GPMeta: a GPU-accelerated method for ultrarapid pathogen identification from metagenomic sequences.

Metagenomic sequencing (mNGS) is a powerful diagnostic tool to detect causative pathogens in clinical microbiological testing owing to its unbiasedness and substantially reduced costs. Rapid and accurate classification of metagenomic sequences is a critical procedure for pathogen identification in dry-lab step of mNGS test. However, clinical practices of the testing technology are hampered by the challenge of classifying sequences within a clinically relevant timeframe. Here, we present GPMeta, a novel GPU-accelerated approach to ultrarapid pathogen identification from complex mNGS data, allowing users to bypass this limitation. Using mock microbial community datasets and public real metagenomic sequencing datasets from clinical samples, we show that GPMeta has not only higher accuracy but also significantly higher speed than existing state-of-the-art tools such as Bowtie2, Bwa, Kraken2 and Centrifuge. Furthermore, GPMeta offers GPMetaC clustering algorithm, a statistical model for clustering and rescoring ambiguous alignments to improve the discrimination of highly homologous sequences from microbial genomes with average nucleotide identity >95%. GPMetaC exhibits higher precision and recall rate than others. GPMeta underlines its key role in the development of the mNGS test in infectious diseases that require rapid turnaround times. Further study will discern how to best and easily integrate GPMeta into routine clinical practices. GPMeta is freely accessible to non-commercial users at https://github.com/Bgi-LUSH/GPMeta.

Chirality-Dependent Valley Polarization in Magnetic van der Waals Heterostructures via Spin-Selective Charge Transfer.

Magnetic proximity interaction provides a promising route to manipulate the spin and valley degrees of freedom in van der Waals heterostructures. Here, we report a control of valley pseudospin in the WS2/MoSe2 heterostructure by utilizing the magnetic proximity effect of few-layered CrBr3 and, for the first time, observe a substantial difference in valley polarization of intra/interlayer excitons under different circularly polarized laser excitations, referred to as chirality-dependent valley polarization. Theoretical and experimental results reveal that the spin-selective charge transfer between MoSe2 and CrBr3, as well as between MoSe2 and WS2, is mostly responsible for the chiral feature of valley polarization in comparison with the proximity exchange field. This means that a long-distance manipulation of exciton behaviors in multilayer heterostructures can be achieved through spin-selective charge transfer. This work marks a significant advancement in the control of spin and valley pseudospin in multilayer structures.

circ_PPAPDC1A promotes Osimertinib resistance by sponging the miR-30a-3p/ IGF1R pathway in non-small cell lung cancer (NSCLC).

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.

Effects of altitude on thyroid disorders according to Chinese three-rung, ladder-like topography: national cross-sectional study.

BACKGROUND: Chinese topography appears a three-rung ladder-like distribution of decreasing elevation from northwest to southeast, which is divided by two sloping edges. Previous studies have reported that prevalence of thyroid diseases differed by altitude, and geographical factors were associated with thyroid disorders. To explore the association between three-rung ladder-like regions and thyroid disorders according to unique Chinese topographic features, we conducted an epidemiological cross-sectional study from 2015-2017 that covered all 31 mainland Chinese provinces. METHODS: A total of 78,470 participants aged ≥ 18 years from a nationally representative cross-sectional study were included. Serum thyroid peroxidase antibody, thyroglobulin antibody, and thyroid-stimulating hormone levels; urine iodine concentration; and thyroid volume were measured. The three-rung ladder-like distribution of decreasing elevation from northwest to southeast in China was categorized into three topographic groups according to elevation: first ladder, > 3000 m above sea level; second ladder, descending from 3000-500 m; and third ladder, descending from 500 m to sea level. The third ladder was further divided into groups A (500-100 m) and B (< 100 m). Associations between geographic factors and thyroid disorders were assessed using linear and binary logistic regression analyses. RESULTS: Participants in the first ladder group were associated with lower thyroid peroxidase (ß = -4.69; P = 0.00), thyroglobulin antibody levels (ß = -11.08; P = 0.01), and the largest thyroid volume (ß = 1.74; P = 0.00), compared with the other groups. The second ladder group was associated with autoimmune thyroiditis (odds ratio = 1.30, 95% confidence interval [1.18-1.43]) and subclinical hypothyroidism (odds ratio = 0.61, 95%confidence interval [0.57-0.66]) (P < 0.05) compared with the first ladder group. Group A (third ladder) (500-100 m) was associated with thyroid nodules and subclinical hypothyroidism (P < 0.05). Furthermore, group B (< 100 m) was positively associated with autoimmune thyroiditis, thyroid peroxidase and thyroglobulin antibody positivity, and negatively associated with overt hypothyroidism, subclinical hypothyroidism, and goiter compared with the first ladder group(P < 0.05). CONCLUSION: We are the first to investigate the association between different ladder regions and thyroid disorders according to unique Chinese topographic features. The prevalence of thyroid disorders varied among the three-rung ladder-like topography groups in China, with the exception of overt hyperthyroidism.

