Effects of Different Tank Sizes on Laboratory Rare Minnow (Gobiocypris rarus)-Under the Same Density.

Laboratory fish play an important role in many research fields, and they are also raised and bred in many laboratories around the world. While many studies have suggested suitable feeding densities for various laboratory fish, significant variations exist in the sizes of rearing tanks across different laboratories. Moreover, there is limited research on the effects of different rearing tank sizes. In this study, we set up the same rearing density (one liter of water corresponding to two fishes) and four treatments with different tank sizes (5 L, 10 L, 15 L, 20 L). We found that different sizes of rearing tanks had no significant effect on the growth and shoaling of laboratory rare minnow. However, the rare minnow in 10 L tank had lower cortisol levels, while the rare minnow in 20 L tank had higher levels of dopamine (DA), serotonin (5-HT) and their metabolites (DOPAC and 5-HIAA). These results show that even under the same rearing density, different sizes of rearing tanks will still have a physiological effect on the rare minnow, and the tank size suitable for laboratory fish should be considered.

Correlation and efficacy of TACE combined with lenvatinib plus PD-1 inhibitor in the treatment of hepatocellular carcinoma with portal vein tumor thrombus based on immunological features.

BACKGROUND: Although the appearance of portal vein tumor thrombus (PVTT) is significantly associated with unfavorable prognosis, there is insufficient evidence to confirm the efficacy and safety of the triple combination of transarterial chemoembolization (TACE), lenvatinib, and programmed cell death-1 (PD-1) inhibitor for patients with hepatocellular carcinoma (HCC) and PVTT. Furthermore, it remains unclear which patient type can obtain the best survival benefit from this combination therapy. METHODS: The data of 160 patients with HCC and PVTT treated with TACE combined with lenvatinib plus PD-1 inhibitor (TACE+LEN + PD-1 group) or TACE combined with lenvatinib (TACE+LEN group) were retrospectively collected and analyzed. To estimate the efficacy and safety of combination therapy for patients with advanced HCC, tumor response, progression-free survival (PFS), overall survival (OS), biochemical indices, and adverse events (AEs) were assessed in this study. More importantly, tumor immune-related cytokines were used to identify biomarkers predicting the therapeutic response of combination therapy. RESULTS: TACE+LEN + PD-1 was superior to TACE+LEN in OS (23.5 vs. 18.3 months, p = 0.0002) and PFS (7.5 vs. 4.3 months, p < 0.0001). Moreover, TACE+LEN + PD-1 achieved more preferable benefits with respect to disease control rate (80.00% vs. 56.67%) and objective response rate (38.57% vs. 24.45%) compared with TACE+LEN in patients with HCC and PVTT (p = 0.025). Multivariate analysis showed that Child-Pugh grade, PVTT classification, treatment option, and interleukin (IL)-6, IL-17, interferon (IFN)-α, and vascular endothelial growth factor (VEGF) levels were independent factors related to OS, whereas PVTT classification, treatment option, and IL-6 and IFN-α levels were independent factors related to PFS. Furthermore, the subgroup analysis illustrated that the inflammatory cytokines VEGF, IL-6, IL-17, and IFN-α might be novel biomarkers for predicting the survival prognosis of patients with advanced HCC and PVTT treated with TACE+LEN + PD-1. The safety in the combination group was acceptable. CONCLUSIONS: Compared with TACE+LEN, the triple combination treatment of TACE+LEN + PD-1 has more promising clinical outcomes and acceptable safety in patients with HCC and PVTT. Child-Pugh grade, PVTT classification, and IL-6, IL-17, IFN-α, and VEGF levels are independent prognostic factors for survival time.

Gut microbiota-derived ursodeoxycholic acid alleviates low birth weight-induced colonic inflammation by enhancing M2 macrophage polarization.

