The antiviral role of largemouth bass STING against iridovirus infection.

Stimulator of interferon gene (STING) plays a crucial role in the innate immune response against viral and bacterial pathogens. However, its function in largemouth bass iridovirus (LMBV) infection remains uncertain. Here, a STING homolog (MsSTING) from largemouth bass (Micropterus salmoides) was cloned and characterized. MsSTING encoded a 407-amino-acid polypeptide, which shared 84.08% and 41.45% identity with golden perch (Perca flavescens) and human (Homo sapiens) homologs, respectively. MsSTING contained four transmembrane domains and a conserved C-terminal domain. The mRNA level of MsSTING was significantly increased in response to LMBV infection in vitro. Subcellular localization observation indicated that MsSTING encoded a cytoplasmic protein, which co-localized predominantly with endoplasmic reticulum (ER) and partially with mitochondria. Moreover, its accurate localization was dependent on the N-terminal transmembrane motif (TM) domains. MsSTING was able to activate interferon (IFN) response, evidenced by the activation of IFN1, IFN3 and ISRE promoters by its overexpression in vitro. Mutant analysis showed that both the N-terminal and C-terminal domain of MsSTING were essential for its activation on IFN response. In addition, overexpression of MsSTING inhibited the transcription and protein levels of viral core genes, indicating that MsSTING exerted antiviral action against LMBV. Consistently, the inhibitory effects were significantly attenuated when the N-terminal or C-terminal domains of MsSTING was deleted. Furthermore, MsSTING overexpression upregulated the transcriptions of interferon-related genes and pro-inflammatory factors, including TANK-binding kinase 1(TBK1), interferon regulatory factor 3 (IRF3), interferon regulatory factor 7 (IRF7), interferon stimulated exonuclease gene 20 (ISG20), interferon-induced transmembrane protein 1(IFITM1), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6). Together, MsSTING exerted antiviral action upon LMBV infection through positive regulation the innate immune response.

Singapore Grouper Iridovirus VP131 Drives Degradation of STING-TBK1 Pathway Proteins and Negatively Regulates Antiviral Innate Immunity.

Iridoviruses are large DNA viruses which cause great economic losses to the aquaculture industry and serious threats to ecological diversity worldwide. Singapore grouper iridovirus (SGIV), a novel member of the genus Ranavirus, causes high mortality in grouper aquaculture. Previous work on genome annotation demonstrated that SGIV contained numerous uncharacterized or hypothetical open reading frames (ORFs), whose functions remained largely unknown. Here, we reported that the protein encoded by SGIV ORF131R (VP131) was localized predominantly within the endoplasmic reticulum (ER). Ectopic expression of GFP-VP131 significantly enhanced SGIV replication, while VP131 knockdown decreased viral infection in vitro, suggesting that VP131 functioned as a proviral factor during SGIV infection. Overexpression of GFP-VP131 inhibited the interferon (IFN)-1 promoter activity and mRNA level of IFN-related genes induced by poly(I:C), Epinephelus coioides cyclic GMP/AMP synthase (EccGAS)/stimulator of IFN genes (EcSTING), TANK-binding kinase 1 (EcTBK1), or melanoma differentiation-associated gene 5 (EcMDA5), whereas such activation induced by mitochondrial antiviral signaling protein (EcMAVS) was not affected. Moreover, VP131 interacted with EcSTING and degraded EcSTING through both the autophagy-lysosome pathway and ubiquitin-proteasome pathway, and targeted for the K63-linked ubiquitination. Of note, we also found that EcSTING significantly accelerated the formation of GFP-VP131 aggregates in co-transfected cells. Finally, GFP-VP131 inhibited EcSTING- or EcTBK1-induced antiviral activity upon red-spotted grouper nervous necrosis virus (RGNNV) infection. Together, our results demonstrated that the SGIV VP131 negatively regulated the IFN response by inhibiting EcSTING-EcTBK1 signaling for viral evasion. IMPORTANCE STING has been identified as a critical factor participating in the innate immune response which recruits and phosphorylates TBK1 and IFN regulatory factor 3 (IRF3) to induce IFN production and defend against viral infection. However, viruses also distort the STING-TBK1 pathway to negatively regulate the IFN response and facilitate viral replication. Here, we reported that SGIV VP131 interacted with EcSTING within the ER and degraded EcSTING, leading to the suppression of IFN production and the promotion of SGIV infection. These results for the first time demonstrated that fish iridovirus evaded the host antiviral response via abrogating the STING-TBK1 signaling pathway.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Grouper interferon-induced protein 35, a CP-interacting protein, inhibits fish nodavirus replication via positively regulating host interferon and inflammatory immune response.

