Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling.

BACKGROUND: Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference. METHODS: We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo. RESULTS: Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo. CONCLUSION: Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.

Pathway cross-talk network strategy reveals key pathways in non-small cell lung cancer.

PURPOSE: The purpose of this study was to explore the pathway cross-talks and key pathways in non-small cell lung cancer (NSCLC) to better understand the underlying pathological mechanism. METHODS: Integrated gene expression data, pathway data and protein-protein interaction (PPI) data were assessed to identify the pathway regulatory interactions in NSCLC, and constructed the background and disease pathway crosstalk networks, respectively. In this work, the attractor method was implemented to identified the differential pathways, and the rank product (RP) algorithm was used to determine the importance of pathways. RESULTS: Based on 787,896 PPI interactions from STRING database and 300 human pathways from KEGG, we constructed the back pathway cross-talk network with 300 nodes and 42239 edges. Integrating with expression data of NSCLC, each pathway cross-talk endowed with a weight value, and disease pathway cross-talks were identified. By RP algorithm and topology analysis of network, we selected 5 key pathways, including Alanine, DNA replication, Fanconi anemia pathway, Cell cycle and MicroRNAs in cancer under the pre-set thresholds. CONCLUSION: We successfully revealed the disease pathway cross-talks and explored 5 key pathways in NSCLC, which may be the underlying therapeutic targets for lung cancer.

MiRNA-155 and miRNA-132 as potential diagnostic biomarkers for pulmonary tuberculosis: A preliminary study.

In our study, we aimed to profile a panel microRNAs (miRNAs) as potential biomarkers for the early diagnosis of pulmonary tuberculosis (PTB) and to illuminate the molecular mechanisms in the development of PTB. Firstly, gene expression profile of E-GEOD-49951 was downloaded from ArrayExpress database, and quantile-adjusted conditional maximum likelihood method was utilized to identify statistical difference between miRNAs of Mycobacterium tuberculosis (MTB)-infected individuals and healthy subjects. Furthermore, in order to assess the performance of our methodology, random forest (RF) classification model was utilized to identify the top 10 miRNAs with better Area Under The Curve (AUC) using 10-fold cross-validation method. Additionally, Monte Carlo Cross-Validation was repeated 50 times to explore the best miRNAs. In order to learn more about the differentially-expressed miRNAs, the target genes of differentially-expressed miRNAs were retrieved from TargetScan database and Ingenuity Pathways Analysis (IPA) was used to screen out biological pathways where target genes were involved. After normalization, a total of 478 miRNAs with higher than 0.25-fold quantile average across all samples were required. Based on the differential expression analysis, 38 differentially expressed miRNAs were identified when the significance was set as false discovery rate (FDR) < 0.01. Among the top 10 differentially expressed miRNAs, miRNA-155 obtained a highest AUC value 0.976, showing a good performance between PTB and control groups. Similarly, miRNA-449a, miRNA-212 and miRNA-132 revealed also a good performance with AUC values 0.947, 0.931 and 0.930, respectively. Moreover, miRNA-155, miRNA-449a, miRNA-29b-1* and miRNA-132 appeared in 50, 49, 49 and 48 bootstraps. Thus, miRNA-155 and miRNA-132 might be important in the progression of PTB and thereby, might present potential signatures for diagnosis of PTB.

Integrating differential pathway analysis with Monte Carlo cross-validation reveals seed cross-talks in non-small cell lung carcinoma.

PURPOSE: The objective of this study was to identify seed pathway cross-talks in non-small cell lung carcinoma (NSCLC), and to reveal potential pathological mechanism at molecular level systematically. METHODS: Differentially expressed genes (DEGs) between NSCLC and normal controls were identified using quantile- adjusted conditional maximum likelihood (QCML) method. Subsequently, differential pathways (DPs) enriched by DEGs were determined according to the Ingenuity Pathways Analysis )IPA) pathways and Fisher's exact test. A discriminating score )DS) was computed for each pair of DPs also called as cross-talk, and random forest )RF) algorithm was implemented to investigated hub cross-talks. Finally, global cross-talks with repeated times > 5 were calculated by Monte Carlo Cross-Validation )MCCV). By taking intersections between hub cross-talks and global crosstalks, we obtained seed cross-talks. RESULTS: We obtained 122 DEGs and 5 DPs between NSCLC samples and normal controls. Based on DS and RF algorithm, 5 hub cross-talks with best area under the curve )AUC) were identified, of which Agranulocyte Adhesion and Diapedesis, and IL-17A Signaling in Fibroblasts were the best with AUC=0.996. After intersected with global cross-talks, we gained 2 seed cross-talks (Agranulocyte Adhesion and Diapedesis, Granulocyte Adhesion and Diapedesis and Agranulocyte Adhesion and Diapedesis, Glutathione Redox Reactions I). CONCLUSIONS: Two seed cross-talks were identified and validated by MCCV, which may give insights for revealing pathological mechanism and potential biomarkers for target therapy in NSCLC.