Dual antiplatelet therapy is associated with favorable outcome in acute minor stroke with an onset-to-door time beyond 24 h.

BACKGROUND/PURPOSE: In patients with noncardioembolic acute minor ischemic stroke (AMIS), dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel within 24 h after stroke onset was more effective than aspirin alone. This study investigated the efficacy and safety of DAPT in AMIS patients with an onset-to-door time (OTDT) of more than 24 h. METHODS: This was a retrospective analysis of a prospective stroke registry from 2015 to 2021. Patients with AMIS and an OTDT within seven days were classified into the Early (≤24 h) and Late groups (>24 h) according to the time of antiplatelet administration after stroke onset. RESULTS: In total, 691 patients were identified. Of these, 446 (64.5%) and 245 (35.5%) patients were classified into the Early and Late groups, respectively. The rates of recurrent infarction and symptomatic intracranial hemorrhage at 90 days were similar between the single antiplatelet therapy (SAPT) and DAPT subgroups in both the Early and Late groups. More patients in the DAPT subgroup had a favorable outcome (modified Rankin scale of 0-1) at 90 days in both Early (84.2% versus 75.0%, p = 0.016) and Late (88.2% versus 76.9%, p = 0.040) groups. DAPT was independently associated with a favorable outcome in both the Early (odds ratio, 1.95; 95% CI, 1.15-3.32; p = 0.013) and Late (odds ratio, 2.72; 95% CI, 1.14-6.48; p = 0.024) groups. CONCLUSION: In patients with AMIS and an OTDT of more than 24 h, DAPT was associated with a favorable outcome at 90 days.

MBL2 polymorphism may be a protective factor of autoimmune thyroid disease susceptibility.

Genetic susceptibility is an essential pathogenetic mechanism in autoimmune thyroid disease (AITD). MBL2 gene polymorphisms have been shown to play a vital role in the pathogenesis of multiple autoimmune disorders, but its contribution to AITD is unclear. The aim of this study was to assess the linkage between MBL2 gene polymorphisms and AITD susceptibility in a Chinese Han population. One thousand seven hundred sixty seven subjects consisting of 965 AITD patients and 802 controls from a Chinese Han population were enrolled in the case-control study. Four common single-nucleotide polymorphisms (SNPs) in the MBL2 gene were tested using high-throughput sequencing technology for sequence-based SNP genotyping. The allele and genotype distribution results showed that the minor alleles of rs198266, rs10824793, and rs4935046 were significantly lower in Hashimoto's thyroiditis (HT) patients than in healthy controls. In further genetic model analysis, the dominant models of rs1982266, rs10824793, and rs4935046 for MBL2 in the AITD group exhibited a lower risk of morbidity. Finally, we discovered that haplotype AAGC was associated with Graves' disease (GD), while AGC was associated with HT. Our study provides strong evidence for a genetic correlation between MBL2 and AITD, and the polymorphism of the MBL2 gene may be a protective factor for AITD, especially for HT. These findings can advance our understanding of the etiology of AITD, as well as provide guidance for prevention and intervention toward AITD.

