Investigation of the feasibility of NRAV as a biomarker for hepatocellular carcinoma.

The long non-coding RNA, Negative Regulator of Antiviral Response (NRAV) has been identified as a participant in both respiratory virus replication and immune checkpoints, however, its involvement in pan-cancer immune regulation and prognosis, particularly those of hepatocellular carcinoma (HCC), remains unclear. To address this knowledge gap, we analyzed expression profiles obtained from The Cancer Genome Atlas (TCGA) database, comparing normal and malignant tumor tissues. We found that NRAV expression is significantly upregulated in tumor tissues compared to adjacent nontumor tissues. Kaplan-Meier (K-M) analysis revealed the prognostic power of NRAV, wherein overexpression was significantly linked to reduced overall survival in a diverse range of tumor patients. Furthermore, noteworthy associations were observed between NRAV, immune checkpoints, immune cell infiltration, genes related to autophagy, epithelial-mesenchymal transition (EMT), pyroptosis, tumor mutational burden (TMB), and microsatellite instability (MSI) across different cancer types, including HCC. Moreover, NRAV upregulation expression was associated with multiple pathological stages by clinical observations. Furthermore, our investigation revealed a substantial elevation in the expression of NRAV in both HCC tumor tissues and cells compared to normal tissues and cells. The inhibition of NRAV resulted in the inhibition of cell proliferation, migration, and invasion in HCC cells, while also influencing the expression of CD274 (PD-L1) and CD44, along with various biomarkers associated with EMT, autophagy, and pyroptosis. The aforementioned results propose NRAV as a promising prognostic biomarker for HCC.

Enantiopure Corral[4]BINOLs as Ultrastrong Receptors for Recognition and Differential Sensing of Steroids.

The precise recognition and sensing of steroids, a type of vital biomolecules, hold immense practical value across various domains. In this study, we introduced corral[4]BINOLs (C[4]BINOLs), a pair of enantiomeric conjugated deep-cavity hosts, as novel synthetic receptors for binding steroids. Due to the strong hydrophobic effect of their deep nonpolar, chiral cavities, the two enantiomers of C[4]BINOLs demonstrated exceptionally high recognition affinities (up to 1012 M-1) for 16 important steroidal compounds as well as good enantioselectiviy (up to 15.5) in aqueous solutions, establishing them as the most potent known steroid receptors. Harnessing their ultrahigh affinity, remarkable enantioselectivity, and fluorescence emission properties, the two C[4]BINOL enantiomers were employed to compose a fluorescent sensor array which achieved discrimination and sensing of 16 structurally similar steroids at low concentrations.

Arginine alleviates Clostridium perfringens α toxin-induced intestinal injury in vivo and in vitro via the SLC38A9/mTORC1 pathway.

Introduction: Clostridium perfringens α toxin is a main virulence factor responsible for gut damage in animals. Arginine is a functional amino acid exhibiting significant immunoregulatory activities. However, the effects and immunoregulatory mechanisms of arginine supplementation on α toxin-induced intestinal injury remain unclear. Methods: In vivo, 256 male Arbor Acres chickens were randomly assigned to a 2×2 factorial arrangement, involving diet treatments (with or without 0.3% arginine supplementation) and immunological stress (with or without α toxin challenge). In vitro, IEC-6 cells were treated with or without arginine in the presence or absence of α toxin. Moreover, IEC-6 cells were transfected with siRNA targeting mTOR and SLC38A9 to explore the underlying mechanisms. Results and discussion: The results showed that in vivo, arginine supplementation significantly alleviated the α toxin-induced growth performance impairment, decreases in serum immunoglobulin (Ig)A and IgG levels, and intestinal morphology damage. Arginine supplementation also significantly reduced the α toxin-induced increase in jejunal proinflammatory cytokines interleukin (IL)-1ß, IL-6 and IL-17 mRNA expression. Clostridium perfringens α toxin significantly decreased jejunal mechanistic target of rapamycin (mTOR) and solute carrier family 38 member 9 (SLC38A9) mRNA expression, while arginine supplementation significantly increased mTOR and SLC38A9 mRNA expression. In vitro, arginine pretreatment mitigated the α toxin-induced decrease in cell viability and the increase in cytotoxicity and apoptosis. Arginine pretreatment also alleviated the α toxin-induced upregulation of mRNA expression of inflammation-related cytokines IL-6, C-X-C motif chemokine ligand (CXCL)10, CXCL11 and transforming growth factor-ß (TGF-ß), as well as apoptosis-related genes B-cell lymphoma-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-extra large (Bcl-XL) and cysteinyl aspartate specific proteinase 3 (Caspase-3) and the ratio of Bax to Bcl-2. Arginine pretreatment significantly increased the α toxin-induced decrease in mTOR, SLC38A9, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (S6K) mRNA expression. Knockdown SLC38A9 and mTOR largely abrogated the positive effects of arginine pretreatment on α toxin-induced intracellular changes. Furthermore, SLC38A9 silencing abolished the increased mTOR mRNA expression caused by arginine pretreatment. In conclusion, arginine administration attenuated α toxin-induced intestinal injury in vivo and in vitro, which could be associated with the downregulation of inflammation via regulating SLC38A9/mTORC1 pathway.

