[Clinical features and prognostic analysis of transarterial chemoembolization combined with targeted immunotherapy in the treatment of patients with hepatitis B virus-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis].

Objective: To study the clinical features and prognostic impact of transarterial chemoembolization (TACE), immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs) combination therapy regimens in the treatment of patients with hepatitis B virus-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis. Methods: Patients with HBV-related intermediate-and advanced-stage hepatocellular carcinoma (HBV) who visited the Affiliated Hospital of Xuzhou Medical University between January 1, 2020, and December 31, 2022, were enrolled. TACE+TKIs +ICIs combination therapy was used to treat all patients. The occurrence and factors influencing cholestasis, as well as the impact on prognosis after combined therapy, were analyzed. The measurement data were compared using a t-test and a non-parametric rank sum test. The count data was compared using the χ(2) test. The survival rates were compared using a log-rank test between different groups. Results: A total of 106 cases with HBV-related intermediate-and advanced-stage hepatocellular carcinoma were enrolled. The probabilities of secondary cholestasis within 3 and 6 months, 1, 2, and 3 years after TACE+ICIs+TKIs combination therapy were 9.4%, 12.3%, 14.2%, 24.5%, and 24.5%, respectively. Patients with secondary cholestasis had persistent symptoms and rapid progression. During the treatment course, the median survival time was significantly longer in patients with hepatocellular carcinoma without secondary cholestasis than that of patients with cholestasis (26.9 months vs. 13.7 months, respectively, P < 0.05). Secondary cholestasis, baseline aspartate aminotransferase, and prothrombin activity levels were independent risk factors that affected the survival and prognosis of patients treated with combination therapy. There was no statistically significant difference in the occurrence of other adverse reactions between the two groups with secondary and non-secondary cholestasis during the treatment course (47.5% vs. 43.3%, χ(2)=0.058, P = 0.810). Conclusion: TACE+ICIs+TKIs therapy combination is relatively common in the treatment of patients with HBV-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis. Moreover, accelerated disease progression is an independent risk factor affecting the survival and prognosis of patients.

Exploring the nursing effect of application Albizia bark on autism in children based on network pharmacology and molecular docking.

OBJECTIVE: Autism is a disorder that manifests itself in early childhood. Early diagnosis of autism may not only help the affected children themselves, but also affect family well-being and social stability. The natural drug Albizia bark has been reported to have some effect in the prevention and treatment of autism in children. Therefore, we used network pharmacology and molecular docking to explore the possible mechanism. MATERIALS AND METHODS: TCMID and BATMAN-TCM was used to retrieve the chemical constituents of Albizia bark, and then obtained the relevant targets about autism by TTD, Gene Cards and OMIM. The resulting ingredients and targets were predicted, then a protein interaction network was constructed, and finally bioinformatics analysis was performed. Finally, molecular docking was used to verify the effective ingredients and targets obtained from the screening. RESULTS: Leucaena saponin B, luteolin, 3', 4', 7-trihydroxyflavone, which may be the key compounds for the treatment of autism. BP mainly involving signal transduction, G protein coupled receptor signal pathway, protein phosphorylation. CC, mainly involving plasma membrane, integral component of plasma membrane, MF, including protein binding, adenosine triphosphate binding, protein kinase activity. Molecular docking showed that AKT1, HRAS, PIK3CA, PIK3R1 and SRC, five potential targets, had good binding ability to Leucaena saponin B. CONCLUSIONS: The natural drug Albizia bark exerts pharmacological effects in a multi-component, multi-target and multi-channel manner, including neural regulation, inflammatory response and immune regulation.

Alterations of the circular RNA profile in the jejunum of neonatal calves in response to colostrum and milk feeding.