In situ Self-Catalyzed Growth of Manganese-Embedded 3D Flakes-Coated Carbon Rod as an Efficient Oxygen-Reduction Reaction Catalyst of Zinc-Air Batteries.

The in situ self-catalyzed growth of manganese-embedded 3D flakes-coated carbon rods (GFC) as an efficient oxygen-reduction reaction (ORR) catalyst of Zinc-air batteries is described for the first time. By optimizing the amount of Mn in the precursor, a series of 3D graphene-like flakes-coated carbon rods were synthesized. GFC with a doping amount of Mn of 10 % (GFC-10) exhibits excellent ORR performance with an onset potential of 0.94 V (vs. reversible hydrogen electrode). The Zinc-air battery is constructed with GFC-10 as the cathode catalyst, and it exhibits a peak power density of 128.9 mW cm-2 and a cycling stability of 75 h at a current density of 10 mA cm-2 , which are superior to the commercial 20 wt% Pt/C-based Zinc-air battery. Interestingly, the introduction of Mn facilitates the self-catalyzed growth of carbon rods, and the change of Mn amount can effectively regulate the morphology of materials. The improved ORR performance of the catalyst is ascribed to the synergistic effect of unique hierarchical porous structure, high-charge transport capacity, abundant carbon defects/edges and Mn-Nx sites. This research provides a new avenue to fabricating highly active Mn-based electrocatalysts for renewable energy systems.

cPKCγ Inhibits Caspase-9-Initiated Neuronal Apoptosis in an Ischemia Reperfusion Model In Vitro Through p38 MAPK-p90RSK-Bad Pathway.

Strokes are one of the leading causes of death and disability in the world. Previously we have found that conventional protein kinase Cγ (cPKCγ) plays neuroprotective role in ischemic strokes. Further, we found that cPKCγ knockdown increased the level of cleaved (cl)-Caspase-3. However, the precise mechanisms underlying cPKCγ-mediated neuronal death remain unclear. To this end, a model incorporating 1 h oxygen-glucose deprivation/24 h reoxygenation (1 h OGD/24 h R) was established in cortical neurons. We found that cPKCγ knockdown remarkably increased neuronal death after OGD. We also found that cPKCγ knockdown increased the level of cl-Caspase-3 through the upstream initiators Capsases-9 (not Caspase-8/12) in OGD-treated neurons. Overexpression of cPKCγ could decrease neuronal death and cl-Caspase-3 and -9 levels. Moreover, cPKCγ knockdown further reduced the phosphorylation levels of p38 MAPK, p90RSK, and Bad. In addition, the protein levels of Bcl-2 and Bcl-xl were decreased after cPKCγ knockdown, whereas that of Bax was increased. In conclusion, our results suggest that cPKCγ partly alleviates ischemic injury through activating the p38 MAPK-p90RSK-Bad pathway and inhibiting Caspase-9 initiated apoptosis. This may have potential as a therapeutic target for ischemic stroke.

PDK inhibition promotes glucose utilization, reduces hepatic lipid deposition, and improves oxidative stress in largemouth bass (Micropterus salmoides) by increasing pyruvate oxidative phosphorylation.