Effects of High-Concentrate-Induced SARA on Antioxidant Capacity, Immune Levels and Rumen Microbiota and Function in Goats.

This study aims to explore the antioxidant, immune, and enzyme metabolism aspects in goats experiencing subacute ruminal acidosis (SARA). Furthermore, we seek to elucidate the relationship between the symbiotic microbiota of goats and their metabolic function. Sixteen goats were equally divided into two groups and fed a normal-concentrate diet (NC, 55% concentrate) or a high-concentrate diet (HC, 90% concentrate) for five weeks. We found that the HC diet reduced the total antioxidant capacity (T-AOC) (p = 0.022) and increased interleukin-1ß (IL-1ß) (p = 0.015), interleukin-4 (IL-4) (p = 0.008) and interleukin-6 (IL-6) (p = 0.002) concentration of goats. Simultaneously, the HC diet significantly increased the concentrations of alkaline phosphatase (ALP) and amylase (AMY) in the blood and rumen fluid of goats (p < 0.05). Microbial analysis in the rumen of goats revealed that the HC diet decreased bacterial richness and diversity, as evidenced by the changed observed species, Chao 1, PD whole tree and Shannon when compared to the NC diet (p < 0.01). The proportion of Proteobacteria increased while that of Spirochaetes and Fibrobacteres significantly decreased with the HC diet (p < 0.05). The Christensenellaceae_R-7_group and Ruminococcaceae_UCG-010 in rumen was notably decreased when a diet was switched from 55% concentrate diet to 90% concentrate diet (p < 0.05). Additionally, microbial functional potentials deduced that the HC diet significantly increased the abundance of the citrate cycle (TCA cycle) (ko00020) associated with carbohydrate metabolism (p = 0.028). Furthermore, the HC diet significantly increased the glutathione metabolism (ko00480) associated with the metabolism of other amino acids (p = 0.008). Our findings suggested that SARA reduced the total antioxidant capacity and increased levels of inflammatory factors in goats, as well as decreased rumen bacterial species and abundance.

Comprehensive analysis of PSMG3 in pan-cancer and validation of its role in hepatocellular carcinoma.

BACKGROUND: Proteasome assembly chaperone 3 (PSMG3), a subunit of proteasome, has been found to be associated with lung cancer. However, the role of PSMG3 in other cancers has not been elucidated. The objective of this study was to explore the immune role of PSMG3 in pan-cancer and confirm the oncogenic significance in liver hepatocellular carcinoma (LIHC). METHODS: We examined the differential expression of PSMG3 across various cancer types using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. We investigated the prognostic value of PSMG3 and examined its relationship with tumor mutation burden (TMB), microsatellite instability (MSI), and immune infiltration. The functional enrichment analysis was performed to explore the potential molecular mechanism of PSMG3. To elucidate the biological function of PSMG3, we conducted in vitro experiments using liver cancer cell lines. RESULTS: PSMG3 was highly expressed in most cancers. The high PSMG3 expression value of PSMG3 was closely related to poor prognosis. We observed correlations between PSMG3 and TMB, and MSI immune infiltration. PSMG3 may be involved in metabolic reprogramming, cell cycle, and PPAR pathways. The over-expression of PSMG3 promoted the proliferation, migration, and invasion capabilities of liver cancer cells. CONCLUSION: Our study demonstrated that PSMG3 was a pivotal oncogene in multiple cancers. PSMG3 contributed to the progression and immune infiltration in pan-cancer, especially in LIHC.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

Effects of Different Proteases on Protein Digestion In Vitro and In Vivo and Growth Performance of Broilers Fed Corn-Soybean Meal Diets.