Interferon (IFN)-induced protein 35 (IFI35, also known as IFP35), a member of IFN induced genes (ISGs), participates in virus infection, cancer progression and the chronic inflammatory diseases. However, its roles during fish nodavirus infection still remained largely unknown. In the present study, a homolog of IFI35 from orange spotted grouper (Epinephelus coioides) (EcIFI35) was cloned and characterized. The open reading frame of EcIFI35 was composed of 1,128 bp, and encoded a 375 amino acid polypeptide, which contained two conserved N-myc-interactor (Nmi)/IFP35 domains (NIDs). Homology analysis indicated that EcIFI35 shared 95.73% and 31.96% identity with homologs of giant grouper (E. lanceolatus) and human (Homo sapiens), respectively. The transcription of EcIFI35 was significantly up-regulated in grouper spleen (GS) cells after challenged with red-spotted grouper nervous necrosis virus (RGNNV), polyinosinic:polycytidylic acid [poly(I:C)] or lipopolysaccharide (LPS). The subcellular localization analysis showed that EcIFI35 encoded a cytoplasmic protein. The ectopic expression of EcIFI35 inhibited RGNNV replication by reducing viral genes transcription and protein synthesis. Co-immunoprecipitation (Co-IP) assay demonstrated that EcIFI35 interacted with RGNNV coat protein (CP), and partly co-localized with CP. EcIFI35 overexpression promoted the expression of IFN-related molecules and pro-inflammatory factors, including IFN regulatory factor 7 (IRF7), mitochondrial antiviral signaling protein (MAVS) and myxovirus resistance gene I (MxI), nuclear factor κB (NF-κB), interleukin 6 (IL-6) and IL-8. Together, our results revealed that EcIFI35 interacted with CP and inhibited fish nodavirus replication through positively regulated host innate immune response.

Synthetic flavagline derivative 1-chloroacetylrocaglaol promotes apoptosis in K562 erythroleukemia cells through miR-17-92 cluster genes.

Chronic myeloid leukemia accounts for human deaths worldwide and could enhance sevenfold by 2050. Thus, the treatment regimen for this disorder is highly crucial at this time. Flavaglines are a natural class of cyclopentane benzofurans exhibiting various bioactivities like anticancer action. Despite the antiproliferative activity of flavaglines against diverse cancer cells, their roles and mechanism of action in chronic myeloid leukemia (CML) remain poorly understood. Thus, this study examines the antiproliferative effect of a newly synthesized flavagline derivative, 1-chloracetylrocaglaol (A2074), on erythroleukemia K562 cells and the zebrafish xenograft model. The study revealed that A2074 could inhibit proliferation, promote apoptosis, and boost megakaryocyte differentiation of K562 cells. This flavagline downregulated c-MYC and miR-17-92 cluster genes, targeting upregulation of the apoptotic protein Bcl-2-like protein 11 (BIM). The work uncovered a critical role of the c-MYC-miR-17-92-BIM axis in the growth and survival of CML cells.

Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

Body Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory Study.

We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use.

Application of Bone Turnover Markers PICP and ß-CTx in the Diagnosis and Treatment of Breast Cancer with Bone Metastases.

