Regulation of Catalysts on Tightly Packaged Solid Propellant Energetic Particles: High Combustion Performance with Low Temperature Sensitivity.

Although the effectiveness of combustion catalysts promoting the combustion performance of solid propellant (SP) was identified in many research studies, its regulation on the temperature sensitivity coefficient of burning rate (δp) has been rarely explored, where SP with low δp is a big challenge with little progress. Herein, several ammonium perchlorate (AP)-enriched (>70 wt %) pomegranate-structured SP energetic particles (SPPs), AP/nitrocellulose (NC)/Al (SPP), SPP/CoWO4-rGO (SPP-Co), SPP/Bi2WO6-rGO (SPP-Bi), and SPP/CuCo2O4/GO (SPP-Cu), were prepared by the electrospray granulation method, tightly packaging AP with high-efficiency catalysts to promote its reactivity and reduce temperature sensitivity. The pressurization rates of SPPs in a constant volume combustion chamber at 50, 0, and -40 °C were obtained to determine δp. The burning rates of SPP-Co, SPP-Bi, and SPP-Cu loose strips are 0.319, 0.312, and 0.356 m/s, which are increased by 11.1%, 8.7%, and 24.0% compared to that of SPP (0.287 m/s), respectively. The peak pressures and pressurization rates of SPP-Co, SPP-Bi, and SPP-Cu at 0 °C are increased by 18.8%, 10.1%, and 9.1% and 62.3%, 67.1%, and 64.1% compared with SPP, respectively, indicating that these catalysts significantly accelerate the combustion process. Compared with SPP, the δp of SPP-Co, SPP-Bi, and SPP-Cu decreased by 26.6%, 60.6%, and 24.7% at 0-50 °C and 19.5%, 61.6%, and 27.6% at -40-0 °C, respectively. It suggests that the Bi2WO6-rGO catalyst reduces the δp by 61% at -40-50 °C, exhibiting the optimal δp regulation performance. This research introduces a novel approach to lower the δp from the chemical by tightly packaging temperature-sensitive AP with high-efficiency catalysts.

Prognostic significance of dynamic changes in liver stiffness measurement in patients with chronic hepatitis B and compensated advanced chronic liver disease.

BACKGROUND AND AIM: Liver stiffness measurements (LSMs) are promising for monitoring disease progression or regression. We assessed the prognostic significance of dynamic changes in LSM over time on liver-related events (LREs) and death in patients with chronic hepatitis B (CHB) and compensated advanced chronic liver disease (cACLD). METHODS: This retrospective study included 1272 patients with CHB and cACLD who underwent at least two measurements, including LSM and fibrosis score based on four factors (FIB-4). ΔLSM was defined as [(follow-up LSM - baseline LSM)/baseline LSM × 100]. We recorded LREs and all-cause mortality during a median follow-up time of 46 months. Hazard ratios (HRs) and confidence intervals (CIs) for outcomes were calculated using Cox regression. RESULTS: Baseline FIB-4, baseline LSM, ΔFIB-4, ΔLSM, and ΔLSM/year were independently and simultaneously associated with LREs (adjusted HR, 1.04, 95% CI, 1.00-1.07; 1.02, 95% CI, 1.01-1.03; 1.06, 95% CI, 1.03-1.09; 1.96, 95% CI, 1.63-2.35, 1.02, 95% CI, 1.01-1.04, respectively). The baseline LSM combined with the ΔLSM achieved the highest Harrell's C (0.751), integrated AUC (0.776), and time-dependent AUC (0.737) for LREs. Using baseline LSM and ΔLSM, we proposed a risk stratification method to improve clinical applications. The risk proposed stratification based on LSM performed well in terms of prognosis: low risk (n = 390; reference), intermediate risk (n = 446; HR = 3.38), high risk (n = 272; HR = 5.64), and extremely high risk (n = 164; HR = 11.11). CONCLUSIONS: Baseline and repeated noninvasive tests measurement allow risk stratification of patients with CHB and cACLD. Combining baseline and dynamic changes in the LSM improves prognostic prediction.

The steatosis-associated fibrosis estimator (SAFE) outperformed the FIB-4 score in screening the population for liver disease.