BACKGROUND: Low birth weight (LBW) is associated with intestinal inflammation and dysbiosis after birth. However, the underlying mechanism remains largely unknown. OBJECTIVE: In the present study, we aimed to investigate the metabolism, therapeutic potential, and mechanisms of action of bile acids (BAs) in LBW-induced intestinal inflammation in a piglet model. METHODS: The fecal microbiome and BA profile between LBW and normal birth weight (NBW) neonatal piglets were compared. Fecal microbiota transplantation (FMT) was employed to further confirm the linkage between microbial BA metabolism and intestinal inflammation. The therapeutic potential of ursodeoxycholic acid (UDCA), a highly differentially abundant BA between LBW and NBW piglets, in alleviating colonic inflammation was evaluated in both LBW piglets, an LBW-FMT mice model, and a DSS-induced colitis mouse model. The underlying cellular and molecular mechanisms by which UDCA suppresses intestinal inflammation were also investigated in both DSS-treated mice and a macrophage cell line. Microbiomes were analyzed by using 16S ribosomal RNA sequencing. Fecal and intestinal BA profiles were measured by using targeted BA metabolomics. Levels of farnesoid X receptor (FXR) were knocked down in J774A.1 cells with small interfering RNAs. RESULTS: We show a significant difference in both the fecal microbiome and BA profiles between LBW and normal birth weight animals in a piglet model. Transplantation of the microbiota of LBW piglets to antibiotic-treated mice leads to intestinal inflammation. Importantly, oral administration of UDCA, a major BA diminished in the intestinal tract of LBW piglets, markedly alleviates intestinal inflammation in LBW piglets, an LBW-FMT mice model, and a mouse model of colitis by inducing M2 macrophage polarization. Mechanistically, UDCA reduces inflammatory cytokine production by engaging BA receptor FXR while suppressing NF-κB activation in macrophages. CONCLUSIONS: These findings establish a causal relationship between LBW-associated intestinal abnormalities and dysbiosis, suggesting that restoring intestinal health and postnatal maldevelopment of LBW infants may be achieved by targeting intestinal microbiota and BA metabolism. Video Abstract.

Efficacy and Safety of TACE Combined with Regorafenib Plus PD-1 Inhibitor in the Treatment of Hepatocellular Carcinoma After Sorafenib Resistance.

Purpose: To evaluate the efficacy and safety of TACE combined with regorafenib plus PD-1 inhibitor as a second-line therapy for hepatocellular carcinoma after sorafenib resistance. Materials and Methods: The clinical data of 76 patients with hepatocellular carcinoma who were drug-resistant to sorafenib from September 2018 to May 2022 in the tumor intervention department were collected. Among them, 35 patients used TACE combined with regorafenib plus PD-1 inhibitor (TACE-R-P) as second-line treatment, and the remaining 41 patients used TACE combined with regorafenib (TACE-R) as second-line treatment. The mRECIST (modified Response Evaluation Criteria in Solid Tumors) standard was used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes in biochemical indicators, and the adverse events (AEs) related to treatment were recorded. Results: A total of 76 patients were included in the study, including 35 patients receiving TACE-R-P treatment and 41 patients receiving TACE-R treatment. Patients in the TACE-R-P group had longer median OS (19.7months vs 15.2months, HR:0.7716, 95% CI:0.4767-1.2490, P=0.03), longer median PFS (6.3months vs 3.8months, HR:0.6032, 95% CI:0.3727-0.9763, P=0.0029), higher objective response rate (37.14% vs 19.51%, P=0.001) and higher disease control rate (71.43% vs 48.78%, P=0.001) than those in the TACE-R group. Multivariate analysis showed that Child-Pugh grade (B/A; HR=1.283, 95% CI: 0.623-1.707, P=0.014), PVTT (Yes/No, HR=1.455, 95% CI: 0.977-2.038, P=0.018), extrahepatic metastasis (Yes/No, HR=1.766, 95% CI: 1.135-2.302, P=0.022) and treatment option (TACE-R/TACE-R-P, HR=1.930, 95% CI: 1.461-2.850, P=0.017) were independent prognostic factors for OS. There was no significant difference in the incidence and severity of AEs between the two groups. Conclusion: TACE-R-P treatment can be more effective than TACE-R treatment for HCC after sorafenib resistance and can be given priority as a second-line treatment for HCC.

Evaluating the Benefits of TACE Combined with Lenvatinib Plus PD-1 Inhibitor for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus.