Circular RNA (circRNA) have been suggested to contribute to regulating gene expression in various tissues and cells of eukaryotes. However, little is known regarding the expression pattern of circRNA and their potential function in the small intestine of neonatal calves that receive colostrum. In the current study, jejunum tissue samples were collected from control calves (2 h after birth; CT; n = 3) and neonatal calves that ingested colostrum (24 h after birth; CO; n = 3) or milk (24 h after birth; MK; n = 3) to compare the circRNA expression patterns using a high-throughput RNA sequencing approach. A total of 21,213, 17,861, and 21,737 circRNA were identified in the CT, CO, and MK groups, respectively. Only 13,254 of these circRNA were common to the 3 groups, suggesting high specificity of circRNA expression depending on nutrient type. In total, 243, 249, and 283 circRNA were differentially expressed in the CO versus CT, CO versus MK, and MK versus CT comparisons, respectively. Gene ontology analysis showed that the differentially expressed circRNA and their predicted or known target genes from the CO and MK groups were mainly involved in macromolecule metabolic process, response to stress, and vesicle-mediated transport. Moreover, pathway analysis showed that the Rap1 signaling pathway, focal adhesion, ubiquitin-mediated proteolysis, and extracellular matrix-receptor interaction were the most significantly enriched pathways. These data collectively indicate that circRNA are abundant and dynamically expressed when calves receive colostrum and act as microRNA sponges to regulate their target genes for jejunum function during the early development of newborn calves.

Changes in serum metabolites in response to ingested colostrum and milk in neonatal calves, measured by nuclear magnetic resonance-based metabolomics analysis.

Uptake of colostrum is of central importance for establishing a passive immunity transfer in neonatal calves. Studies of absorption and transmission of colostral immunoglobulins have been widely reported; however, changes in the serum in response to the absorption of colostral components in neonatal calves have not been completely characterized. Here, a nuclear magnetic resonance-based metabolomics approach was used to investigate the changes in metabolites in ingested colostrum, milk, and serum after neonatal calves were fed colostrum or milk. Twenty-seven neonatal male Holstein calves were assigned to 1 of the following groups: (1) calves not fed colostrum or milk and slaughtered approximately 2 h after birth (control group, n = 6), (2) calves fed colostrum at 1 to 2 h after birth and slaughtered 8 h after birth (n = 6), (3) calves fed 2 colostrum meals (at 1-2 and 10-12 h after birth) and slaughtered 24 h after birth (n = 6), (4) calves fed 3 colostrum meals (at 1-2, 10-12, and 22-24 h after birth) and slaughtered 36 h after birth (n = 6), or (5) calves fed 2 milk meals (1-2 and 10-12 h after birth) and slaughtered 24 h after birth (n = 3). Concentrations of valine, leucine, lactate, lysine, and isoleucine were higher and concentrations of lactose were lower in the groups fed colostrum and milk compared with groups not fed colostrum and milk, respectively. Metabolite changes between groups fed or not fed colostrum and milk were similar and may reflect the primary metabolic requirements of ingestion by the small intestine of neonatal calves. Concentrations of serum metabolites choline, valine, leucine, and glutamate were higher in the serum of calves that received colostrum compared with control calves. Furthermore, concentrations of serum phenylalanine, valine, and glutamate were significantly higher, whereas serum concentrations of citrate and very low density lipoproteins were lower in calves that received colostrum compared with calves fed milk. Our results indicate that concentrations of leucine, valine, and glutamate, which were higher in the calves that ingested colostrum, may transfer into the bloodstream, and that these metabolites are associated with health benefits in the neonatal calves that received colostrum. These findings provide novel information to help us understand the mechanism by which colostrum components are metabolized and absorbed in the small intestine and then transferred into bloodstream of neonatal calves.

[Research on the relationship between atmospheric inhalable particulate matter and cardiovascular diseases burden in Tianjin].