INTRODUCTION AND OBJECTIVES: Assessing fibrosis risk noninvasively is essential. The steatosis-associated fibrosis estimator (SAFE) score shows promise but needs validation. PATIENTS AND METHODS: This was a three-part study. In part 1, we compared the SAFE score with the Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) in the National Health and Nutrition Examination Survey (NHANES) cohort (2017-2020), using transient elastography (TE) as screening reference. In part 2, we examined patients who underwent liver biopsies at an Asian center between 2018 and 2020 to assess these models in various liver diseases. In part 3, the SAFE score was applied to adults in the NHANES cohort (1999-2016) to assess the correlation with mortality. RESULTS: In part 1, we studied 6,677 patients, comprising 595 screening positive (TE ≥8 kPa). SAFE (cutoff 100) displayed a lower proportion of false positives (10.4 %) than FIB-4 (cutoff 1.3) and NFS (cutoff -1.455) (22.1 % and 43.6 %) while retaining a low proportion of false negatives (5.5 %). In part 2, SAFE outperformed FIB-4 (P = 0.04) and NFS (P = 0.04) in staging significant fibrosis (≥S2) in NAFLD and had similar accuracies in other etiologies. In part 3, the FIB-4, NFS, and SAFE score were associated with all-cause mortality in the general population, with c-statistics of 0.738, 0.736, and 0.759, respectively. CONCLUSIONS: The SAFE score reduced futile referrals more effectively than FIB-4 without raising the missed TE ≥ 8 kPa rate. It correlated with all-cause mortality in the general population and excelled in staging significant fibrosis in NAFLD.

Matrix-transmitted paratensile signaling enables myofibroblast-fibroblast cross talk in fibrosis expansion.

While the concept of intercellular mechanical communication has been revealed, the mechanistic insights have been poorly evidenced in the context of myofibroblast-fibroblast interaction during fibrosis expansion. Here we report and systematically investigate the mechanical force-mediated myofibroblast-fibroblast cross talk via the fibrous matrix, which we termed paratensile signaling. Paratensile signaling enables instantaneous and long-range mechanotransduction via collagen fibers (less than 1 s over 70 µm) to activate a single fibroblast, which is intracellularly mediated by DDR2 and integrin signaling pathways in a calcium-dependent manner through the mechanosensitive Piezo1 ion channel. By correlating in vitro fibroblast foci growth models with mathematical modeling, we demonstrate that the single-cell-level spatiotemporal feature of paratensile signaling can be applied to elucidate the tissue-level fibrosis expansion and that blocking paratensile signaling can effectively attenuate the fibroblast to myofibroblast transition at the border of fibrotic and normal tissue. Our comprehensive investigation of paratensile signaling in fibrosis expansion broadens the understanding of cellular dynamics during fibrogenesis and inspires antifibrotic intervention strategies targeting paratensile signaling.

Real-Time Trajectory Prediction Method for Intelligent Connected Vehicles in Urban Intersection Scenarios.

Intelligent connected vehicles (ICVs) have played an important role in improving the intelligence degree of transportation systems, and improving the trajectory prediction capability of ICVs is beneficial for traffic efficiency and safety. In this paper, a real-time trajectory prediction method based on vehicle-to-everything (V2X) communication is proposed for ICVs to improve the accuracy of their trajectory prediction. Firstly, this paper applies a Gaussian mixture probability hypothesis density (GM-PHD) model to construct the multidimension dataset of ICV states. Secondly, this paper adopts vehicular microscopic data with more dimensions, which is output by GM-PHD as the input of LSTM to ensure the consistency of the prediction results. Then, the signal light factor and Q-Learning algorithm were applied to improve the LSTM model, adding features in the spatial dimension to complement the temporal features used in the LSTM. When compared with the previous models, more consideration was given to the dynamic spatial environment. Finally, an intersection at Fushi Road in Shijingshan District, Beijing, was selected as the field test scenario. The final experimental results show that the GM-PHD model achieved an average error of 0.1181 m, which is a 44.05% reduction compared to the LiDAR-based model. Meanwhile, the error of the proposed model can reach 0.501 m. When compared to the social LSTM model, the prediction error was reduced by 29.43% under the average displacement error (ADE) metric. The proposed method can provide data support and an effective theoretical basis for decision systems to improve traffic safety.

[Clinical phenotype and genetic analysis of twelve children with ring chromosomes].