INTRODUCTION: This study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus programmed death (PD)-1 inhibitor (TACE-L-P) versus TACE combined with sorafenib plus PD-1 inhibitor (TACE-S-P) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). METHODS: The clinical data of patients with HCC and PVTT treated with TACE-L-P or TACE-S-P from January 2018 to March 2022 were collected. The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST (mRECIST) standard were used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes of biochemical indicators, and the adverse events (AEs) related to treatment were recorded. RESULTS: A total of 165 patients were included in the study, including 80 patients receiving TACE-L-P treatment and 85 patients receiving TACE-S-P. Patients in the TACE-L-P group had longer median OS (21.7 months vs. 15.6 months, P = 0.0027), longer median PFS (6.3 months vs. 3.2 months, P < 0.0001), higher objective response rate (41.25% vs. 30.59%, P = 0.008), and higher disease control rate (86.25% vs. 62.35%, P = 0.008) than those in the TACE-S-P group. Multivariate analysis of the TACE-L-P group showed that VP classification of PVTT, Child-Pugh grade, interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), procalcitonin (PCT), and C-reactive protein (CRP) were independent factors significantly affecting patients' OS (P < 0.05). There was no significant difference in the incidence and severity of AEs between the two groups. CONCLUSION: TACE-L-P treatment can improve the survival of patients with HCC and PVTT with an acceptable safety, but higher inflammatory indicators will affect the therapeutic effect.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Sorafenib plus drug-eluting bead transarterial chemoembolization for early intrahepatic stage-progressed advanced hepatocellular carcinoma refractory to conventional transarterial chemoembolization.

PURPOSE: To investigate the effectiveness and safety of the combination of sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of early intrahepatic stage-progressed advanced hepatocellular carcinoma (ISPA-HCC). METHODS: This study was approved by the ethics committees of six tertiary medical centers in China. Between October 2017 and October 2020, 213 patients with advanced HCC received either sorafenib combined with on-demand DEB-TACE (DTS group, n = 103) or sorafenib monotherapy (S group, n = 110). Overall survival (OS), time to progression (TTP), local tumor response, and adverse events (AEs) were compared between the two groups. RESULTS: The incidences of nause/vomiting, abdonimal pain, hyperbilirubinemia, fever and ALT/AST increasing were higher in the DTS group. The post-treatment partial response, objective response, and disease control rates were significantly higher in the DTS group than in the S group (51.5% vs. 23.6%; 56.3% vs. 25.5%; 77.7% vs. 56.4%, respectively). The median OS was significantly longer in the DTS group than in the S group [16.3 vs. 10.0 months; hazard ratio (HR) = 0.43; P < 0.001], as was the TTP (6.7 vs. 4.3 months; HR = 0.60; P = 0.001). In the DTS group, patients who received ≥ 2 sessions of DEB-TACE benefited more than those who received two sessions of DEB-TACE. Multivariate analysis revealed that the α-fetoprotein level and treatment allocation were independent predictors of OS and TTP. CONCLUSION: The combination of sorafenib and DEB-TACE is safe and effective for the treatment of early ISPA-HCC.

Idarubicin-Loaded DEB-TACE plus Lenvatinib versus Lenvatinib for patients with advanced hepatocellular carcinoma: A propensity score-matching analysis.

AIMS: To investigate the efficacy and safety of lenvatinib and idarubicin-loaded drug-eluting beads transarterial chemoembolization (IDADEB-TACE) in primary advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included patients with primary advanced HCC who received either lenvatinib monotherapy or lenvatinib plus IDADEB-TACE as first-line treatment from September 2019 to September 2020 at three institutes. Overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events were compared. Propensity score-matching was used to reduce the influence of confounding factors on the outcomes. RESULTS: The study reviewed 118 patients who received lenvatinib plus IDADEB-TACE (LIDA group) and 182 who received lenvatinib alone (LEN group). After propensity score-matching, 78 pairs of patients remained. Compared to patients in the LEN group, those in the LIDA group had better post-treatment ORR (57.7% vs. 25.6%, p < 0.001, respectively), median OS and TTP (15.7 vs. 11.3 months, hazard ratio [HR] = 0.50, p < 0.001; 8.0 vs. 5.0 months, HR = 0.60, p = 0.003, respectively), 6- and 12-month OS rates (88.5% vs. 71.4%; 67.6% vs. 43.4%, respectively), and progression-free rates at 6 and 12 months (60.3% vs. 42.3%; 21.1% vs. 10.3%, respectively). Vascular invasion, α-fetoprotein level, and treatment type were independent OS predictors, and vascular invasion and treatment type were independent TTP predictors. Incidences of nausea/vomiting, fever, abdominal pain, and increased ALT/AST were higher in the LIDA group than in the LEN group. CONCLUSIONS: Lenvatinib plus IDADEB-TACE is well-tolerated and more effective than lenvatinib monotherapy in patients with advanced HCC.