In omnivorous fish, the pyruvate dehydrogenase kinases (PDKs)-pyruvate dehydrogenase E1α subunit (PDHE1α) axis is essential in the regulation of carbohydrate oxidative catabolism. Among the existing research, the role of the PDKs-PDHE1α axis in carnivorous fish with poor glucose utilization is unclear. In the present study, we determined the effects of PDK inhibition on the liver glycolipid metabolism of largemouth bass (Micropterus salmoides). DCA is a PDK-specific inhibitor that inhibits PDK by binding the allosteric sites. A total of 160 juvenile largemouth bass were randomly divided into two groups, with four replicates of 20 fish each, fed a control diet and a control diet supplemented with dichloroacetate (DCA) for 8 weeks. The present results showed that DCA supplementation significantly decreased the hepatosomatic index, triglycerides in liver and serum, and total liver lipids of largemouth bass compared with the control group. In addition, compared with the control group, DCA treatment significantly down-regulated gene expression associated with lipogenesis. Furthermore, DCA supplementation significantly decreased the mRNA expression of pdk3a and increased PDHE1α activity. In addition, DCA supplementation improved glucose oxidative catabolism and pyruvate oxidative phosphorylation (OXPHOS) in the liver, as evidenced by low pyruvate content in the liver and up-regulated expressions of glycolysis-related and TCA cycle/OXPHOS-related genes. Moreover, DCA consumption decreased hepatic malondialdehyde (MDA) content, enhanced the activities of superoxide dismutase (SOD), and increased transforming growth factor beta (tgf-ß), glutathione S-transferase (gst), and superoxide dismutase 1 (sod1) gene expression compared with the control diet. This study demonstrated that inhibition of PDKs by DCA promoted glucose utilization, reduced hepatic lipid deposition, and improved oxidative stress in largemouth bass by increasing pyruvate OXPHOS. Our findings contribute to the understanding of the underlying mechanism of the PDKs-PDHE1α axis in glucose metabolism and improve the utilization of dietary carbohydrates in farmed carnivorous fish.

Poly(butylene adipate-co-terephthalate) biodegradation by Purpureocillium lilacinum strain BA1S.

Poly(butylene adipate-co-terephthalate) (PBAT), a promising biodegradable aliphatic-aromatic copolyester material, can be applied as an alternative material to reduce the adverse effects of conventional plastics. However, the degradation of PBAT plastics in soil is time-consuming, and effective PBAT-degrading microorganisms have rarely been reported. In this study, the biodegradation properties of PBAT by an elite fungal strain and related mechanisms were elucidated. Four PBAT-degrading fungal strains were isolated from farmland soils, and Purpureocillium lilacinum strain BA1S showed a prominent degradation rate. It decomposed approximately 15 wt.% of the PBAT films 30 days after inoculation. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and Liquid chromatography mass spectrometry (LC‒MS) were conducted to analyze the physicochemical properties and composition of the byproducts after biodegradation. In the presence of PBAT, the lipolytic enzyme activities of BA1S were remarkably induced, and its cutinase gene was also significantly upregulated. Of note, the utilization of PBAT in BA1S cells was closely correlated with intracellular cytochrome P450 (CYP) monooxygenase. Furthermore, CreA-mediated carbon catabolite repression was confirmed to be involved in regulating PBAT-degrading hydrolases and affected the degradation efficiency. This study provides new insight into the degradation of PBAT by elite fungal strains and increases knowledge on the mechanism, which can be applied to control the biodegradability of PBAT films in the future. KEY POINTS: • Purpureocillium lilacinum strain BA1S was isolated from farmland soils and degraded PBAT plastic films at a prominent rate. • The lipolytic enzyme activities of strain BA1S were induced during coculture with PBAT, and the cutinase gene was significantly upregulated during PBAT degradation. • CreA-mediated carbon catabolite repression of BA1S plays an essential role in regulating the expression of PBAT-degrading hydrolases.

Minocycline and Pyrrolidine Dithiocarbamate Attenuate Hypertension via Suppressing Activation of Microglia in the Hypothalamic Paraventricular Nucleus.

Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.

Engineering Interlayer Electron-Phonon Coupling in WS2/BN Heterostructures.