OBJECTIVE: To explore the prevalence and clinical manifestations of ring chromosomes among children featuring abnormal development. METHODS: From January 2015 to August 2021, 7574 children referred for abnormal development were selected, and their peripheral blood samples were subjected to G-banded chromosomal karyotyping analysis. RESULTS: Twelve cases of ring chromosomes were detected, which have yielded a prevalence of 0.16% and included 1 r(6), 2 r(9), 1 r(13), 1 r(14), 2 r(15), 1 r(21) and 3 r(X). The children had various clinical manifestations including growth and mental retardation, limb malformation, and congenital heart disease. For two children with r(9) and two with r(15) with similar breakpoints, one child with r(9) and one with r(15) only had growth retardation, whilst another with r(9) and another with r(15) also had peculiar facies and complex congenital heart disease. The r(X) has featured some manifestations of Turner syndrome. CONCLUSION: Ring chromosomes are among the common causes for severe growth and mental retardation in children with diverse clinical phenotypes. Clinicians should pay attention to those with developmental anomalies and use chromosomal analysis to elucidate their genetic etiology.

Asporin inhibits collagen matrix-mediated intercellular mechanocommunications between fibroblasts during keloid progression.

Keloids are fibrotic lesions that grow unceasingly and invasively and are driven by local mechanical stimuli. Unlike other fibrotic diseases and normal wound healing, keloids exhibit little transformation of dermal fibroblasts into α-SMA+ myofibroblasts. This study showed that asporin is the most strongly expressed gene in keloids and its gene-ontology terms relate strongly to ECM metabolism/organization. Experiments with human dermal cells (HDFs) showed that asporin overexpression/treatment abrogated the HDF ability to adopt a perpendicular orientation when subjected to stretching tension. It also induced calcification of the surrounding 3D collagen matrix. Asporin overexpression/treatment also prevented the HDFs from remodeling the surrounding 3D collagen matrix, leading to a disorganized network of thick, wavy collagen fibers that resembled keloid collagen architecture. This in turn impaired the ability of the HDFs to contract the collagen matrix. Asporin treatment also made the fibroblasts impervious to the fibrous collagen contraction of α-SMA+ myofibroblasts, which normally activates fibroblasts. Thus, by calcifying collagen, asporin prevents fibroblasts from linearly rearranging the surrounding collagen; this reduces both their mechanosensitivity and mechanosignaling to each other through the collagen network. This blocks fibroblast activation and differentiation into the mature myofibroblasts that efficiently remodel the extracellular matrix. Consequently, the fibroblasts remain immature, highly proliferative, and continue laying down abundant extracellular matrix, causing keloid growth and invasion. Notably, dermal injection of asporin-overexpressing HDFs into murine wounds recapitulated keloid collagen histopathological characteristics. Thus, disrupted interfibroblast mechanocommunication may promote keloid progression. Asporin may be a new diagnostic biomarker and therapeutic target for keloids.

Advanced Pedestrian State Sensing Method for Automated Patrol Vehicle Based on Multi-Sensor Fusion.

At present, the COVID-19 pandemic still presents with outbreaks occasionally, and pedestrians in public areas are at risk of being infected by the viruses. In order to reduce the risk of cross-infection, an advanced pedestrian state sensing method for automated patrol vehicles based on multi-sensor fusion is proposed to sense pedestrian state. Firstly, the pedestrian data output by the Euclidean clustering algorithm and the YOLO V4 network are obtained, and a decision-level fusion method is adopted to improve the accuracy of pedestrian detection. Then, combined with the pedestrian detection results, we calculate the crowd density distribution based on multi-layer fusion and estimate the crowd density in the scenario according to the density distribution. In addition, once the crowd aggregates, the body temperature of the aggregated crowd is detected by a thermal infrared camera. Finally, based on the proposed method, an experiment with an automated patrol vehicle is designed to verify the accuracy and feasibility. The experimental results have shown that the mean accuracy of pedestrian detection is increased by 17.1% compared with using a single sensor. The area of crowd aggregation is divided, and the mean error of the crowd density estimation is 3.74%. The maximum error between the body temperature detection results and thermometer measurement results is less than 0.8°, and the abnormal temperature targets can be determined in the scenario, which can provide an efficient advanced pedestrian state sensing technique for the prevention and control area of an epidemic.

Polyene phosphatidylcholine overcomes oxaliplatin resistance in human gastric cancer BGC823 cells.