The Effect of Unpredictable Chronic Stress on Rare Minnow (Gobiocypris rarus): Growth, Behaviour and Physiology.

Fishes often adjust their behaviour patterns and physiological responses to cope with changing environments, and different life experiences affect them differently. Fishes might adapt to short-term stress, whereas long-term unpredictable stress may lead to various adverse effects. Although some studies have constructed unpredictable stress models of fish, the effect of unpredictable chronic stress (UCS) in the laboratory is poorly understood in fishes. In the current study, we exposed adult rare minnow to an unpredictable chronic stress protocol over 7 and 14 days and measured their response in terms of growth performance, cortisol, neurotransmitter levels (DA, 5-HT, and related metabolites), and behaviour patterns to comprehensively assess the effects of UCS on laboratory rare minnow. We discovered that specific growth rates were significantly decreased, and cortisol levels were lowered in both 7-days and 14-days stress groups. In the behaviour test, the activity level of the 14-days stress group increased, but there was no significant difference in the number of crossings to the center areas, time spent in the center areas, or the speed. In addition, the levels of DA and 5-HT did not change in the stress groups, but the DOPAC and 5-HIAA levels in the 14 days stress group were significantly higher than those in the control group. These results suggested that UCS influences rare minnow growth performance, behaviour patterns, and cortisol levels, and similar stress should be minimised in the laboratory.

Long-term exposure to microplastics induces intestinal function dysbiosis in rare minnow (Gobiocypris rarus).

Microplastics are ubiquitous in the natural environment, especially in waters, and their potential impact is also a key issue of concern. In this study, we used 1 µm, 1000 µg/L, polystyrene (PS-MPs) particles to analyze the effects after exposure for 14 and 28 days in rare minnow (Gobiocypris rarus). Results indicated that PS-MPs induce structural alterations in the intestinal tissue, including epithelial damage, villi damage and the inflammatory cell infiltration, while the changes were severer after exposure for 28 days. Polystyrene microplastics also significantly increased the activities of catalase (CAT, increased 142 % and 385 % in 14d and 28d), superoxide dismutase (SOD, increased 17.76 % and 23.43 % in the 14d and 28d) and the content of malondialdehyde (MDA, increased 14.5 % and 442 % in the 14d and 28d), glutathione (GSH, increased 146 % and 298 % in the 14d and 28d). The results not only showed the characterization of gut microbial communities in rare minnow, but also indicated that microbial diversity and composition were altered in gut of fish exposed to PS-MPs. In the control groups, Proteobacteria (31.36-54.54 %), Actinobacteriota (39.99-52.54 %), Fusobacteriota (1.43-1.78 %), Bacteriadota (0.31-0.57 %) were the four dominant bacterial phyla in the intestinal of rare minnow. After exposure to microplastics, In the gut microbiota, the proportion of Proteobacteria increased 9.27 % and 30 % with exposure time, while Actinobacteria decreased 37.89 % and significantly different after 28 days. In addition, metabolomic analysis suggested that exposure to PS-MPs induced alterations of metabolic profiles in rare minnow and differential metabolites were involved in energy metabolism, inflammatory responsible secretion, oxidative stress, nucleotide and its metabolomics. In conclusion, our findings suggest that long-term exposure to microplastics could induce intestinal inflammation, oxidative stress, microbiota dysbiosis and metabolic disorder in rare minnow, and the alterations and severity were exacerbated by prolonged exposure. This study has extended our cognition of the toxicity of polystyrene, and enriched theoretical data for exploring the toxicological mechanism of microplastics.

Consumption of Dietary Fiber with Different Physicochemical Properties during Late Pregnancy Alters the Gut Microbiota and Relieves Constipation in Sow Model.