Investigating the impact of feed-induced, subacute ruminal acidosis on rumen epimural transcriptome and metatranscriptome in young calves at 8- and 17-week of age.

Introduction: With the goal to maximize intake of high-fermentable diet needed to meet energy needs during weaning period, calves are at risk for ruminal acidosis. Using the calves from previously established model of feed-induced, ruminal acidosis in young calves, we aimed to investigate the changes in rumen epimural transcriptome and its microbial metatranscriptome at weaning (8-week) and post-weaning (17-week) in canulated (first occurred at 3 weeks of age) Holstein bull calves with feed-induced subacute ruminal acidosis. Methods: Eight bull calves were randomly assigned to acidosis-inducing diet (Treated, n = 4; pelleted, 42.7% starch, 15.1% neutral detergent fiber [NDF], and 57.8% nonfiber carbohydrates), while texturized starter was fed as a control (Control, n = 4; 35.3% starch, 25.3% NDF, and 48.1% nonfiber carbohydrates) starting at 1 week through 17 weeks. Calves fed acidosis-inducing diet showed significantly less (p < 0.01) body weight over the course of the experiment, in addition to lower ruminal pH (p < 0.01) compared to the control group. Rumen epithelial (RE) tissues were collected at both 8 weeks (via biopsy) and 17 weeks (via euthanasia) and followed for whole transcriptome RNA sequencing analysis. Differentially expressed genes (DEGs) analysis was done using cufflinks2 (fold-change ≥2 and p < 0.05) between treated and control groups at 8-week of age, and between 8- and 17-week for the treated group. Results: At 8-week of age, DEGs between treatment groups showed an enrichment of genes related to the response to lipopolysaccharide (LPS) (p < 0.005). The impact of prolonged, feed-induced acidosis was reflected by the decreased expression (p < 0.005) in genes involved in cell proliferation related pathways in the RE at 17-week of age in the treated group. Unique sets of discriminant microbial taxa were identified between 8-and 17-week calves in the treated group and the treatment groups at 8-week, indicating that active microbial community changes in the RE are an integral part of the ruminal acidosis development and progression.

Identifying the Stripping of Oxide Debris from Graphene Oxide: Evidence from Experimental Analysis and Molecular Simulation.

In this study, characteristics of oxidation debris (OD) and its stripping mechanism from graphene oxide (GO) were explored. The results demonstrated that OD contains three components, namely, protein-, fulvic acid-, and humic acid-like substances; among these, protein-like substances with lower molecular weight and higher hydrophilicity were most liable to be stripped from GO and were the primary components stripped from GO at pH < 10, whereas humic acid- and fulvic acid-like substances were stripped from GO at pH > 10. During the stripping of OD, hydrogen bonds from carboxyl and carbonyl were the first to break, followed by hydrogen bonds from epoxy. Subsequently, π-π interactions were broken, and hydrogen bond interactions induced by hydroxyl groups were the hardest to break. After the stripping of OD, the recombination of OD on GO was observed, and regions containing relatively fewer oxygen-containing functional groups were favorable binding sites for the readsorbed OD. The stripping and recombination of OD on GO resulted in an uneven GO surface, which should be considered during the development of GO-based environmental materials and the evaluation of their environmental behavior.