In van der Waals (vdW) heterostructures, the interlayer electron-phonon coupling (EPC) provides one unique channel to nonlocally engineer these elementary particles. However, limited by the stringent occurrence conditions, the efficient engineering of interlayer EPC remains elusive. Here we report a multitier engineering of interlayer EPC in WS2/boron nitride (BN) heterostructures, including isotope enrichments of BN substrates, temperature, and high-pressure tuning. The hyperfine isotope dependence of Raman intensities was unambiguously revealed. In combination with theoretical calculations, we anticipate that WS2/BN supercells could induce Brillouin-zone-folded phonons that contribute to the interlayer coupling, leading to a complex nature of broad Raman peaks. We further demonstrate the significance of a previously unexplored parameter, the interlayer spacing. By varying the temperature and high pressure, we effectively manipulated the strengths of EPC with on/off capabilities, indicating critical thresholds of the layer-layer spacing for activating and strengthening interlayer EPC. Our findings provide new opportunities to engineer vdW heterostructures with controlled interlayer coupling.

A gene chip study suggests that miR-17-3p is associated with diabetic foot ulcers.

Background of the Study Diabetic foot ulcers (DFUs) are severe effect of diabetes. This research aimed to discover the role of micro-ribonucleic acid (miRNA) in treating DFUs involved in maggot debridement therapy (MDT) via a miRNA chip study. A miRNA chip approach was adopted. Patients with diabetes (type 1 or 2) who had at least one-foot ulcer (current or previous) were enrolled in the study. The alterations of miRNA expressions in the granulation tissue during treatment with MDT were measured. Following MDT, the increased expression of miR17-92 was verified in vivo. The miR-17-3p expression increased, and Flk-1 (vascular endothelial growth factor) expression was significantly reduced in patients with DFUs who received MDT (P < 0.01). Results from human umbilical vein endothelial cells that excrete or secrete showed consistency with in vitro findings (P < 0.001, P < 0.05). The overexpression of miR-17-3p demonstrated inhibitory activity on tube formation (P < 0.05). When DFUs were treated with MDT, it revealed that miR-17-3p had a negative regulatory effect on Flk-1.

Maggot debridement therapy stimulates wound healing by altering macrophage activation.

The purpose of this study is to determine the impact of maggot debridement therapy (MDT) on macrophages during the healing process of diabetic foot ulcers (DFU). The activation phenotype of macrophages during wound healing following MDT was evaluated using double staining immunohistochemistry (IHC). In addition, markers associated with macrophage activation were discovered using immunoblotting and real-time polymerase chain reaction (PCR). During the process of diabetic wound healing following MDT, the presence and over-expression of M2 macrophages were observed, while the under-expression of M1 macrophages was noted. In addition, the activation markers of macrophages exhibited a correlation with the indicated Th1/Th2 cytokines. MDT interventions have the potential to modulate macrophage activity, thereby aiding in the healing of diabetic foot wounds.

Hsa_circ_0003945 promotes progression of hepatocellular carcinoma by mediating miR-34c-5p/LGR4/ß-catenin axis activity.

Accumulating evidence suggests that circular RNAs (circRNAs) play essential roles in regulating cancer progression, but many circRNAs in hepatocellular carcinoma (HCC) remain unknown. Dysregulated circRNAs in HCC were identified through bioinformatics analysis of Gene Expression Omnibus data sets. Quantitative real-time PCR (qRT-PCR), Sanger sequencing, RNase R digestion and actinomycin D treatment were conducted to confirm the characterization of circRNAs. CCK-8, wound-healing and Transwell assays were performed to assess the functional roles of Hsa_circ_0003945 (Circ_0003945) in HCC cell lines. Subcellular fractionation and fluorescence in situ hybridization (FISH) were performed to locate Circ_0003945 in HCC cells. Dual-luciferase reporter assay was executed to verify the binding of Circ_0003945 to microRNAs (miRNAs) or the miRNAs to their target genes. In this study, we found that Circ_0003945 was upregulated in HCC tissue, and higher Circ_0003945 expression was positively correlated with tumour size and tumour stage. Furthermore, high plasma levels of circulating Circ_0003945 were confirmed in HCC patients compared with those in non-HCC groups. The functional experiments revealed that overexpression or knockdown of Circ_0003945 promoted or attenuated tumour growth and migration, respectively. Mechanistically, Circ_0003945 might exert as a miR-34c-5p sponge to upregulate the expression of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), activating the ß-catenin pathway, and finally facilitating HCC progression. Additionally, a ß-catenin activator could reverse the effect of Circ_0003945 knockdown. In conclusion, Circ_0003945 exerts a tumour-promoting role in HCC cells by regulating the miR-34c-5p/LGR4/ß-catenin axis, which may be a potential target for HCC therapy.