Constipation is a common problem in sows and women during late pregnancy. Dietary fiber has potential in the regulation of intestinal microbiota, thereby promoting intestinal motility and reducing constipation. However, the effects of fibers with different physicochemical properties on intestinal microbe and constipation during late pregnancy have not been fully explored. In this study, a total of 80 sows were randomly allocated to control and one of three dietary fiber treatments from day 85 of gestation to delivery: LIG (lignocellulose), PRS (resistant starch), and KON (konjaku flour). Results showed that the defecation frequency and fecal consistency scores were highest in PRS. PRS and KON significantly increased the level of gut motility regulatory factors, 5-hydroxytryptamine (5-HT), motilin (MTL), and acetylcholinesterase (AChE) in serum. Moreover, PRS and KON promoted the IL-10 level and reduced the TNF-α level in serum. Furthermore, maternal PRS and KON supplementation significantly reduced the number of stillborn piglets. Microbial sequencing analysis showed that PRS and KON increased short-chain fatty acids (SCFAs)-producing genera Bacteroides and Parabacteroides and decreased the abundance of endotoxin-producing bacteria Desulfovibrio and Oscillibacter in feces. Moreover, the relative abundance of Turicibacter and the fecal butyrate concentration in PRS were the highest. Correlation analysis further revealed that the defecation frequency and serum 5-HT were positively correlated with Turicibacter and butyrate. In conclusion, PRS is the best fiber source for promoting gut motility, which was associated with increased levels of 5-HT under specific bacteria Turicibacter and butyrate stimulation, thereby relieving constipation. Our findings provide a reference for dietary fiber selection to improve intestinal motility in late pregnant mothers.

Integration of ABC curve, three dimensions of alpha diversity indices, and spatial patterns of fish assemblages into the health assessment of the Chishui River basin, China.

Index of biotic integrity (IBI) based on fish has been applied globally. However, few have considered that fish assemblages change among different aggregate ecoregions when conducted their health assessment. Indeed, some comprehensive indices, such as functional and phylogenetic diversity indices and ABC curve, can be used to identify aspects that are not captured by traditional metrics. Consequently, we try to integrate comprehensive indices and spatial patterns of fish assemblages to develop IBI systems and then verified their effectiveness and accuracy for assessing the environmental health of the Chishui River basin. The comprehensive disturbance index (CDI), based on 11 water quality parameters and 4 human land use, was set to distinguish reference sites and impaired sites. According to the spatial patterns of fish assemblages, the 40 sites were finally divided into 2 aggregate ecoregions, include wadeable streams and nonwadeable rivers. 97 candidate metrics were selected to develop our IBI systems based on the systematic screening method. The result also showed that our IBI systems performed well in discriminating anthropogenic disturbances at both aggregate ecoregions, which suggests that our systems could provide a reliable evaluation. The mean IBI score of the Chishui River basin was 72.09 ± 16.58, and was classified as good status. However, S1 (Chishuiyuan Town), Baisha River, Tongzi River, and Xishui River were disturbed by various human activities. We conclude that the spatial patterns of fish assemblages should be combined with more comprehensive indices to assess river health. On the other hand, we do believe that the process of developing and verifying our IBI systems could be regarded as a reference for biomonitoring in more mountain river systems.

The Effect of Environmental Enrichment on Laboratory Rare Minnows (Gobiocypris rarus): Growth, Physiology, and Behavior.

Environmental enrichment is a method to increase environmental heterogeneity, which may reduce stress and improve animal welfare. Previous studies have shown that environmental enrichment can increase the growth rate, decrease aggressive and anxiety-like behaviors, improve learning ability and agility, and reduce cortisol levels in animals. These effects usually differ between species. Unfortunately, habitat enrichment on laboratory fish is poorly studied and seldom adopted in care guidance. Rare minnows (Gobiocypris rarus) have been cultured as a native laboratory fish in China in barren banks without environmental enrichment since 1990; they have been widely used in studies on ecotoxicology, environmental science, and other topics. The purpose of this study was to investigate the effect of environment enrichment on the growth, physiological status, and anxiety-like behavior of laboratory rare minnows. We observed and analyzed SGR, cortisol levels, DA, DOPAC, 5-HT and 5-HIAA, and anxiety-like behavior indexes after one month of treatment in barren (control) and enrichment tanks. We found that there were no significant differences in SGR, anxiety-like behavior, DA, DOPAC, or 5-HIAA levels between the two treatments. However, higher cortisol and 5-HT levels were observed in the enrichment tanks. This study suggests that rare minnows might be influenced by their living environment, and future related studies should consider their environmental enrichment.

Combined Use of Transjugular Intrahepatic Portosystemic Shunt and Transarterial Chemoembolization in the Treatment of Esophageal and Gastric Variceal Bleeding: A Retrospective Study of 80 Patients with Hepatocellular Carcinoma and Portal Hypertension.