First Report on Apothecium Deformity of Morchella importuna Caused by Alternaria alternata in China.

Morel mushrooms (Morchella spp.) are highly regarded globally for their distinctive texture and savory flavor. In 2022, the cultivation area for morel mushrooms in China reached nearly 20,000 hectares, with predominant cultivars including M. sextelata, M. importuna and M. exima (Bian et al., 2024). In March 2022, however, deformities of friting bodies were observed in M. importna at morel mushroom farms in Huaihua city (28.43°N, 110.47°), China, with an incidence rate ranging from 5% to 10%. The disease symptoms begin with the invasion of the hymenium of morel mushroom by white cotton-like mycelia, ultimately resulting in halted fruiting body growth and the manifestation of anomalous fruiting body morphology. Infected samples were collected from the morel growers. Following sterilization with 75% ethanol of the surrounding tissue of infected samples, the white hyphae from the morel lesions were picked out using a dissecting needle, and incubated onto potato saccharose agar medium supplemented with 60 mg/L streptomycin at 25°C. Studies showed that seven out of nine fungal isolates exhibiting identical morphological features rapidly grew on the same culture medium described above, reaching a length of 75 mm in 4 to 5 days at 25°C. The white and thick hyphal colonies of these isolates gradually filled with brown spore powder. Generally, the conidia of the hyphal colonies were polyblastic with protrusions at the tips, measuring 75 to 165 × 36 to 50 µm (n = 30) in width and length, displaying colors varying from light reddish brown to grayish brown, and possessing one or five septa. To confirm the identity of the pathogen, the region of the internal transcribed spacer region (ITS), 28S nuclear ribosomal large subunit (LSU), and RNA polymerase II second largest subunit (rpb2) genes of the representative isolate H2 were amplified by PCR (Taguiam, et al. 2021). The generated ITS (OR338304), rpb2 (OR452112) and LSU (OR338334) from the isolate H2 had 98-100% similarity to the Alternaria alternata strains ATCC 6663 and CBS 880.95 in BLASTn analysis. ITS, rpb2 and LSU sequences were assembled using Sequence Matrix, and their homogeneity was assessed with PAUP (Vaidya et al., 2011). Bayesian (MrBayes-3.2.7a) and maximum-likelihood (RAxML1.3.1) methods, utilizing the best fit GTR+G+I model obtained from MrModeltest 2.3, were employed for phylogenetic analysis (Aveskamp et al. 2010). Based on morphological characteristics and phylogenetic analysis, the isolate H2 was identified as A. alternata. In the second year post-disease, disease-free morels, with a height of 3 cm, were cultivated in field greenhouses and used for test. A 15 ml suspension (1 × 106 conidia/ml) was applied to 15 young fruiting bodies and their corresponding substrate soil. The results showed that the reappearance of white cotton-like mycelia and deformed M. importuna fruiting bodies within 7 days post-inoculation with the spore suspension, as opposed to the controls. The isolates (H2-1, H2-2 and H2-3) were reisolated from the infected tissues and identified as A. alternata based on its morphological features and phylogenetic analyses. In this study, a similar investigation was previously conducted on cultivated quinoa (Chenopodium quinoa) in Eastern Denmark (Colque-Little et al., 2023). This study marks the first documentation of A. alternata causing deformities in M. importuna fruiting bodies. These deformities occur under conditions of high-temperature (>22°C) and high humidity (>88%). Our findings provide crucial insights for managing A. alternata in M. importuna cultivation in China.

Morpho-Molecular Characterization Reveals a New Genus, Three Novel Species and Two New Host Records in Xylariomycetidae.