BACKGROUND: This study is to investigate the application of the bone turnover markers type I procollagen carboxyterminal propeptide (PICP) and ß-isomerized forms of type I collagen breakdown products (ß-CTx) in the diagnosis and treatment of breast cancer with bone metastases. METHODS: A total of 162 breast cancer patients were included in this study. There were 70 cases with bone metastasis (BM group) and 92 cases without bone metastasis (non-bone metastasis, NBM group). The levels of the bone turnover markers PICP and ß-CTx were measured using Electro-Chemiluminescence Immunoassay to compare the difference between BM and NBM group, before and after treatments in the NBM group, and to analyse the relationship with therapeutic effects. RESULTS: The BM group had higher PICP and ß-CTx levels than the NBM group and also higher in the non-luminal type group than the luminal type group, the differences were all statistically significant. However, no statistically significant differences were found among the pN0, pN1, pN2, and pN3 subgroups of the NBM group. Among the 70 cases of BM patient after 3 months of treatment, there were 48 cases that showed clinical benefits, with significantly reduced PICP and ß-CTx levels (p = 0.02, p = 0.00, respectively), but 22 cases showed disease progression with elevated PICP and ß-CTx levels (p = 0.01, p = 0.04, respectively). CONCLUSIONS: The bone turnover markers PICP and ß-CTx have crucial value in the diagnosis and treatment efficacy evaluation for women of breast cancer with bone metastases.

Effects of medical consortium policy on health services: an interrupted time-series analysis in Sanming, China.

Objectives: China has implemented reforms to enhance the operational efficiency of three-level medical services through medical consortiums (MCs). This study evaluated the impact of MCs reform on health services in Sanming, China. Methods: An interrupted time-series analysis (ITSA) was conducted to assess the impact of MCs on changes in health service levels and trends across the overall situation of MCs and different institutional types within MCs, including county hospitals and grassroots medical institutions. The evaluation focused on various indicators such as outpatient and emergency visits, inpatients, average length of stay, occupancy rate of hospital beds, and hospital bed turnover times. Monthly data were collected from April 2015 to June 2019 through reports on the Sanming Municipal Health Commission website and the Sanming public hospital management monitoring platform. Results: After the intervention of MCs reform, a significant increase was observed in the total number of inpatients (ß3 = 174.28, p < 0.05). However, no statistically significant change was observed in the total number of outpatient and emergency visits (ß3 = 155.82, p = 0.91). Additionally, the implementation of MCs reform led to an amplification in service volumes provided by county hospitals, with significant increases in the number of outpatient and emergency visits (ß3 = 1376.54, p < 0.05) and an upward trend in the number of inpatients (ß3 = 98.87, p < 0.01). However, no significant changes were observed under the MCs policy for grassroots medical institutions regarding the number of outpatient and emergency visits (ß3 = -1220.72, p = 0.22) and number of inpatients (ß3 = 75.42, p = 0.09). Conclusion: The Sanming MCs reform has achieved some progress in augmenting service volumes. Nevertheless, it has not led to an increase in service volumes at the grassroots medical institutions. There persists an insufficiency in the efficiency of services and a need for further improvement in primary healthcare. To address these concerns, it is imperative for county hospitals to offer targeted assistance that can enhance motivation among grassroots medical institutions. Besides the MCs should explore initiatives, including improved management of medical equipment, allocation of funding, and personnel resources.

Development and Application of Colloidal Gold Test Strips for the Rapid Detection of Canine Brucellosis.

Brucellosis is a global problem, with the causative agent being the genus Brucella. B. canis can cause undulant fever in dogs, which is a zoonotic disease that can spread not only among dogs but also to humans. This poses a public health threat to society. In this study, a rapid and straightforward immune colloidal gold test strip was developed for the diagnosis of canine brucellosis through the detection of anti-LPS antibodies in serum samples. Rabbit anti-canine IgG conjugated with colloidal gold was employed as the colloidal gold-labeled antibody. The extracted high-purity R-LPS was employed as the capture antigen in the test line (T-line), while goat anti-rabbit IgG was utilized as the capture antibody in the control line (C-line). The colloidal gold strip exhibited high specificity in the detection of brucellosis, with no cross-reaction observed with the common clinical canine diseases caused by Canine coronavirus (CCV), Canine distemper virus (CDV), and Canine parvovirus (CPV). In comparison to the commercial iELISA kit, the sensitivity and specificity of the colloidal gold test strip were found to be 95.23% and 98.76%, respectively. The diagnostic coincidence rate was 98.47%. The findings of this study indicate that colloidal gold test strips may be employed as a straightforward, expeditious, sensitive, and specific diagnostic instrument for the identification of canine brucellosis, particularly in resource-limited regions.

