repair were compared. BMMSC-CBCs showed better proliferation capacity than CBCs (p < 0.01) and stronger osteogenic differentiation ability than BMMSCs (p < 0.05). Heel-strike like mechanical loading improved proliferation and osteogenic differentiation ability and expression levels of TGFß1 as well as BMP2 of seed cells in vitro (p < 0.05). At week 12 post-operation, group D showed the best bone repair, followed by groups B and C, while group A finished last (p < 0.05). During week 4 to 12 post-operation, group D peaked in terms of expression levels of TGFß1, BMP2, and OCN, followed by groups B and C, while group A finished last (p < 0.05). Thus, BMMSC-CBCs showed good proliferation and osteogenic differentiation ability, and they were thought to be better as seed cells than BMMSCs and CBCs. The optimized TEB implantation combined with heel-strike like mechanical loading had a synergistic effect on bone defect healing, and enhanced expression of TGFß1 and BMP2 played an important role in this process.

Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress-Brief Report.

OBJECTIVE: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT-/-) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT-/- hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (<8 months) and aged (>16 months) male and female wild-type and LCAT-/- hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT-/- hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT-/- hamsters, the lesion areas at the aortic roots were ≈40×104 µm3 in males and 18×104 µm3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 µmol/L in males and 30 µmol/L in females, which are significantly associated with the atherosclerotic lesions. CONCLUSIONS: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT-/- hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

Detection of antibiotics in the urine of children and pregnant women in Jiangsu, China.

Exposure to low concentrations of antibiotics links to multiple health hazards, such as drug resistance of bacteria, and childhood obesity. In this study, seven antibiotics were measured in the urine of 107 children and 126 pregnant women in Jiangsu Province by ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). The overall urinary antibiotics detection rate was 38.6%. Most (98.3%) of the participants' antibiotics concentrations were no more than 10 ng/mL. Children had a significantly higher detection rate than pregnant women (47.7% vs. 31.0%, P = 0.009), as well as the concentration (95th percentile: 6.49 vs. 4.08 ng/mL, P = 0.002). The detection rates of individual antibiotics ranged from 0.4% to 15.0%, and the concentrations ranged from lower than the limit of detection (LOD) through up to 31.96 ng/mL individually. Two or more antibiotics were detected in 11.2% of the urines. Tetracyclines were more frequently detected than phenicols (30.9% vs.12.4%). Oxytetracycline was the most frequently detected (15.0%). Multivariate logistic regression showed that consuming puffed food every day was associated with a significantly increased likelihood of detection, and higher concentration of overall antibiotics, and of doxycycline. Children were more likely to be detected of doxycycline and florfenicol, and to have elevated concentration of doxycycline, compared with pregnant women. This study highlights the relatively heavier antibiotics exposure in children, and a possible impact of puffed food on it, which needs to be warranted in future studies.

Isolation, characterization and biocontrol efficacy of a T4-like phage virulent to multidrug-resistant Enterobacter hormaechei.

Enterobacter hormaechei is an important emerging pathogen, often exhibiting resistance to multiple clinically important antibiotics. In this study, E. hormaechei was found, for the first time, to be lethal to fish. Bacteriophages are considered potential treatments for bacterial infections. The lytic phage vB_EhoM-IME523 (abbreviated 'IME523') infecting multidrug-resistant E. hormaechei was isolated from hospital sewage. IME523 exhibits T4-like morphology, including a prolate icosahedral head 110 ± 1.89 nm (mean ± SD) long and 82 ± 0.75 nm wide, and a contractile tail of ca. 110 ± 0.91 nm in length. The complete genome length of phage IME523 is 172763 bp, with a G + C content of 39.97%. The whole genome sequence of IME523 has a 93.10% average nucleotide identity (ANI) and a 53.3% in silico DNA-DNA hybridization (isDDH) value with the closest-related Enterobacter phage vB_EclM_CIP9 ('CIP9'). ANI and isDDH values between IME523 and other phages were lower than 78 and 22%, respectively. IME523 and CIP9 formed a monophyletic branch in a phylogenetic tree based on the terminase large subunit, DNA polymerase protein and whole genome phylogenetic analysis. Results suggest that IME523 is a novel species in the subfamily Tevenvirinae and forms a novel genus together with CIP9. No IME523 open reading frame was found to be associated with virulence factors or antibiotic resistance genes. IME523 showed promising protection to zebrafish and brocade carp against E. hormaechei challenge.

Calcitriol inhibits COX-1 and COX-2 expressions of renal vasculature in hypertension: Reactive oxygen species involved?

Vitamin D modulates about 3% human gene transcription besides the classical action on calcium/phosphorus homeostasis. The blood pressure-lowing and other protective action on cardiovascular disease have been reported. The present study aims to examine whether COX-1 and COX-2 were implicated in endothelial dysfunction in hypertension and calcitriol, an active form of vitamin D preserved endothelial function through regulating COX expression. Isometric study demonstrated the impaired endothelium-dependent relaxation (EDR) in renal arteries from spontaneously hypertensive rats were reversed by 12 h-calcitriol treatment and COX-1 and COX-2 inhibitors. Combined uses of COX-1 and COX-2 inhibitor induced more improved relaxations. Exaggerated expressions of COX-1 and COX-2 in renal artery from SHR were inhibited by 12 h-administration of calcitriol, NADPH oxidase inhibitor DPI, or reactive oxygen species (ROS) scavenger tempol. Furthermore, in normotensive WKY rats, calcitriol prevents against the blunted EDR in renal arteries by 12 h-Ang II exposure, with similar improvements by COX-1 and COX-2 inhibitors. Accordingly, increased COX-1 and COX-2 expressions by Ang II exposure were corrected by losartan, DPI, or tempol. Studies on human renal artery also revealed the beneficial action of calcitriol is mediated by suppressing COX-1 and COX-2 expressions, dependent on vitamin D receptor (VDR) activation. Taken together, our findings showed that COX-1 and COX-2 are positively involved in the renovascular dysfunction in hypertension and via VDR, calcitriol benefits renovasular function by suppressing COX-1 and COX-2 expressions. Furthermore, ROS is involved in the COX-1 and COX-2 up-regulations of renal arteries, maybe serving as a mediator in the inhibitory action of calcitriol on COX expression.

Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.

Characteristics and complete genome sequence of the virulent Vibrio alginolyticus phage VAP7, isolated in Hainan, China.

A novel Vibrio alginolyticus phage, VAP7, was isolated from seawater collected from Sanya, Hainan province, China. Whole-genome sequencing analysis revealed that phage VAP7 has a linear, double-stranded DNA genome of 144,685 bp with an average G+C content of 41.9% and a high degree of sequence similarity to Vibrio phage VP-1. Annotation results identified 193 open reading frames and one transfer RNA-encoding gene in the phage genome. The morphology and the results of phylogenetic analysis suggest that VAP7 should be classified as a new member of the family Ackermannviridae. Moreover, phage VAP7 grew over a wide pH (5.0-10.0) and temperature (4-40 °C) range. Host-range experiments revealed that VAP7 could infect 31 Vibrio alginolyticus strains. Thus, VAP7 infecting Vibrio alginolyticus strains represents a potential new candidate for use in phage therapy.