Xylariomycetidae comprises extremely diverse taxa that are widespread on decaying wood worldwide. An investigation of the diversity of microfungi on oil tree plantations in Sichuan Province was conducted during 2020-2021. Twelve saprobic taxa representing five species were identified as members of Amphisphaeriales and Xylariales through morphological comparisons. Phylogenetic analyses of combined ITS, LSU, rpb2, tub2 and tef1 sequence data indicated a distinct clade formed by three strains within Xylariomycetidae, unrelated to any currently recognized families. Thus, a novel anthostomella-like genus, Bicellulospora, is proposed and treated as Xylariales genera incertae sedis. Bicellulospora is characterized by dark brown to black, immersed, subglobose ascomata with a clypeus, cylindrical asci, and hyaline to yellowish brown, inequilaterally ellipsoidal ascospores with a large upper cell and a dwarf lower cell. Two new species of Amphisphaeria, namely A. oleae and A. verniciae, are introduced based on multi-gene phylogenetic analyses (ITS, LSU, rpb2 and tub2) coupled with morphological characteristics. Amphisphaeria micheliae and Endocalyx ptychospermatis are reported as new host records.

Transarterial chemoembolization with/without immune checkpoint inhibitors plus tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a single center, propensity score matching real-world study.

OBJECTIVES: To explore the efficacy and safety of Transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: 456 patients with HCC receiving either TACE in combination with ICIs and TKIs (combination group, n = 139) or TACE monotherapy (monotherapy group, n = 317) were included from Apr 2016 to Dec 2021 in this retrospective study. We employed propensity score matching (PSM), performed 1:2 optimal pair matching, to balance potential bias. RESULTS: The mean follow-up time is 24.7 months (95% CI 22.6-26.8) for matched patients as of March 2022. After matching, the combination group achieved longer OS and PFS (median OS:21.9 vs. 16.3 months, P = 0.022; median PFS: 8.3 vs. 5.1 months, P < 0.0001) than TACE monotherapy group. The combination group had better objective response rate (ORR) and disease control rate (DCR) (ORR: 52.5% vs. 32.8%, P < 0.001; DCR: 82.7% vs. 59.6%, P < 0.001). Subgroup analysis showed that patients who received "TKIs + ICIs" after the first TACE procedure (after TACE group) achieved longer OS than those before the first TACE procedure (before TACE group) (26.8 vs. 19.2 months, P = 0.011). Adverse events were consistent with previous studies of TACE-related trials. CONCLUSIONS: TACE plus TKIs and ICIs appeared to deliver longer PFS and OS in HCC patients than TACE monotherapy. "TKIs + ICIs" co-treatment within 3 months after the first TACE procedure might be a better medication strategy.

Aggregation of graphene oxide upon the stripping of oxidized debris: An experimental and molecular dynamics simulation study.

The most recent structural study of graphene oxide (GO) indicates that the oxidized debris (ODs) adhered to as-prepared GO will strip in certain aquatic settings. The impact of ODs stripping on the characteristics of GO has been widely reported, but its effects on GO aggregation have received less attention. Here, the influence of OD stripping on the GO aggregation property was identified, and the aggregation of as-prepared GO and GO upon OD stripping was compared. Upon ODs stripping, the pKa values of GO shifted from 3.91, 6.25, and 9.84 to 4.54, 6.65, and 10.21, respectively. Further analysis indicated the removal of ODs reduced the net negative charge and improved the hydrophobicity of GO, hence promoting the aggregation of GO. The acceleration of GO-Ca2+-OD aggregate formation was facilitated by the collective effects of ODs stripping, functional group deprotonation, double layer compression, OD bridging, and charge neutralization. The metal ions and stripped ODs attach to GO edges and link GO, which perform like bridges and contribute to further aggregation. In general, the existence of ODs adds complexity to the constructions and characteristics of GO, and it is important to take this into account while evaluating the aggregation characteristic of GO-based materials.

A Versatile Thioesterase Involved in Dimerization during Cinnamoyl Lipid Biosynthesis.