BACKGROUND The main cause of death in patients with hepatocellular carcinoma (HCC) with portal hypertension is esophageal and gastric variceal bleeding caused by severe portal hypertension; therefore, the treatment of portal hypertension is particularly important to prolong the survival of patients. The therapeutic efficacy and safety of transarterial chemoembolization (TACE) combined with a transjugular intrahepatic portosystemic shunt (TIPS) for HCC with esophageal and gastric variceal bleeding has been rarely reported. The aim of this study was to analyze the clinical efficacy of TIPS combined with TACE in the treatment of HCC with esophageal and gastric variceal bleeding. MATERIAL AND METHODS A total of 80 patients with HCC with esophageal and gastric variceal bleeding from July 2015 to November 2019 were retrospectively investigated. Clinical outcomes, biochemical indexes, and complications were compared between TIPS plus TACE and endoscopy plus TACE treatments. RESULTS Gastrointestinal rebleeding and adverse reactions (P<0.05) after TIPS combined with TACE were lower than that after endoscopy combined with TACE treatment. Furthermore, TIPS plus TACE had superior clinical outcomes than endoscopy plus TACE, which was associated with promising progression-free survival, overall survival, objective response rate, and disease control rate, and improved liver function. CONCLUSIONS TIPS combined with TACE was better than endoscopy combined with TACE in the treatment of patients with HCC and esophageal and gastric variceal bleeding. TIPS combined with TACE had a better therapeutic effect on improving liver function and prolonging patient survival time.

Evaluation of the Benefits of TACE Combined with Sorafenib for Hepatocellular Carcinoma Based on Untreatable TACE (unTACEable) Progression.

PURPOSE: Outcomes after the treatment for unresectable or advanced-stage hepatocellular carcinoma (HCC) are unsatisfied. We evaluated the therapeutic benefits of a combination therapy strategy for these patients through transarterial chemoembolization (TACE) plus sorafenib. PATIENTS AND METHODS: In total, 85 patients with HCC classified as intermediate and advanced stage from June 2012 to November 2017 were retrospectively investigated. We divided patients into the monotherapy (n=43; TACE alone) and combined therapy (n=42; TACE plus sorafenib) groups. RESULTS: Compared with the TACE alone group, the TACE plus sorafenib experienced significantly prolonged progression-free survival (PFS) (mean 21 months vs 12 months; P = 0.0005) and overall survival (OS) (mean 32 months vs 21 months; P = 0.0157). The disease control rate (DCR) of TACE plus sorafenib group was 80.95%, which was significantly increased than the TACE alone group (55.81%) (P<0.05), as well as objective response rate (ORR) (23.81% vs 16.28%). Besides, the rates of liver-related AEs and liver failure in the TACE plus sorafenib group were not increased in contrast to TACE alone group, and there were no new safety concerns. To sum up, the superiority of combination therapy with significantly prolonging progression-free and overall survival was observed, meanwhile finding a significant increase in tumor response rate and manageable safety in the combined therapy in contrast to the monotherapy group. CONCLUSION: Based on unTACEble progression, the superiority of the combination therapy is that TACE plus sorafenib has been bringing about significantly better outcomes compared with TACE alone for HCC patients.

Advanced hepatocellular carcinoma treated by transcatheter arterial chemoembolization with drug-eluting beads plus lenvatinib versus sorafenib, a propensity score matching retrospective study.