This study was conducted to investigate the effects of different proteases alone or in combination on protein digestibility of broilers. In vitro, the properties of four proteases in broilers, including acidic protease (AcP), alkaline protease (AlP), neutral protease (NeP) and keratinase (Ker), on endogenous protease activity and their effects on protein digestibility of common ingredients in broiler diets were investigated using a gut-mimicking model. In vivo, 640 1-day-old male broilers were randomly divided into 8 groups of 10 with 8 replicates of 10 birds per replicate cage. Eight dietary treatments included a corn-soybean meal basal diet (control), and the basal diet with 1.6 U AcP/g, 0.8 U NeP/g, 0.8 U AlP/g, 0.4 U Ker/g, 1.6 U AcP/g + 0.8 U NeP/g, 1.6 U AcP/g + 0.8 U AlP/g, or 1.6 U AcP/g + 0.4 U Ker/g added. The experiment lasted for 31 days. The results showed that the optimum pH values of AcP, NeP, AlP and Ker were 3.0, 9.0, 11.0 and 11.0 in vitro, respectively. Ker recovery proportion was 37.68% at pH 3.3-6.2. AcP alone or in combination with NeP, AlP or Ker increased in vitro crude protein digestibility (IVCPD) and decreased ileal apparent digestibility of crude protein in 31-day-old broilers (p < 0.05). All protease supplementation reduced the ileal apparent digestibility of amino acids compared to the control (p < 0.05). Acidic protease had a positive effect on trypsin and chymotrypsin activities, while AlP and Ker showed a negative effect. In vivo, average daily gain and average daily feed intake were significantly (p < 0.05) increased in broiler diets supplemented with AcP compared to the control group. When adding exogenous proteases to broiler diets, their sensitivity to digestive pH and their negative effects on endogenous protease activity, dosage and combination effects should be taken into account. In addition, the properties and dosage of proteases and the protein level in the feed should be considered.

The Applications and Mechanisms of Superoxide Dismutase in Medicine, Food, and Cosmetics.

Superoxide dismutase (SOD) is a class of enzymes that restrict the biological oxidant cluster enzyme system in the body, which can effectively respond to cellular oxidative stress, lipid metabolism, inflammation, and oxidation. Published studies have shown that SOD enzymes (SODs) could maintain a dynamic balance between the production and scavenging of biological oxidants in the body and prevent the toxic effects of free radicals, and have been shown to be effective in anti-tumor, anti-radiation, and anti-aging studies. This research summarizes the types, biological functions, and regulatory mechanisms of SODs, as well as their applications in medicine, food production, and cosmetic production. SODs have proven to be a useful tool in fighting disease, and mimetics and conjugates that report SODs have been developed successively to improve the effectiveness of SODs. There are still obstacles to solving the membrane permeability of SODs and the persistence of enzyme action, which is still a hot spot and difficulty in mining the effect of SODs and promoting their application in the future.

Fermented Chinese Herbal Medicine Promoted Growth Performance, Intestinal Health, and Regulated Bacterial Microbiota of Weaned Piglets.

To investigate the effects of fermented Chinese herbal medicine on growth performance, diarrhea rate, nutrient digestibility, and intestinal health of weaned piglets, and to provide the theoretical basis for applying fermented Chinese herbal medicines to weaned piglet production, a total of 162 weaned and castrated piglets at 25 days of age (Duroc × Landrace × Yorkshire, half male and half female) with an initial body weight of 7.77 ± 0.03 kg were randomly divided into the following three groups according to the principle of similar body weight: basal diet (CON) group, basal diet + 3 kg/t fermented Chinese herbal medicine (LFHM) group, and basal diet + 5 g/kg fermented Chinese herbal medicine (HFHM) group. Each group underwent six replicates and there were nine piglets in each replicate. The experiment lasted 24 days, i.e., 3 days for preliminary feeding, and 21 days for the experiment. From Day 1 of the experiment, the piglets were observed and recorded for diarrhea each day. As compared with the CON group, the results indicated: Following the addition of fermented Chinese herbal medicine, the piglets in the LFHM and HFHM groups increased final weight (FW); average daily feed intake (ADFI); average daily gain (ADG) (p < 0.01); apparent digestibility of crude protein (CP) (p < 0.05); as well as chymotrypsin, α-amylase, and lipase activities (p < 0.01). In addition, α-amylase activity in the LFHM group was higher than that in the HFHM group (p < 0.05); chymotrypsin activity in the LFHM group was lower than that in the HFHM group (p < 0.05); as compared with the CON group, the LFHM and the HFHM increased villus height (VH) and crypt depth (CD) in piglet jejunum; isovaleric acid concentration with the HFHM was higher than those with the CON and the LFHM (p < 0.05), but butyrate concentration with the HFFM was lower than those with the CON and the LFHM (p < 0.05). The high-throughput 16S rRNA sequencing of intestinal microbiota results showed that the LFHM and the HFHM affected the microbial α diversity index in weaned piglet colon (p < 0.01). In conclusion, fermented Chinese herbs can improve the growth performance of weaned piglets by promoting the secretion of intestinal digestive enzymes, changing intestinal microbial diversity, regulating the contents of intestinal short chain fatty acids (SCFAs), promoting intestinal health, and improving nutrients digestibility.