The cinnamoyl lipid compound youssoufene A1 (1), featuring a unique dearomatic carbon-bridged dimeric skeleton, exhibits increased inhibition against multidrug resistant Enterococcus faecalis as compared to monomeric youssoufenes. However, the formation process of this intriguing dearomatization/dimerization remains unknown. In this study, an unusual "gene-within-gene" thioesterase (TE) gene ysfF was functionally characterized. The gene was found to naturally encodes two proteins, an entire YsfF with α/ß-hydrolase and 4-hydroxybenzoyl-CoA thioesterase (4-HBT)-like enzyme domains, and a nested YsfFHBT (4-HBT-like enzyme). Using an intracellular tagged carrier-protein tracking (ITCT) strategy, in vitro reconstitution and in vivo experiments, we found that: i) both domains of YsfF displayed thioesterase activities; ii) YsfF/YsfFHBT could accomplish the 6π-electrocyclic ring closure for benzene ring formation; and iii) YsfF and cyclase YsfX together were responsible for the ACP-tethered dearomatization/dimerization process, possibly through an unprecedented Michael-type addition reaction. Moreover, site-directed mutagenesis experiments demonstrated that N301, E483 and H566 of YsfF are critical residues for both the 6π-electrocyclization and dimerization processes. This study enhances our understanding of the multifunctionality of the TE protein family.

Clostridium perfringens α toxin damages the immune function, antioxidant capacity and intestinal health and induces PLCγ1/AMPK/mTOR pathway-mediated autophagy in broiler chickens.

Clostridium perfringens α toxin is generated by all types of C. perfringens and is closely related to necrotic enteritis in poultry. This study was conducted to investigate the effects of α toxin on immune function, antioxidant capacity, intestinal health and the underlying mechanisms in broiler chickens. A total of 144 twenty-day-old broiler chickens were randomly assigned to four treatments. On d 21, the birds were intraperitoneally injected with PBS (control group) or α toxin at 0.025, 0.1 or 0.4 U/kg of body weight. Samples were collected at 3 h and 24 h post injection (p.i.). Results showed that α toxin challenge linearly decreased the average daily gain during the 3 days after infection and decreased plasma IgA and IgM levels 3 h p.i. Plasma diamine oxidase and d-lactate levels were linearly elevated by α toxin challenge at 3 h p.i. and 24 h p.i. Alpha toxin challenge linearly decreased plasma and jejunal mucosal catalase, glutathione peroxidase and total superoxide dismutase activities at 3 h p.i. and linearly decreased glutathione peroxidase and total superoxide dismutase activities at 24 h p.i. The ileal villus height to crypt depth ratio decreased linearly with increasing α toxin levels at 3 h p.i. and 24 h p.i. Alpha toxin challenge linearly elevated jejunal IL-1ß, IL-6, IL-8 and tumor necrosis factor α mRNA expression at 3 h p.i. Additionally, α toxin challenge linearly reduced the jejunal claudin-1, claudin-3 and zonula occludens 1 mRNA expression at 3 h p.i. and the claudin-3, occludin and zonula occludens 1 mRNA expression at 24 h p.i. What's more, α toxin linearly increased the jejunal PLCγ1, AMPKα1 and ATG5 mRNA expression and linearly decreased the mTOR mRNA expression. In conclusion, C. perfringens α toxin challenge decreased body weight gain, impaired immune function, antioxidant capacity and intestinal health, and induced PLCγ1/AMPK/mTOR pathway-mediated autophagy. The recommended intraperitoneal injection dose for moderate injury was 0.1 U/kg of body weight and the recommended sampling time was 3 h p.i. in broiler chickens.

Involvement of expanded cytotoxic and proinflammatory CD28null T cells in primary Sjögren's syndrome.