Objective: To evaluate the association between atmospheric inhalable particulate matter (PM(10)) concentration and cardiovascular diseases burden in Tianjin. Methods: The data on daily mean concentrations of main pollutants (PM(10), nitrogen dioxide(NO(2)) and sulfur dioxide(SO(2))), meteorological factors (temperature and relative humidity) and population death monitoring data in Tianjin, from January 1, 2001 to December 31, 2010, were collected and analyzed in this study. The death counts and years of life lost were simultaneously used as the indicators of disease burden. The generalized additive model was used to assess the associations between PM(10) and daily death counts and years of life lost due to cardiovascular system diseases in Tianjin by adjusting the confounding factors such as long-term trend, seasons, meteorological factors and other factors related to the long-term variability. Results: The daily average concentration of PM(10) was 117.6 µg/m³ in Tianjin during 2001 to 2011. The daily average number of deaths of cardiovascular system diseases, cerebrovascular diseases and ischemic heart diseases in Tianjin were 38.4, 14.8 and 17.2 people respectively, and the daily average years of life lost were 776.8, 306.5 and 326.1 person years respectively. The effects of PM(10) on the daily death counts of the three diseases categories were statistically significant (all P<0.01) in Tianjin and the maximum effect occurs at the moment when PM(1)0 was at moving average concentration of today and lagged 1-day (Lag01). The effects of decreasing order were ischemic heart diseases, cardiovascular system diseases and cerebrovascular diseases, excess risks were 0.53% (95% CI 0.35%-0.71%), 0.40% (95%CI 0.28%-0.53%) and 0.38% (95%CI 0.19%-0.56%). The effects of atmospheric PM(10) on the years of life lost of the three diseases were also statistically significant on the different lag days (all P<0.01) in Tianjin and the maximum effect of PM(10) appeared in Lag01. The effects from the largest to the lowest were 2.86 (95%CI 1.79-3.93) person years for cardiovascular system diseases, 1.59 (95%CI 0.95-2.23) person years for ischemic heart diseases and 1.07 (95%CI 0.43-1.71) person years for cerebrovascular diseases, respectively. In multi-pollutant models, after controlling SO(2), the effect of PM(10) on the daily life loss of above 3 kinds of diseases was higher than that of single pollutant model. In contrast, after controlling SO(2) or SO(2) with NO(2), the effect was lower. After controlling NO(2), the effect of PM(10) on the daily life loss of cerebrovascular disease was no longer statistically significant (P>0.05). Conclusions: Exposure to atmospheric PM(10) can significantly increase the cardiovascular diseases burden in Tianjin, especially for ischemic heart diseases. These results suggested that particular attention should be paid to reduce the exposure to atmospheric inhalable particulate matter for patients with ischemic heart diseases.

[Correlation study between respiratory death and airborne particles in Beijing: Spatiotemporal analysis based on satellite remote sensing data].

OBJECTIVE: To use vertical and humidity correcting method to calibrate aerosol optical depth (AOD), and to explore the feasibility of calibrated-AOD as exposure index to measure the level of air pollutants from the ground and to establish the exposure-response relationship between calibrated-AOD and people's health outcomes. METHODS: First of all, we interpolated AOD, PM2.5, relative humidity and planetary boundary layer height using Kriging method to obtain data at different locations and matched different data with respiratory death in Beijing by geographical coordinates. Then, the planetary boundary layer height and aerosol hygroscopic growth factor calculated based on relative humidity was used to calbrate the AOD. To compare the effects of calibrated-AOD and PM2.5, we used standardization method to get non dimensionless calibrated-AOD and PM2.5. At last, we used the generalized additive mixed model (GAMM) to estimate the acute effects of calibrated-AOD and PM2.5 on respiratory death and chronic obstructive pulmonary disease (COPD) death, after controlling the time trend, temperature and humidity effects, days of the week effect and holiday effects. RESULTS: The correlation coefficient between calibrated-AOD and PM2.5 was 0.72. The effects of calibrated-AOD on respiratory death and COPD death was the strongest at lag 0-3, one unit of calibrated-AOD increases was associated with 3.64% (95%CI: 0.58%-6.78%) increase of respiratory death and 4.92% (95%CI: 1.81%-8.14%) increase of COPD death. As for PM2.5, the strongest effects appeared at lag 0-1, one unit of PM2.5 (about 155 µg/m3) increases was associated with excess risks of 3.96% (95%CI: 0.82%-7.19%) and 6.12% (95%CI: 1.44%-11.02%) for respiratory death and COPD death respectively. Compared with PM2.5, the effects of calibrated-AOD on respiratory death and COPD death had narrower confidence intervals. The calibrated-AOD was sensitive to capture the lag effects, and the cumulative lag effects of calibrated-AOD were all significant on multiple lag days which indicated that the calibrated-AOD was sensitive to capture cumulative lag effects of air pollutants on respiratory death and COPD death as well. CONCLUSION: We believe that calibrated-AOD can be used as an index to reflect the effects of air pollutants on respiratory death in Beijing. In the absence of ground monitoring, calibrated-AOD can be used to mea-sure the relationship between air pollutants and some health outcomes.

Signature of Strong Spin-Orbital Coupling in the Large Nonsaturating Magnetoresistance Material WTe2.