An exosome-related lncRNA signature correlates with prognosis, immune microenvironment, and therapeutic responses in hepatocellular carcinoma.

BACKGROUND: Exosomes act as essential modulators of cancer development and progression in hepatocellular carcinoma. However, little is known about the potential prognostic value and underlying molecular features of exosome-related long non-coding RNAs. METHODS: Genes associated with exosome biogenesis, exosome secretion, and exosome biomarkers were collected. Exosome-related lncRNA modules were identified using PCA and WGCNA analysis. A prognostic model based on data from the TCGA, GEO, NODE, and ArrayExpress was developed and validated. A comprehensive analysis of the genomic landscape, functional annotation, immune profile, and therapeutic responses underlying the prognostic signature was performed on multi-omics data, and bioinformatics methods were also applied to predict potential drugs for patients with high risk scores. qRT-PCR was used to validate the differentially expressed lncRNAs in normal and cancer cell lines. RESULTS: Twenty-six hub lncRNAs were identified as highly correlated with exosomes and overall survival and were used for prognosis modeling. Three cohorts consistently showed higher scores in the high-risk group, with an AUC greater than 0.7 over time. These higher scores implied poorer overall survival, higher genomic instability, higher tumor purity, higher tumor stemness, pro-tumor pathway activation, lower anti-tumor immune cell and tertiary lymphoid structure infiltration, and poor responses to immune checkpoint blockade therapy and transarterial chemoembolization therapy. CONCLUSION: Through developing an exosome-related lncRNA predictor for HCC patients, we revealed the clinical relevance of exosome-related lncRNAs and their potential as prognostic biomarkers and therapeutic response predictors.

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis.

Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored. Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub. Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis. Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.

CD44v6+ Hepatocellular Carcinoma Cells Maintain Stemness Properties through Met/cJun/Nanog Signaling.

Cancer stem cells (CSCs) are characterized by their self-renewal and differentiation abilities. CD44v6 is a novel CSC marker that can activate various signaling pathways. Here, we hypothesized that the HGF/Met signaling pathway promotes stemness properties in CD44v6+ hepatocellular carcinoma (HCC) cells via overexpression of the transcription factor, cJun, thus representing a valuable target for HCC therapy. Magnetic activated cell sorting was used to separate the CD44v6+ from CD44v6- cells, and Met levels were regulated using lentiviral particles and the selective Met inhibitor, PHA665752. An orthotopic liver xenograft tumor model was used to assess the self-renewal ability of CD44v6+ cells in immunodeficient NOD/SCID mice. Luciferase reporter and chromatin immunoprecipitation assays were also conducted using cJun-overexpressing 293 T cells to identify the exact binding site of cJun in the Nanog promoter. Our data demonstrate that CD44v6 is an ideal surface marker of liver CSCs. CD44v6+ HCC cells express higher levels of Met and possess self-renewal and tumor growth abilities. Xenograft liver tumors were smaller in nude mice injected with shMet HCC cells. Immunohistochemical analysis of liver tissue specimens revealed that high Met levels in HCC cells were associated with poor patient prognosis. Further, a cJun binding site was identified 1700 bp upstream of the Nanog transcription start site and mutation of the cJun binding site reduced Nanog expression. In conclusion, the HGF/Met signaling pathway is important for maintenance of stemness in CD44v6+ HCC cells by enhancing expression of cJun, which binds 1700 bp upstream of the Nanog transcription start site.