Intrinsic or acquired resistance to oxaliplatin (L-OHP) is a major reason of treatment failure in gastric cancer and limits therapeutic success. Here we generated an oxaliplatin resistant gastric cancer cell line, BGC823/L-OHP, to investigate the effect of a hepatoprotective compound, polyene phosphatidylcholine (PPC), on conquest of oxaliplatin resistance. BGC823/L-OHP cells showed less sensitive to L-OHP directed growth inhibition than the parental BGC823 cells. PPC treatment significantly increased anti-proliferative activity of L-OHP on resistant cells and promoted L-OHP triggered apoptosis, indicating that drug resistance was overcome. Mechanistically, L-OHP incubation stimulated upregulation of an ABC family protein, ABCF2, and the expression was inhibited by PPC. Moreover, expression levels of the stemness factor Nanog and its regulator TLR4 were notably enhanced in BGC823/L-OHP cells and reduced by PPC treatment. To conclude, PPC can overcome oxaliplatin resistance in gastric cancer cells via promoting apoptosis, inhibiting ABCF2, as well via reducing cancer stem cell-like features. The combination therapeutic strategy could serve to increase oxaliplatin effectiveness in the clinic.

Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis.

The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FµNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FµNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FµNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FµNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

The Effect of Growth Hormone on Lipid Accumulation or Maturation in Adipocytes.

BACKGROUND: Adipogenesis of adipocytes includes two stages: initiation and maturation. Growth hormone (GH) secretion is decreased in obese subjects and GH levels are inversely correlated with abdominal fat mass. The effects of growth hormone (GH) on lipids accumulation or maturation of adipocytes remains elusive. METHODS: In the present study, effect of GH on lipid accumulation in vitro and in vivo was examined. cDNA microarray, quantitative real time-PCR (qPCR) and western blotting was used to analyze the expression of genes related to adipocyte lipid accumulation or degradation in pre- or mature 3T3-F442A adipocytes treated with GH and in epididymal adipose tissue of C57BL/6 mice administrated with GH. Level of adiponectin in supernatants of cultured F442A adipocytes was determined by enzyme-linked immune-sorbent assay. RESULTS: We found that in 3T3-F442A especially 6 days post initiation of adipogenesis, GH intervention resulted in decreased expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP, while the expression of UCP1 was markedly enhanced. cDNA microarray analysis and qPCR showed that the expression of SOCS2 and Adipor2 was increased under GH-treatment in mature 3T3-F442A adipocytes. GH treatment increased the mRNA expression of adiponectin and UCP1 in mature adipocytes. The above results were confirmed by in vivo study. CONCLUSIONS: GH potentially negatively modulates the maturation and accumulation of lipid in adipocytes.

Evaluation of the effectiveness of surgical resection and ablation for the treatment of early-stage hepatocellular carcinoma: A retrospective cohort study.

BACKGROUND: The optimal treatment strategy for early-stage hepatocellular carcinoma (HCC) remains controversial, specifically in regard to surgical resection (SR) and ablation. The aim of this study was to investigate the impact of SR and ablation on recurrence and prognosis in early-stage HCC patients, to optimize treatment strategies and improve long-term survival. METHODS: A retrospective analysis was conducted on 801 patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage 0/A HCC and treated with SR or ablation between January 2015 and December 2019. The effectiveness and complications of both treatments were analyzed, and patients were followed up to measure recurrence and survival. Propensity score matching (PSM) was employed to increase comparability between the two groups. The Kaplan-Meier method was used to analyze recurrence and survival, and a Cox risk proportional hazard model was used to identify risk factors that affect recurrence and surviva. RESULTS: Before PSM, the overall survival (OS) rates were similar in both groups, with recurrence-free survival (RFS) rates better in the SR group than in the ablation group. After PSM, there was no significant difference in OS between the two groups. However, the RFS rates were significantly better in the SR group than in the ablation group. The ablation group exhibited superior outcomes compared to the SR group, with shorter treatment times, reduced bleeding, shorter hospital stays, and lower hospital costs. Concerning the location of the HCC within the liver, comparable efficacy was observed between SR and ablation for disease located in the noncentral region or left lobe. However, for HCCs located in the central region or right lobe of the liver, SR was more effective than ablation. CONCLUSIONS: This study revealed no significant difference in OS between SR and ablation for early-stage HCC, with SR providing better RFS and ablation demonstrating better safety profiles and lower hospital costs. These findings offer valuable insights for clinicians in determining optimal treatment strategies for early-stage HCC patients, particularly in terms of balancing efficacy, safety, and cost considerations.

Proton pump inhibitor use is associated with increased liver steatosis.