OBJECTIVE: The absence of CD28 is a feature of antigen-experienced, highly differentiated and aged T cells. The pathogenicity of CD28null T cells remains elusive in primary Sjögren's syndrome (pSS). Therefore, this study was performed to explore the characteristics of CD28null T cells in both peripheral blood and minor salivary glands (MSGs) of pSS patients. METHODS: pSS patients and paired healthy controls (HCs) were enrolled. The phenotype of peripheral CD28null T cells was analyzed using flow cytometry. In vitro functional assays were performed to evaluate the cytotoxic and proinflammatory effects of peripheral CD28null T cells. In addition, polychromatic immunofluorescence staining was performed to investigate infiltrating CD28null T cells in MSGs. RESULTS: A significant expansion of peripheral CD28null T cells was observed in pSS patients compared with HCs (p < 0.001), which were primarily CD8+CD28null T cells. The proportion of peripheral CD8+CD28null T cells moderately correlated with the erythrocyte sedimentation rate (r = 0.57, p < 0.01) and IgG levels (r = 0.44, p < 0.01). Peripheral CD28null T cells had stronger capacities to secrete granzyme B and perforin, but comparable capacities to secrete IFN-γ and TNF-α than their CD28+ counterparts. An abundant amount of cytotoxic and pro-inflammatory CD28null T cells was also found in MSGs. Moreover, a high expression of the chemokine receptor CXCR3 was found on peripheral and tissue-resident CD28null T cells, with its ligands CXCL9/10 abundantly present in MSGs. CONCLUSION: Increasing CD28null T cells with strong cytotoxicity and proinflammatory effects were observed in both peripheral blood and MSGs from pSS patients. The precise mechanism of action and migration still needs further investigation.

Topographic metabolism-function relationships in Alzheimer's disease: A simultaneous PET/MRI study.

Disruptions of neural metabolism and function occur in parallel during Alzheimer's disease (AD). While many studies have shown diverse metabolic-functional relationships in specific brain regions, much less is known about how large-scale network-level functional activity is associated with the topology of metabolism in AD. In this study, we took the advantages of simultaneous PET/MRI and multivariate analyses to investigate the associations between AD-related stereotypical spatial patterns (topographies) of glucose metabolism, measured by fluorodeoxyglucose PET, and functional connectivity, measured by resting-state functional MRI. A total of 101 participants, including 37 patients with AD, 25 patients with mild cognitive impairment (MCI), and 39 cognitively normal controls, underwent PET/MRI scans and cognitive assessments. Three pairs of distinct but optimally correlated metabolic and functional topographies were identified, encompassing large-scale networks including the default-mode, executive and control, salience, attention, and subcortical networks. Importantly, the metabolic-functional associations were not only limited to one-to-one-corresponding regions, but also occur in remote and non-overlapping regions. Furthermore, both glucose metabolism and functional connectivity, as well as their linkages, exhibited various degrees of disruptions in patients with MCI and AD, and were correlated with cognitive decline. In conclusion, our results support distributed and heterogeneous topographic associations between metabolism and function, which are jeopardized by AD. Findings of this study may deepen our understanding of the pathological mechanism of AD through the perspectives of both local energy efficiency and long-term interactions between synaptic disruption and functional disconnection contributing to the clinical symptomatology in AD.

Generation of streptocarbazoles with cytotoxicities by pathway engineering and insights into their biosynthesis.

Streptocarbazoles are a class of indolocarbazole (ICZ) compounds produced by Streptomyces strains that feature unique cyclic N-glycosidic linkages between the 1,3-carbon atoms of the glycosyl moiety and the two indole nitrogen atoms. Although several streptocarbazole compounds display effective cytotoxic activity, their biosynthesis remains unclear. Herein, through the inactivation of the aminotransferase gene spcI in the staurosporine biosynthetic gene cluster spc followed by heterologous expression, two new streptocarbazole derivatives (1 and 3) and three known ICZs (2, 4, and 5) were generated. Their structures were determined by a combination of spectroscopic methods, circular dichroism measurements, and single-crystal X-ray diffraction. Compounds 1-4 displayed moderate cytotoxicity against HCT-116 cell line, and compounds 3 and 4 were effective against Huh 7 cell line. Double-gene knockout experiments allowed us to propose a biosynthetic pathway for streptocarbazole productions. Furthermore, by overexpression of the involving key enzymes, the production of streptocarbazoles 1 and 3 were improved by approximately 1.5-2.5 fold. IMPORTANCE: Indolocarbazoles (ICZs) are a group of antitumor agents, with several analogs used in clinical trials. Therefore, the identification of novel ICZ compounds is important for drug discovery. Streptocarbazoles harbor unique N-glycosidic linkages (N13-C1' and N12-C3'), distinguishing them from the representative ICZ compound staurosporine; however, their biosynthesis remains unclear. In this study, two new streptocarbazoles (1 and 3) with cytotoxic activities were obtained by manipulating the staurosporine biosynthetic gene cluster spc followed by heterologous expression. The biosynthetic pathway of streptocarbazoles was proposed, and their productions were improved through the overexpression of the key enzymes involved. This study enriches the structural diversity of ICZ compounds and would facilitate the discovery of new streptocarbazoles via synthetic biological strategies.