Novel Linkages Between Bacterial Composition of Hindgut and Host Metabolic Responses to SARA Induced by High-Paddy Diet in Young Goats.

At present, feeding a high-corn diet to goats is used to provide enough protein and energy supply to meet their higher dietary requirements. In fact, because corn grain is commonly scarce in the traditional rice cropping region of southern Asia, paddy is thereby used as an alternative feed applied in goat diets. However, the effects of the high paddy proportion on the microbiota and metabolites of the intestine are unclear. Here, we investigate the effects of high paddy proportion on bacterial community, potential function, and metabolic reaction in the cecum of goats. Sixteen Liuyang black goats were divided into two groups fed either a normal-paddy (NP) diet (55% concentrate) or a high-paddy (HP) diet (90% concentrate) for 5 weeks. Total short-chain fatty acid (SCFA) concentration was higher in the hindgut chyme of the HP-fed goats than in that of the NP-fed goats (p = 0.001). The acetic proportion was significantly decreased and the propionic proportion was increased in the HP group (p < 0.05). The HP diet decreased the value of pH, lactic acid concentration, and lactate dehydrogenase activity but increased the activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and amylase, together with lipopolysaccharide concentration in the hindgut chyme of goats (p < 0.05). The abundance rates of the Eubacterium_coprostanoligenes_group was increased (p = 0.050), whereas the abundance of Prevotellaceae_UCG_004, dgA-11_gut_group, Christensenellaceae_R-7_group, Ruminococcaceae_UCG-010, and Desulfovibrio were significantly decreased with the HP diet (p < 0.05). These results suggested that the HP diet altered the microbiota and metabolites, which negatively modified intestinal epithelial health in goats.

Spindle and kinetochore-associated complex subunit 3 (SKA3) promotes stem cell-like properties of hepatocellular carcinoma cells through activating Notch signaling pathway.

BACKGROUND: Cancer stemness contributes to hepatocellular carcinoma (HCC) initiation, metastasis, drug resistance, and recurrence. The spindle and kinetochore-associated (SKA) complex has been shown to be involved in tumor progression; however, its effects on cancer stem cell-like properties have not yet been examined. This research sought to study each subunit of the SKA complex in HCC systematically. METHODS: Bioinformatic analyses were carried out to examine the expression and clinical data of the SKA complex's each subunit in HCC. The expression of the target genes was detected by quantitative reverse transcription-polymerase chain reaction and Western blot assays. Clone formation and Transwell assays were performed to assess the proliferation and migration abilities of the SKA complex's each subunit. Sphere formation assays and subcutaneous xenograft experiments were performed to investigate the effects of SKA complex subunit 3 (SKA3) on the self-renewal and tumorigenic abilities of HCC. RESULTS: Each subunit of the SKA complex was highly expressed in HCC, but only SKA complex subunit 1 (SKA1) and SKA3 were associated with the poor overall survival of HCC patients. Additionally, the HCC cells overexpressing SKA3 exhibited increased migration, invasion, proliferation, self-renewal, Sorafenib resistance and tumorigenic abilities. Notch signaling played a vital role in the process by which SKA3 promoted HCC stemness. CONCLUSIONS: SKA3 promotes HCC stem cell-like properties via the Notch signaling pathway. As SKA3 appears to act as a regulator of stemness in HCC, it might be a potential molecular target for HCC.

Microbiome-Metabolites Analysis Reveals Unhealthy Alterations in the Gut Microbiota but Improved Meat Quality with a High-Rice Diet Challenge in a Small Ruminant Model.

Effects of a high-rice dietary proportion on the meat quality, acute phase reaction proteins (APRPs) and colonic microbiota and metabolites in goats are rarely reported. This study was designed to investigate the meat quality and metabolism in goats. Sixteen goats were equally divided into two groups and fed a control diet (Con, 55% concentrate) or a high-rice diet (HR, 90% concentrate) for five weeks. We found that the HR diet improved the slaughtering characteristic and meat quality but induced an acute phase reaction and decreased bacterial richness and diversity when compared to the control group. Furthermore, the levels of acetate, propionate and total VFA concentrations were higher in the colonic contents of the HR-fed goats than in those of the control group (p < 0.05). Meanwhile, the HR diet decreased the pH value, lactic acid concentration and increased the activity of amylase and lipopolysaccharide concentration in the colonic contents of goats (p < 0.05). The proportion of Oscillibacter increased while Phocaeicola and Christensenellaceae_R-7_group significantly decreased with the HR diet (p < 0.05). Collectively, the HR diet induced an acute phase reaction and altered the colonic bacterial community, which increases the health risk to growing goats.