Despite proton pump inhibitors (PPIs) being generally safe, there are questions about their potential long-term complications. The present study aimed to investigate the association between PPI therapy and the incidence of hepatic steatosis and liver fibrosis in the outpatient population of the United States. The present study included 7,395 individuals aged ≥20 years who underwent hepatic vibration-controlled transient elastography (VCTE) examination. The data were obtained from the January 2017 to March 2020 pre-pandemic National Health and Nutrition Examination Survey. Among the 7,395 adults who were included (mean age, 50.59 years; 3,656 male), 9.8% were prescribed PPIs. Following multivariable adjustment, the use of PPIs was significantly associated with hepatic steatosis [odds ratio (OR), 1.25; 95% confidence interval (CI), 1.02-1.53]. Prolonged use of PPIs was found to increase the risk of developing hepatic steatosis over time (P=0.006). Sensitivity analyses using different definitions of hepatic steatosis, such as a controlled attenuation parameter ≥285 dB/m (OR, 1.19; CI, 1.01-1.40), non-alcoholic fatty liver disease (OR, 1.50; 95% CI, 1.16-1.93) and metabolic dysfunction-associated steatotic liver disease (OR, 1.26; 95% CI, 1.05-1.52), consistently demonstrated an association between PPI prescription and hepatic steatosis. The administration of PPI therapy was linked with hepatic steatosis in US adults, although no significant association was observed with liver stiffness, as determined by VCTE.

Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study.

BACKGROUND: Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. METHODS: Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. RESULTS: From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1-77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6-14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3-83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3-4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5-1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. CONCLUSIONS: Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03781219.

Lentiviral vector-mediated siRNA knockdown of c-MYC: cell growth inhibition and cell cycle arrest at G2/M phase in Jijoye cells.

Inhibition of c-MYC has been considered as a potential therapy for lymphoma treatment. We explored a lentiviral vector-mediated small interfering RNA (siRNA) expression vector to stably reduce c-MYC expression in B cell line Jijoye cells and investigated the effects of c-MYC downregulation on cell growth, cell cycle, and apoptosis in vitro. The expression of c-MYC mRNA and protein levels were inhibited significantly by c-MYC siRNA. The c-MYC downregulation resulted in the inhibition of cell proliferation and cell cycle arrest at G2/M phase, which was associated with decreased expression of cyclin B and cyclin-dependent kinase 1 (CDK1) and increased expression of CDK inhibitor p21 proteins. In addition, downregulation of c-MYC induced cell apoptosis characterized by DNA fragmentation and caspase-3 activation. Taken together, these results suggest that lentiviral vector-mediated siRNA for c-MYC may be a promising approach for targeting c-MYC in the treatment of Burkitt lymphoma.

Different responses of tumor and normal cells to low-dose radiation.

AIM OF THE STUDY: We demonstrated stimulation of both erythrocyte immune function and superoxide dismutase activity in tumor-bearing mice in response to whole-body 75 mGy X-rays. In addition, we enhanced the chemotherapeutic effect by exposing tumor-bearing mice to low-dose radiation (LDR). This study aims to investigate the different responses of tumor cells and normal cells to LDR. MATERIAL AND METHODS: Survival fraction, micronucleus frequency, and cell cycle of Lewis cells and primary human fibroblast AG01522 cells were measured. S180 sarcoma cells were implanted in mice, and tumor sizes were measured in vivo. RESULTS: In response to LDR exposure in vitro, a stimulating effect was observed in AG01522 cells but not in Lewis cells. Low-dose radiation did not cause an adaptive response in the Lewis cell cycle. Lack of an LDR-induced radioadaptive response in tumor cells was observed in tumor-bearing mouse models. Furthermore, a higher apoptotic effect and lower expression of the anti-apoptosis gene Bcl-2 were found in tumor cells of tumor-bearing mice exposed to D1 + D2 than those in tumor cells of tumor-bearing mice exposed to D2 alone. CONCLUSIONS: Different responses of tumor cells and normal cells to LDR were found. Low-dose radiation was found to stimulate the growth of normal cells but not of tumor cells in vitro and in vivo, which is a very important and clinically relevant phenomenon.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients.