We report the detailed electronic structure of WTe2 by high resolution angle-resolved photoemission spectroscopy. We resolved a rather complicated Fermi surface of WTe2. Specifically, there are in total nine Fermi pockets, including one hole pocket at the Brillouin zone center Γ, and two hole pockets and two electron pockets on each side of Γ along the Γ-X direction. Remarkably, we have observed circular dichroism in our photoemission spectra, which suggests that the orbital angular momentum exhibits a rich texture at various sections of the Fermi surface. This is further confirmed by our density-functional-theory calculations, where the spin texture is qualitatively reproduced as the conjugate consequence of spin-orbital coupling. Since the spin texture would forbid backscatterings that are directly involved in the resistivity, our data suggest that the spin-orbit coupling and the related spin and orbital angular momentum textures may play an important role in the anomalously large magnetoresistance of WTe2. Furthermore, the large differences among spin textures calculated for magnetic fields along the in-plane and out-of-plane directions also provide a natural explanation of the large field-direction dependence on the magnetoresistance.

HBcAg-specific IL-21-producing CD4+ T cells are associated with relative viral control in patients with chronic hepatitis B.

Function exhaustion of specific cytotoxic CD8+ T cell in chronic virus infection partly results from the low levels of CD4 help, but the mechanisms by which CD4 help T cell required to control hepatitis B virus infection are not well understood. In this study, we investigated the role of interleukin-21-producing CD4+ T cell response in viral control of hepatitis B virus infection. HBcAg-specific interleukin-21-producing CD4+ T cells in blood were detected in patients with hepatitis B virus infection. Patients with acute hepatitis B had greater HBcAg-specific interleukin-21-producing CD4+ T cells in blood compared with chronic hepatitis B patients, and there was no statistical significance between immune active chronic hepatitis B patients and inactive healthy carrier patients for these cells, whereas frequencies of these cells negatively correlated with HBV DNA levels but positively correlated with HBc18-27-specific IFN-γ-producing CD8+ T cells. Moreover, interleukin-21 sustained HBc18-27-specific CD8+ T cells in vitro, and interleukin-21 production by HBcAg-specific IL-21-producing CD4+ T cells of acute hepatitis B patients enhanced IFN-γ and perforin expression by CD8+ T cells from chronic hepatitis B patients. Our results demonstrate that HBcAg-specific interleukin-21-producing CD4+ T cell responses might contribute to viral control by sustaining CD8+ T cell antiviral function.

Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2.

Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor-ß1 (TGF-ß1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 or downregulation of HDAC1 by RNAi both suppressed TGF-ß1-induced apoptosis. In addition, overexpression of HDAC1 enhanced TGF-ß1-induced apoptosis, and the rescue of HDAC1 expression in HDAC1 RNAi cells restored the apoptotic response of cells to TGF-ß1. These data indicate that HDAC1 functions as a proapoptotic factor in TGF-ß1-induced apoptosis. In contrast, downregulation of HDAC2 by RNAi increased spontaneous apoptosis and markedly enhanced TGF-ß1-induced apoptosis, suggesting that HDAC2 has a reciprocal role in controlling cell survival. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) by MEK1 inhibitor PD98059 or expression of a kinase-dead mutant of MEK1 restored the apoptotic response to TGF-ß1 in HDAC1 RNAi cells. Strikingly, HDAC2 RNAi caused an inhibition of ERK1/2, and the spontaneous apoptosis can be abolished by reactivation of ERK1/2. Taken together, our data demonstrate that HDAC1 and 2 reciprocally affect cell viability by differential regulation of ERK1/2; these observations provide insight into the roles and potential mechanisms of HDAC1 and 2 in apoptosis.

Activated p56lck directs maturation of both CD4 and CD8 single-positive thymocytes.

p56(lck) is a protein tyrosine kinase expressed throughout T cell development. It associates noncovalently with the cytoplasmic domains of the CD4 and CD8 coreceptor molecules and has been implicated in TCR signaling in mature T cells. Its role in early thymocyte differentiation has been demonstrated in vivo, both by targeted gene disruption and by transgene expression. Previously, we showed that expression of a dominant-negative form of p56(lck) in double-positive thymocytes inhibits positive selection. We now demonstrate that expression of constitutively activated p56(lck) (p56(lck)F505) accelerates the transition from the double-positive to the single-positive stage. Importantly, p56(lck)F505 drives survival and lineage commitment of thymocytes in the absence of TCR engagement by appropriate MHC molecules. These results indicate that activation of p56(lck) constitutes an early step in conveying maturational signals after TCR ligation by a positively selecting ligand. Our study provides direct in vivo evidence for the role of p56(lck) in regulating TCR signaling.