Diet with a High Proportion of Rice Alters Profiles and Potential Function of Digesta-Associated Microbiota in the Ileum of Goats.

Effects of a high proportion of concentrate in the diet on the ileal microbiota and metabolites in small ruminants are rarely reported. This study was designed to investigate the ileal microbiota and its relationship with host metabolic function in goats and aimed to elucidate the mechanisms involving in the ileal adaptation to a diet containing a high proportion of rice. Sixteen goats were equally divided into two groups and fed a diet with a normal concentrate proportion (NC, 55% concentrate) or a high-concentrate diet (HC, 90% concentrate). Results showed that the HC diet decreased bacterial diversity and elevated the abundance of five genera (Clostridium_sensu_stricto_1, Eubacterium_nodatum_group, Ruminococcus_gauvreauii_group, Eubacterium_coprostanoligenes_group and Ruminococcus 1), but reduced the number of Anaerotruncus. Microbial functional potentials indicated that the HC diet activated the pathways related to metabolism of carbohydrate, glycan, lipid and vitamins, but inhibited the pathways associated with cell motility and signal transduction. The activities of amylase and alkaline phosphatase were greater (p < 0.05) in the intestinal digesta of the HC-fed goats. However, there were no differences in the villus height, crypt depth and the ratio of villus height to crypt depth in the ileum between the two groups. These results indicate that the HC diet alters the bacterial community and pathways related to the metabolism of dietary nutrients and cell motility and signal transduction of bacteria in the ileum of goats.

Ruxolitinib Plus Decitabine Effectively Treats Myelodysplastic Syndrome/Myeloproliferative Neoplasm, Unclassifiable, by Decreasing the Variant Allele Frequency of KRAS.

Myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) is a subtype of MDS/MPN that exhibits a combination of the features of both MDS and MPN. To date, no curative treatment is available for MDS/MPN-U; however, previous studies have suggested a potential survival advantage for ruxolitinib and hypomethylating agents. We reported a case of a JAK2-negative but KRAS-positive MDS/MPN-U patient treated with ruxolitinib plus decitabine. After treatment, the patient's clinical symptoms were moderated, and the size of the spleen and the peripheral blood cell counts were reduced. These effects might be due to the regimen's ability to reduce STAT5 activation and upregulate microRNA-181c to downregulate the variant allele frequency (VAF) of KRAS.

miR-143 inhibits migration and invasion through regulating LASP1 in human esophageal cancer.

BACKGROUND: Esophageal cancer (EC) is one of the common cancers in China with high incidence and poor prognosis. Increasing evidence has emphasized the important roles of differentially expressed miRNAs in esophageal squamous cell carcinoma (ESCC) progression. Previous studies indicated that miR-143-3p and LASP1 influence cell growth in ESCC and other cancer types. However, the function and molecular mechanism of action of miR-143 and LASP1 in ESCC have not been fully explored. METHODS: miR-143 and LASP1 expression were detected by quantitative real-time PCR. The protein level of LASP1 was measured by western blot. Cell proliferation was evaluated by MTT assay. Cell migration and invasion capacity was measured by transwell assay. Targeting of LASP1 mRNA by miR-143 was verified by luciferase reporter assay. Overall survival of ESCC patients with different miR-143 expression level was evaluated by Kaplan-Meier survival analysis. RESULTS: miR-143 expression was down-regulated, while LASP1 expression was up-regulated in ESCC tissues and cells compared to non-malignant counterparts. LASP1 mRNA was identified as a target of miR-143. Low miR-143 expression or high LASP1 expression significantly associated with ESCC patients' decreased survival. miR-143 mimic transfection inhibited ESCC cell proliferation, migration and invasion in vitro, which was impaired by LASP1 overexpression. CONCLUSION: miR-143 suppressed cell proliferation, migration, and invasion by down-regulating LASP1.