Hydroxychloroquine use reduces mortality risk in systemic lupus erythematosus: A systematic review and meta-analysis of cohort studies.

OBJECTIVE: Hydroxychloroquine (HCQ) is widely used in patients with systemic lupus erythematosus (SLE), but its effects on the mortality have not reached a definite conclusion. In this systematic review and meta-analysis, we aimed to assess whether HCQ use could reduce the risk of mortality in SLE patients. METHODS: PubMed, Embase, Web of Science, and Cochrane database were searched from inception to April 17, 2022 without language restrictions to explore the relationship between HCQ use and SLE mortality. The relative risk (HR) was pooled using the STATA software. RESULTS: A total of 21 studies with a pooled patient population of 26,037 were included in the study, including 14 studies on the association between HCQ alone and mortality risk and seven studies on the association between HCQ/chloroquine (CQ) and mortality risk. The pooled findings suggested that HCQ significantly reduced the overall mortality risk of SLE (pooled HR 0.46, 95% CI 0.38-0.57, p < 0.001). In subgroup analysis of SLE complications, HCQ use also decreased the risk of death in SLE patients with renal (HR=0.43, 95% CI 0.26-0.70, p = 0.001) and cardiopulmonary involvement (HR=0.37, 95% CI= 0.25-0.54, p < 0.001). In addition, HCQ use was also protective against the risk of mortality in SLE patients in different regions, such as Asia (HR=0.46, 95% CI=0.33-0.64, p < 0.001), Europe (HR= 0.40, 95% CI = 0.22-0.71, p = 0.002), and America (HR=0.52, 95% CI= 0.42-0.64, p < 0.001). CONCLUSION: Our data suggested that HCQ use was associated with a reduced risk of mortality in patients with SLE.

Exosomal microRNAs in the DLK1-DIO3 imprinted region derived from cancer-associated fibroblasts promote progression of hepatocellular carcinoma by targeting hedgehog interacting protein.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and third leading cause of cancer-related death worldwide in 2020. Exosomes derived from cancer-associated fibroblasts (CAFs-exo) can promote tumor progression in various human cancers. However, the underlying regulatory mechanism controlling how CAFs-exo can promote HCC progression remains poorly understood. METHODS: CAFs and para-cancer fibroblasts (PAFs) were isolated from HCC tissues and corresponding para-cancer tissues, then were cultured in vitro. CAFs and PAFs were characterized by immunofluorescence and western blot (WB) assays. Exosomes were isolated by ultracentrifugation, and characterized by transmission electron microscopy, nanoflow cytometry, and WB assay. The internalization of exosomes by HCC cells was observed under a fluorescence microscope. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Wound healing and transwell assays were used for migration and invasion experiments. RT-PCR assay was used to examine differentially expressed microRNAs (miRNAs) in exosomes and HCC cells. The TargetScan database was used to predict miRNA target genes. Hedgehog interacting protein (HHIP) expression analysis, prognostic analysis, and enrichment analysis of HHIP-related co-expressed genes were performed using the TIMER, UALCAN, Kaplan-Meier plotter, and LinkedOmics databases. RESULTS: CAFs-exo were internalized by HCC cells. CAFs-exo contributed to the aggressive phenotype of HCC cells, while inhibiting exosome secretion reversed these effects. Mechanistically, miRNAs in the DLK1-DIO3 imprinted region (miR-329-3p, miR-380-3p, miR-410-5p, miR-431-5p) were increased in HCC cells co-cultured with CAFs-exo compared with PAFs-exo. Expression of HHIP, a possible miR-431-5p target gene, was significantly downregulated in HCC cells. Low HHIP expression level in tumor tissues could predict poor prognosis in HCC patients. HHIP-related co-expressed genes were mainly associated with cell adhesion molecules. CONCLUSIONS: CAFs-exo can promote HCC progression by delivering miRNAs in the DLK1-DIO3 imprinted region to HCC cells, subsequently inhibiting HHIP expression. HHIP is a potential prognostic biomarker in HCC.