An Evaluation of Paddy Rice as an Alternative Energy Source in Protein-Restricted Diets for Growing, Early-Finishing, and Late-Finishing Pigs.

Three experiments were conducted to evaluate paddy rice as an alternative energy feedstuff in low-protein diets for pigs. In Experiment 1, a total of 400 growing pigs (20.68 ± 0.29 kg initial bodyweight), were randomly allocated four dietary treatments with 0, 10, 15, and 20% paddy rice for 30 days. Feeding 10% or 15% paddy rice had no adverse impacts on average daily gain (ADG) and feed to gain ratio (F:G), while the inclusion of 20% rice in diets significantly influenced the growth performance of pigs. In Experiment 2, 364 early-finishing pigs (42.25 ± 0.47 kg) were divided into four treatments with 0, 15, 20, and 25% paddy rice for 35 days. Feeding 15% or 20% paddy rice had no negative consequences on growth performance, while pigs fed with 25% rice had the lowest ADG and the greatest F:G. In Experiment 3, 364 late-finishing pigs (79.52 ± 1.28 kg) were divided into four treatments with 0, 20, 25, and 30% paddy rice for 60 days. Paddy rice can be included at up to 30% in diets without compromising growth performance, while feeding with 25% rice significantly improved the performance for pigs compared with the corn-fed control.

Higher risk of hepatotoxicity associated with cabozantinib in cancer patients.

BACKGROUND: The efficacy of cabozantinib has attracted interest in various solid tumors. The primary aim of this study was to evaluate the risk of hepatotoxicity associated with cabozantinib in the patients with cancer. METHODS: PubMed, Cochrane, and EMBASE databases were searched for published randomized controlled trials (RCTs) from inception to September 9, 2023. The mainly outcomes were all-grade and grade ≥3 elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), expressed as relative risk (RR) and 95% confidence interval (CI). All data were pooled using fixed-effect or random-effects models according to the heterogeneity of the included RCTs. RESULTS: Among the 922 records identified, 8 RCTs incorporating 2613 patients with cancer were included. For patients receiving cabozantinib, the relative risks of all-grade AST elevation (RR, 2.63; 95% CI, 2.16-3.20, P < 0.001), all-grade ALT elevation (RR, 2.89; 95% CI, 2.31-3.60, P < 0.001), grade ≥3 AST elevation (RR, 2.26; 95% CI, 1.34-3.83, P = 0.002), and grade ≥3 ALT elevation (RR, 3.40; 95% CI, 1.65-7.01, P < 0.001) were higher than those of patients who did not receive cabozantinib group. Further subgroup analysis showed that the relative risk of hepatotoxicity associated with cabozantinib was higher than that in the other TKIs (erlotinib, sunitinib, and sorafenib) and the non-TKI drug groups (everolimus, prednisone, mitoxantrone, and paclitaxel). CONCLUSIONS: Compared with other solid tumor drugs, such as everolimus, sorafenib, sunitinib, paclitaxel, mitoxantrone-prednisone et al., cabozantinib has a higher risk of hepatotoxicity.

Prognostic characteristics of a six-gene signature based on ssGSEA in sarcoma.