Recently, a prospective randomized study suggested that transcatheter arterial chemoembolization (TACE) plus lenvatinib, as opposed to TACE plus sorafenib, was an effective and promising treatment for patients with advanced hepatocellular carcinoma (HCC) having portal vein thrombus (PVTT) and large tumor burden. However, no propensity score matching retrospective studies on TACE with drug-eluting beads (DEB-TACE) plus lenvatinib (DEB-TACE+LEN) versus DEB-TACE plus sorafenib (DEB-TACE+SOR) for advanced HCC has been reported to date. The medical records of consecutive patients with advanced HCC who underwent DEB-TACE+LEN or DEB-TACE+SOR between January 2017 and December 2020 were retrospectively reviewed. Mutation genes (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by whole-exome sequencing (WES). Adverse events (AEs), objective response rate (ORR), disease control rate (DCR), overall survival (OS) and time to progression (TTP) were compared between patients who underwent DEB-TACE+LEN and DEB-TACE+SOR. In total, 150 patients were enrolled in this study. The DEB-TACE+LEN group (n=50) showed significantly better ORR (64.0% vs. 33.3%; P=0.008), OS (hazard ratio [HR]=0.63, 95% confidence interval (CI): 0.41-0.98; P=0.043), and TTP (HR=0.65, 95% CI: 0.45-0.94; P=0.023) than that in the DEB-TACE+SOR group (n=100). Subgroup analyses showed that in patients with portal vein tumor thrombus (PVTT), OS and TTP were significantly longer in the DEB-TACE+LEN group than in the DEB-TACE+SOR group (HR=0.59, 95% CI: 0.36-0.98; P=0.043; HR=0.89, 95% CI: 0.35-2.29; P=0.035). In patients with FGF21 amplification, OS was also significantly longer in the DEB-TACE+LEN group than that in the DEB-TACE+SOR group (HR=0.19, 95% CI: 0.06-0.66; P=0.003). The patients in DEB-TACE+LEN group had a significantly lower incidence of hand-foot skin reaction (32.0% vs. 49.0%; P=0.048), but a higher incidence of proteinuria (26.0% vs. 10.0%; P=0.010) than that in the DEB-TACE+SOR group. In conclusion, DEB-TACE+LEN conferred better ORR, OS and TTP than did DEB-TACE+SOR in patients with advanced HCC, especially those with PVTT and FGF21 amplification, with acceptable AEs; thus making it a superior treatment modality for these patients.

Effects of dietary fibers with different physicochemical properties on fermentation kinetics and microbial composition by fecal inoculum from lactating sows in vitro.

BACKGROUND: Efficient utilization of dietary fibers (DFs) is important for optimizing feed resource utilization and animal health. The aim of the current study was to assess the effects of DFs with varying physicochemical properties (bulky, viscous, and fermentable) on fermentation kinetics and microbial composition during in vitro fermentation by fecal inoculum from lactating sow. According to the physicochemical properties, three different DFs, lignocellulose (LC), modified cassava starch (MCS) and konjac flour (KF) were selected as bulky fiber, fermentable fiber and viscous fiber respectively. Gas production, short-chain fatty acids (SCFAs) profiles and microbial composition were monitored during the fermentation. RESULTS: Results showed that the gas production in 72 h (GP72h ) ranked as: KF > MCS > LC (P < 0.05). The halftime of asymptotic gas production ranked as: KF < MCS = LC (P < 0.001). At 36 h of fermentation, MCS group showed higher concentrations of formic acid and lactate than LC and KF groups, whereas KF group showed higher concentrations of propionate and butyrate than LC and MCS groups (P < 0.05). At 72 h of fermentation, KF group showed higher concentrations of formic acid, lactate and propionate than LC and MCS groups, whereas MCS group showed higher concentrations of acetate and butyrate than LC and KF groups (P < 0.05). At 36 h of fermentation, Anaerovibrio and Erysipelatoclostridium abundances were higher in KF group, whereas Proteiniclasticum abundance was higher in MCS group. At 72 h of fermentation, the abundance of Fibrobacter in LC group was higher than that in MCS and KF groups. In addition, we also observed that the abundances of certain specific bacteria (Anaerovibrio and Erysipelatoclostridium) were closely related to the SCFAs production (propionate and butyrate) at different fermentation times. CONCLUSION: Collectively, the present study revealed that KF is a fast fermentation fiber which could produce propionate and butyrate rapidly, whereas LC is difficult to be fermented by bacteria. In addition, the fermentation of DFs with different physicochemical properties had divergent impacts on microbial composition and SCFA production. These findings deepen our understanding of the mechanisms of interaction between DFs and intestinal microbiota, and provide new ideas for the rational use of fiber resources in lactating sows. © 2020 Society of Chemical Industry.

Bone Marrow-Derived Mesenchymal Stem Cells Restored High-Fat-Fed Induced Hyperinsulinemia in Rats at Early Stage of Type 2 Diabetes Mellitus.

Numerous studies have proposed the transplantation of mesenchymal stem cells (MSCs) in the treatment of typical type 2 diabetes mellitus (T2DM). We aimed to find a new strategy with MSC therapy at an early stage of T2DM to efficiently prevent the progressive deterioration of organic dysfunction. Using the high-fat-fed hyperinsulinemia rat model, we found that before the onset of typical T2DM, bone marrow-derived MSCs (BM-MSCs) significantly attenuated rising insulin with decline in glucose as well as restored lipometabolic disorder and liver dysfunction. BM-MSCs also favored the histological structure recovery and proliferative capacity of pancreatic islet cells. More importantly, BM-MSC administration successfully reversed the abnormal expression of insulin resistance-related proteins including GLUT4, phosphorylated insulin receptor substrate 1, and protein kinase Akt and proinflammatory cytokines IL-6 and TNFα in liver. These findings suggested that MSCs transplantation during hyperinsulinemia could prevent most potential risks of T2DM for patients.