Psoriasis Susceptibility 1 Candidate 1 (PSORS1C1) Polymorphism is Associated with Autoimmune Thyroid Disease in a Chinese Han Population.

BACKGROUND: Autoimmune thyroid disease (AITD) is an inherited, complex gene- and immune-related disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is a susceptibility gene associated with many autoimmune diseases, but its role in an individual's predisposition to AITD is unknown. METHODS: This study included 1065 Chinese Han patients with AITD and 943 matched healthy individuals. The rs3130983, rs3778638, rs3815087, and rs4959053 single nucleotide polymorphisms (SNPs) in PSORS1C1 were determined using multiplex polymerase chain reaction technology. RESULTS: Of the four SNPs, only the distribution of the rs3778638 genotypes was different between the AITD (AA, 2.67%; AG, 19.15%; and GG, 78.18%) and control (AA, 1.52%; AG, 22.2%; and GG, 75.87%) groups (P = .046). An association between rs3778683 and GD was observed (p = .039) but not with HT. No linkage disequilibrium was observed for rs3130983, rs3815087, rs3778638, and rs4959053 in PSORS1C1 among the patients with AITD and controls. CONCLUSION: This study suggests the influence of PSORS1C1 rs3778638 on the susceptibility to GDs, supporting this locus as a common autoimmunity risk factor.

Bifunctional TGF-ß trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors.

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-ß (TGF-ß) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-ß neutralizing activity in vitro and sequesters plasma TGF-ß in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+ T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.

High serum soluble CD155 level predicts poor prognosis and correlates with an immunosuppressive tumor microenvironment in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with poor prognosis. There is no research about the clinical significance of serum soluble CD155 (sCD155) level for HCC. We aim to explore the prognostic and diagnostic value of sCD155 in HCC patients undergoing curative resection. METHODS: Serum sCD155 level in HCC patients was determined by enzyme-linked immunosorbent assay. The prognostic significance of sCD155 was evaluated by Cox regression and Kaplan-Meier analyses. CD155 expression and biomarkers of immune cells in HCC tissues were detected by immunohistochemistry staining. The diagnostic significance of sCD155 was evaluated using receiver operating characteristic curve. RESULTS: Serum sCD155 level was significantly increased in HCC patients and predicted poor prognosis. The prognostic value of sCD155 remained in low recurrent risk subgroups of HCC. Serum sCD155 level was positively related to CD155 expression in HCC tissues. High serum sCD155 level was associated with decreased numbers of CD8+ T cells and CD56+ NK cells and increased number of CD163+ M2 macrophages. Serum sCD155 level had better performance in distinguishing HCC patients from healthy donors and patients with chronic liver conditions than α-fetoprotein. Among patients with α-fetoprotein ≤ 20 ng/ml, serum sCD155 level could differentiate HCC patients from non-HCC patients. CONCLUSION: Serum sCD155 level represents a promising biomarker for diagnosis and prognosis of HCC. High serum sCD155 level may reflect an immunosuppressive tumor microenvironment in HCC.