BACKGROUND: The clinical and histological features of chronic hepatitis B (CHB) patients who fall into the "grey zone (GZ)" and do not fit into conventional natural phases are unclear. AIM: To explore the impact of varying the threshold of alanine aminotransferase (ALT) levels in identifying significant liver injury among GZ patients. METHODS: This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy. The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines. GZ CHB patients were classified into four groups: GZ-A (HBeAg positive, normal ALT levels, and HBV DNA ≤ 107 IU/mL), GZ-B (HBeAg positive, elevated ALT levels, and HBV DNA < 104 or > 107 IU/mL), GZ-C (HBeAg negative, normal ALT levels, and HBV DNA ≥ 2000 IU/mL), and GZ-D (HBeAg negative, elevated ALT levels, and HBV DNA ≤ 2000 IU/mL). Significant hepatic injury (SHI) was defined as the presence of notable liver inflammation (≥ G2) and/or significant fibrosis (≥ S2). RESULTS: The results showed that 50.22% of patients were classified as GZ, and 63.7% of GZ patients developed SHI. The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria (35 U/L for men and 25 U/L for women) can more accurately identify patients with significant liver damage in the GZ phases. In total, the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 64.86% [(221 + 294)/794]. When we lowered the ALT treatment threshold to the new criteria (30 U/L for men and 19 U/L for women), the same outcome was revealed, and the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 75.44% [(401 + 198)/794]. Additionally, the proportion of SHI was 49.1% in patients under 30 years old and increased to 55.3% in patients over 30 years old (P = 0.136). CONCLUSION: These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study.

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

Impact of hepatic steatosis on treatment response of autoimmune hepatitis: A retrospective multicentre analysis.

Background: There is a paucity of data on whether steatosis impacts autoimmune hepatitis (AIH) treatment response. We aimed to evaluate the influence of baseline steatosis on the biochemical response, fibrosis progression, and adverse longterm outcomes of AIH. Methods: Steatosis was diagnosed by a controlled attenuation parameter (CAP) ≥ 248 dB / m. Only patients who underwent immunosuppressive therapy with available liver histological material at diagnosis and qualified CAP within seven days of the liver biopsy were included. Univariate and multivariate analyses were subsequently conducted. Results: The multicentre and retrospective cohort enrolled 222 subjects (88.3% female, median age 54 years, median follow-up 48 months) in the final analysis, and 56 (25.2%) patients had hepatic steatosis. Diabetes, hypertension, and significant fibrosis at baseline were more common in the steatosis group than in the no steatosis group. After adjusting for confounding factors, hepatic steatosis was an independent predictor of insufficient biochemical response (OR: 8.07) and identified as an independent predictor of long-term adverse outcomes (HR: 4.07). By subgroup multivariate analysis (different degrees of steatosis, fibrosis, and prednisone dose), hepatic steatosis independently showed a relatively stable correlation with treatment response. Furthermore, in contrast to those without steatosis, a significant increase in liver stiffness (LS) was observed in patients with steatosis (4.1%/year vs. -16%/year, P < 0.001). Conclusions: Concomitant hepatic steatosis was significantly associated with poor response to treatment in AIH patients. Routine CAP measurements are therefore essential to guide the management of AIH.

Effects of Low-dose Splenic Irradiation on T lymphocyte Immune Function.

ABSTRACT: Relevant studies have confirmed that the stimulation of spleen function caused by low-dose splenic irradiation can have positive effects on tumors and other diseases. This study aimed to determine radiation-induced changes in spleen index, lymphocyte subsets, spleen cell apoptosis, and pathological features of the spleen in mice. The mouse model was established by irradiating the spleen at different doses. The mice were divided into the following groups: blank control, low-dose, low-dose fractionated irradiation, and challenge dose irradiation. The mice were sacrificed under humanitarian conditions, and spleen tissue and peripheral blood were collected. The spleen index was calculated, and flow cytometry was used to analyze spleen T lymphocyte subsets and spleen apoptosis. The pathological changes in the spleen were determined by hematoxylin and eosin (H&E) staining. The spleen index of mice in the low-dose fractionated irradiation group was significantly increased compared with that in the blank control group. The spleen indexes of the low-dose irradiation and low-dose fractionated irradiation groups were much higher than that of the challenge dose irradiation group. Compared with the blank control group, the percentage of CD3+ and CD4+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation and low-dose fractionated irradiation groups was significantly increased, whereas that from the challenge dose irradiation group was obviously decreased. CD8+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation, low-dose fractionated irradiation, and challenge dose irradiation groups were significantly lower than those in the blank control group. The apoptosis rate of the spleen in the challenge dose irradiation group was significantly higher than that in the blank control, low-dose irradiation, and low-dose fractionated irradiation groups. H&E staining analysis of the spleen showed pathological changes in the different irradiation groups compared with the blank control group. Low-dose irradiation and low-dose fractionated irradiation can change the T lymphocyte subsets in the peripheral blood and spleen of mice, which can promote immune excitation and improve immune effects.