Expression characterization and transcription regulation analysis of porcine Yip1 domain family member 3 gene.

OBJECTIVE: The Yip1 domain family (YIPF) proteins were proposed to function in endoplasmic reticulum (ER) to Golgi transport and maintenance of the morphology of the Golgi, which were homologues of yeast Yip1p and Yif1p. YIPF3, the member 3 of YIPF family was a homolog of Yif1p. The aim of present study was to investigate the expression and regulation mechanism of porcine YIPF3. METHODS: Quantitative realtime polymerase chain reaction (qPCR) was used to analyze porcine YIPF3 mRNA expression pattern in different tissues and pig kidney epithelial (PK15) cells stimulated by polyinosine-polycytidylic acid (poly [I:C]). Site-directed mutations combined with dual luciferase reporter assays and electrophoretic mobility shift assay (EMSA) were employed to reveal transcription regulation mechanism of porcine YIPF3. RESULTS: Results showed that the mRNA of porcine YIPF3 (pYIPF3) was widely expressed with the highest levels in lymph and lung followed by spleen and liver, while weak in heart and skeletal muscle. Subcellular localization results indicated that it expressed in Golgi apparatus and plasma membranes. Upon stimulation with poly (I:C), the level of this gene was dramatically up-regulated in a time- and concentration-dependent manner. pYIPF3 core promoter region harbored three cis-acting elements which were bound by ETS proto-oncogene 2 (ETS2), zinc finger and BTB domain containing 4 (ZBTB4), and zinc finger and BTB domain containing 14 (ZBTB14), respectively. In which, ETS2 and ZBTB4 both promoted pYIPF3 transcription activity while ZBTB14 inhibited it, and these three transcription factors all played important regulation roles in tumorigenesis and apoptosis. CONCLUSION: The pYIPF3 mRNA expression was regulated by ETS2, ZBTB4, and ZBTB14, and its higher expression in immune organs might contribute to enhancing ER to Golgi transport of proteins, thus adapting to the immune response.

Expression and Influence of Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 and Vascular Endothelial Growth Factor in Diabetic Foot Ulcers.

A high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP9/TIMP1) ratio is associated with poor ulcer healing, yet how the ratio of MMP9/TIMP1 changes in diabetic foot ulcers (DFUs) with infection and how these changes may affect wound healing remain unclear. Therefore, the objective of this investigation was to explore relationships among the MMP9/TIMP1 ratio, infection, and DFUs. After being informed of the details of this study, 32 patients signed consent forms. Skin biopsies were performed for all patients. Wound tissues were obtained from all patients with wounds, and healthy skin samples were collected from patients without wounds during orthopedic surgery. Microbial cultures were obtained using the samples from diabetic patients with wounds. All patients were divided into 4 groups according to colony-forming units (CFUs) per gram of tissue (>1 × 106 or <1 × 106): group A (diabetic wounds with high quantities of bacteria), group B (diabetic wounds with low quantities of bacteria), group C (diabetic patients without wounds), and group D (nondiabetic patients with wounds). In addition, the biopsies were evaluated by both reverse transcription-quantitative polymerase chain reaction and Western blotting to assess the levels of MMP9, TIMP1, and vascular endothelial growth factor (VEGF). The results show that for both mRNA and protein, expression of MMP9 (fold change 1.14 ± 0.12 vs 0.60 ± 0.08 vs 0.39±0.09 vs 0.13 ± 0.06, P < .01) decreased, whereas that of TIMP1 (1.01 ± 0.09 vs 2.86 ± 0.85 vs 4.88 ± 0.83 vs 7.29 ± 1.55, P < .01) and VEGF (1.01 ± 0.22 vs 3.55 ± 0.97 vs 5.72 ± 0.55 vs 6.92 ± 1.55, P < .01) increased from group A to group D. These results suggest that an increase in the MMP9/TIMP1 ratio in infected DFUs may induce a decrease in VEGF expression.