Extracellular volume fraction can predict the treatment response and survival outcome of colorectal cancer liver metastases.

OBJECTIVE: To assess the prognostic value of pre- and post-therapeutic changes in extracellular volume (ECV) fraction of liver metastases (LMs) for treatment response (TR) and survival outcomes in colorectal cancer liver metastases (CRLM). METHODS: 186 LMs were confirmed by pathology or follow-up (Training: 130; Test: 56). We analyzed the changes in ECV fraction of LMs before and after 2 cycles of chemotherapy combined with bevacizumab. After 12 cycles, we evaluated the TR on LMs based on the RECIST v1.1. Relative changes in ECV fraction and Hounsfield Units (HU), defined as ΔECV and ΔHU, were associated with progression-free survival (PFS), overall survival (OS), and TR. We identified TR predictors with multivariate logistic regression and PFS, OS risk factors with COX analysis. RESULTS: 186 LMs were classified as TR lesions (TR+: 84) and non-TR lesions (TR-:102). ΔECV, ΔHUA-E, and texture could distinguish the TR of LMs in training and test set (P < 0.05). ΔECV [Odds ratio (OR): 1.03; 95% Confidence interval (CI): 1.02-1.05, P < 0.01] was an independent predictor of TR-. Area under the curve (AUC), sensitivity and specificity of TR model in training and test set were 0.87, 0.84, 90.14%, 90.32%, 72.88%, 64.00%, respectively. High CRD_score indicates that patients have shorter PFS [Hazard ratio (HR): 2.01; 95%CI: 1.02-3.98, P = 0.045)] and OS (HR: 1.89, 95%CI: 1.04-3.42, P = 0.038). CONCLUSION: ΔECV can be used as an independent predictor of TR of CRLM chemotherapy combined with bevacizumab.

Piperacillin/tazobactam treatment in children: evidence of subtherapeutic concentrations.

Objective: Piperacillin/tazobactam (PIP/TAZ) is used for the treatment of lower respiratory tract bacterial infections in children. This study was performed to evaluate if the current dosing regimen results in therapeutic drug concentrations. Patients and methods: Patients suspected or proven to have lower respiratory tract bacterial infection and administrated PIP/TAZ intravenously for a duration of no less than 0.5 h, q6h-q12h daily, were enrolled. Blood samples were collected, and PIP concentrations were determined by high-performance liquid chromatography. The individual predicted concentration of PIP was evaluated using the individual empirical Bayesian estimate method. The evaluated PK/PD targets included (1) 70% time when the predicted free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. Probability of target attainment (PTA) was assessed by the proportion of patients who reached the PK/PD targets. The PIP concentrations between different groups of patients were compared. Results: A total of 57 samples were collected from 57 patients with a median age of 2.26 years (0.17-12.58). For the PK/PD targets of 70% fT > MIC and 50% fT > 4× MIC for Pseudomonas aeruginosa and Klebsiella pneumoniae, the PTA was all 0. The median Cmin of PIP was significantly higher in infants than in children, and the median Cmin after administration in q8h was significantly higher than that after administration in q12h. Conclusion: The current dose regimen of PIP/TAZ leads to extremely low plasma concentrations in most children with lower respiratory tract bacterial infections. More optimized dosing regimens or better alternative therapies need to be further explored.

Drug-drug interactions of simnotrelvir/ritonavir: an open-lable, fixed-sequence, two-period clinical trial.