BACKGROUND: Sarcoma is a rare malignant tumor originating of the interstitial or connective tissue with a poor prognosis. Next-generation sequencing technology offers new opportunities for accurate diagnosis and treatment of sarcomas. There is an urgent need for new gene signature to predict prognosis and evaluate treatment outcomes. METHODS: We used transcriptome data from the Cancer Genome Atlas (TCGA) database and single sample gene set enrichment analysis (ssGSEA) to explore the cancer hallmarks most associated with prognosis in sarcoma patients. Then, weighted gene coexpression network analysis, univariate COX regression analysis and random forest algorithm were used to construct prognostic gene characteristics. Finally, the prognostic value of gene markers was validated in the TCGA and Integrated Gene Expression (GEO) (GSE17118) datasets, respectively. RESULTS: MYC targets V1 and V2 are the main cancer hallmarks affecting the overall survival (OS) of sarcoma patients. A six-gene signature including VEGFA, HMGB3, FASN, RCC1, NETO2 and BIRC5 were constructed. Kaplan-Meier analysis suggested that higher risk scores based on the six-gene signature associated with poorer OS (P < 0.001). The receiver Operating characteristic curve showed that the risk score based on the six-gene signature was a good predictor of sarcoma, with an area under the curve (AUC) greater than 0.73. In addition, the prognostic value of the six-gene signature was validated in GSE17118 with an AUC greater than 0.72. CONCLUSION: This six-gene signature is an independent prognostic factor in patients with sarcoma and is expected to be a potential therapeutic target for sarcoma.

Synergistic effects of achieving perinatal interventions on bronchopulmonary dysplasia in preterm infants.

To investigate the effect of perinatal interventions on the risk of severe BPD (sBPD) and death in extremely preterm infants (EPIs) and their synergistic effects. This was a secondary analysis of the prospective cohort Chinese Neonatal Network (CHNN). Infants with a birth weight of 500 to 1250 g or 24-28 weeks completed gestational age were recruited. The impacts and the synergistic effects of six evidence-based perinatal interventions on the primary outcomes of sBPD and death were assessed by univariate and multivariable logistic regression modeling. Totally, 6568 EPIs were finally enrolled. Antenatal corticosteroid (adjusted OR, aOR, 0.74; 95%CI, 0.65-083), birth in centers with tertiary NICU (aOR, 0.64; 95%CI, 0.57-0.72), preventing intubation in the delivery room (aOR, 0.65; 95%CI, 0.58-0.73), early caffeine therapy (aOR, 0.59; 95%CI, 0.52-0.66), and early extubating (aOR, 0.42; 95%CI 0.37-0.47), were strongly associated with a lower risk of sBPD and death while early surfactant administration was associated with a lower risk of death (aOR, 0.84; 95%CI, 0.72, 0.98). Compared with achieving 0/1 perinatal interventions, achieving more than one intervention was associated with decreased rates (46.6% in 0/1 groups while 38.5%, 29.6%, 22.2%, 16.2%, and 11.7% in 2/3/4/5/6-intervention groups respectively) and reduced risks of sBPD/death with aORs of 0.76(0.60, 0.96), 0.55(0.43, 0.69), 0.38(0.30, 0.48), 0.28(0.22, 0.36), and 0.20(0.15, 0.27) in 2, 3, 4, 5, and 6 intervention groups respectively. Subgroup analyses showed consistent results. CONCLUSION: Six perinatal interventions can effectively reduce the risk of sBPD and death in a synergistic form. WHAT IS KNOWN: • Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease associated with prematurity. The effective management of BPD requires a comprehensive set of interventions. However, the extent to which these interventions can mitigate the risk of severe outcomes, such as severe BPD or mortality, or if they possess synergistic effects remains unknown. WHAT IS NEW: • The implementation of various perinatal interventions, such as prenatal steroids, birth in centers with tertiary NICU, early non-Invasive respiratory support, surfactant administration within 2 hours after birth, early caffeine initiation within 3 days, and early extubation within 7 days after birth has shown promising results in the prevention of severe bronchopulmonary dysplasia (BPD) or mortality in extremely preterm infants. Moreover, these interventions have demonstrated synergistic effects when implemented in combination.