OBJECTIVES: Simnotrelvir is a small molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp. Hence, the drug-drug interaction (DDI) potential of simnotrelvir/ritonavir should be investigated. METHODS: This DDI study was an open-label, fixed-sequence, two-period Phase I clinical trial in Chinese healthy adult subjects, divided into 3 cohorts, including simnotrelvir/ritonavir co-administrated with a strong CYP3A and P-gp inhibitor (itraconazole) and inducer (rifampicin), and with a specific CYP3A substrate (midazolam). RESULTS: The results demonstrated that compared to administration of simnotrelvir/ritonavir alone, the co-administration with itraconazole increased the geometric least-square mean ratio (GMR) of the expose (AUC0-t) of simnotrelvir by 25% (GMR 125%, 90% confidence interval (CI) 114% - 137%), whereas co-administration with rifampicin significantly decreased the AUC0-t of simnotrelvir by 81.5% (GMR 18.5%, 90% CI 16.4% - 20.9%). Notably, simnotrelvir/ritonavir increased the AUC0-t of midazolam by 16.69-fold (GMR 1769%, 90% CI 1551% - 2018%). The co-administration of simnotrelvir/ritonavir and rifampicin caused the increased amount and severity of treatment-emergent adverse events, especially hepatotoxicity. CONCLUSIONS: The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, while the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam. GOV IDENTIFIER: NCT05665647.

Ribosomal protein L32 enhances hepatocellular carcinoma progression.

PURPOSE: The underlying mechanisms of hepatocellular carcinoma (HCC) have not been fully investigated, and effective biomarkers for HCC are still needed to be explored. Therefore, our study sought to thoroughly examine the clinical significance and biological functions of the ribosomal protein L32 (RPL32) in HCC by coupling bioinformatic methods with experimental analysis. METHODS: To determine the clinical significance of RPL32, bioinformatic analyses were performed to examine RPL32 expression in HCC patient samples and to correlate RPL32 expression and HCC patient survival rates, genetic alterations, and immune cell infiltration. Cell counting kit-8 assays, colony formation, flow cytometry, and transwell assays were performed to examine the effects of RPL32 on HCC cell proliferation, apoptosis, migration, and invasion in HCC cell lines (SMMC-7721 and SK-HEP-1) where RPL32 was silenced using small interfering ribonucleic acid. RESULTS: In the current study, we show that RPL32 was highly expressed in HCC samples. Moreover, high levels of RPL32 were associated with unfavorable outcomes in patients with HCC. Promoter methylation and copy number variation of RPL32 were associated with RPL32 mRNA expression. Results from the RPL32 silencing experiments indicated that the proliferation, apoptosis, migration, and invasion of SMMC-7721 and SK-HEP-1 cells were attenuated upon RPL32 depletion. CONCLUSION: RPL32 correlates with a favorable prognosis in patients with HCC and promotes the survival, migration, and invasion of HCC cells.

Research Note: Heat stress affects immune and oxidative stress indices of the immune organs of broilers by changing the expressions of adenosine triphosphate-binding cassette subfamily G member 2, sodium-dependent vitamin C transporter-2, and mitochondrial calcium uniporter.

This study aimed to determine the mechanisms of heat-induced oxidative stress in the thymus and spleen of broilers. After 28 d, 30 broilers were randomly divided into the control (25°C ± 2°C; 24 h/d) and heat-stressed (36°C ± 2°C; 8 h/d) groups; the experiment lasted for 1 wk. The broilers in each group were euthanized, and some samples were collected and analyzed at 35 d. The results showed that the birds subjected to heat stress reduced the weight (P < 0.01) and the indices of thymus (P < 0.01), the activities of T-AOC (P < 0.01) and SOD (P < 0.05) of spleen, and levels of IL-10 (P < 0.05) and the GSH-PX (P < 0.05) in thymus and spleen, and increased the IL-6 content of thymus (P < 0.05), the MDA content (P < 0.01), and the reactive oxygen species (ROS) levels (P < 0.01) in thymus and spleen. Moreover, the expression of the IgG gene in the thymus and spleen of heat-stressed broilers was increased (P < 0.05); however, the expression of the IgM gene in the spleen was increased (P < 0.05), with no difference (P > 0.05) in the thymus of heat-stressed broilers compared with the control. Furthermore, the relative expression of adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) in the thymus and spleen both increased (P < 0.05). The sodium-dependent vitamin C transporter-2 (SVCT-2) (P < 0.01) and mitochondrial calcium uniporter (MCU) (P < 0.01) mRNA levels in the thymus of heat-stressed broilers increased, and the expression of ABCG2 (P < 0.05), SVCT-2 (P < 0.01), and MCU (P < 0.01) proteins in the thymus and spleen of heat-stressed broilers increased compared with the control group. This study confirmed that heat stress-induced oxidative stress in the immune organs of broilers, further reducing immune function.

A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants.

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.

Deep learning imaging reconstruction of reduced-dose 40 keV virtual monoenergetic imaging for early detection of colorectal cancer liver metastases.

OBJECTIVE: To explore whether reduced-dose (RD) gemstone spectral imaging (GSI) and deep learning image reconstruction (DLIR) of 40 keV virtual monoenergetic image (VMI) enhanced the early detection and diagnosis of colorectal cancer liver metastases (CRLM). METHODS: Thirty-five participants with pathologically confirmed colorectal cancer were prospectively enrolled from March to August 2022 after routine care abdominal computed tomography (CT). GSI mode was used for contrast-enhanced CT, and two portal venous phase CT images were obtained [standard-dose (SD) CT dose index (CTDIvol) = 15.51 mGy, RD CTDIvol = 7.95 mGy]. The 40 keV-VMI were reconstructed via filtered back projection (FBP) and iterative reconstruction (ASIR-V 60 %, AV60) of both SD and RD images. RD medium-strength deep learning image reconstruction (DLIR-M) and RD high-strength deep learning image reconstruction (DLIR-H) were used to reconstruct the 40 keV-VMI. The contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of the liver and the lesions were objectively evaluated. The overall image quality, lesion conspicuity, and diagnostic confidence were subjectively evaluated, to compare the differences in evaluation results among the different images. RESULTS: All 35 participants (mean age: 59.51 ± 11.01 years; 14 females) underwent SD and RD GSI portal venous-phase CT scans. The dose-length product of the RD GSI scan was reduced by 49-53 % lower than that of the SD GSI scan (420.22 ± 31.95) vs (817.58 ± 60.56). A total of 219 lesions were identified, including 55 benign lesions and 164 metastases, with an average size of 7.37 ± 4.14 mm. SD-FBP detected 207 lesions, SD-AV60 detected 201 lesions, and DLIR-M and DLIR-H detected 199 and 190 lesions, respectively. For lesions ≤ 5 mm, there was no statistical difference between SD-FBP vs DLIR-M (χ2McNemar = 1.00, P = 0.32) and SD-AV60 vs DLIR-M (χ2McNemar = 0.33, P = 0.56) in the detection rate. The CNR, SNR, and noise of DLIR-M and DLIR-H 40 keV-VMI images were better than those of SD-FBP images (P < 0.01) but did not differ significantly from those of SD-AV60 images (P > 0.05). When the lesions ≤ 5 mm, there were statistical differences in the overall diagnostic sensitivity of lesions compared with SD-FBP, SD-AV60, DLIR-M and DLIR-H (P＜0.01). There were no statistical differences in the sensitivity of lesions diagnosis between SD-FBP, SD-AV60 and DLIR-M (both P＞0.05). However, the DLIR-M subjective image quality and lesion diagnostic confidence were higher for SD-FBP (both P < 0.01). CONCLUSION: Reduced dose DLIR-M of 40 keV-VMI can be used for routine follow-up care of colorectal cancer patients, to optimize evaluations and ensure CT image quality. Meanwhile, the detection rate and diagnostic sensitivity and specificity of small lesions, early liver metastases is not obviously reduced.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.