Locoregional treatment improves overall survival for liver cancer during second-line regorafenib or immune checkpoint inhibitor.

For advanced hepatocellular carcinoma (HCC), the best second-line treatment after first-line treatment with sorafenib is unclear. This study aimed to compared the efficacy of second-line regorafenib (a tyrosine kinase inhibitor) and immune checkpoint inhibitors (ICIs) in patients with advanced HCC after sorafenib therapy. This retrospective study included 89 patients with HCC treated with sorafenib, and then regorafenib (n = 58) or an ICI (n = 31). Treatment response, overall survival (OS) and progression-free survival (PFS) of the 2 groups were compared, and factors associated with post-treatment mortality or disease progression were evaluated. During follow-up period, compared to regorafenib, treatment with an ICI results in a slight increase in a 20% decrease of AFP (35.7% vs. 31.8%), complete response rate (6.5% vs. 0%), objective response rate (16.1% vs. 6.9%), median overall survival (13.3 vs. 5 months), and median PFS (3.0 vs. 2.6 months). Combined locoregional treatment (LRT) (hazard ratio [HR] = 0.40, 95% confidence interval [CI]: 0.15-0.99) during second-line treatment was associated with a decreased risk of post-treatment mortality. After propensity scoring matching, combined LRT during second-line treatment had longer post-treatment OS than patients without combined LRT. A 20% decrease of AFP (HR = 0.54, 95% CI: 0.31-0.94) was associated with a decreased risk of post-treatment disease progression. In conclusions, second-line treatment with regorafenib or ICI prolongs OS in patients with advanced HCC treated with sorafenib. Combined LRT during second-line treatment is associated with decreased post-treatment mortality. A 20% decrease of AFP level may be predictive of a lower rate of disease progression.

Erector spinae plane block level does not impact analgesic efficacy in enhanced recovery for lumbar spine surgery.

BACKGROUND CONTEXT: Postoperative pain control following spine surgery can be difficult. The Enhanced Recovery After Surgery (ERAS) programs use multimodal approaches to manage postoperative pain. While an erector spinae plane block (ESPB) is commonly utilized, the ideal distance for injection from the incision, referred to as the ES (ESPB to mid-surgical level) distance, remains undetermined. PURPOSE: We evaluated the impact of varying ES distances for ESPB on Numerical Rating Scale (NRS) measures of postoperative pain within the ERAS protocol. STUDY DESIGN/SETTING: Retrospective observational study. PATIENT SAMPLE: Adult patients who underwent elective lumbar spine fusion surgery. OUTCOME MEASURES: Primary outcome measures include the comparative postoperative NRS scores across groups at immediate (T1), 24 (T2), 48 (T3), and 72 (T4) hours postsurgery. For secondary outcomes, a propensity matching analysis compared these outcomes between the ERAS and non-ERAS groups, with opioid-related recovery metrics also assessed. METHODS: All included patients were assigned to one of three ERAS groups according to the ES distance: Group 1 (G1, ES > 3 segments), Group 2 (G2, ES = 2-3 segments), and Group 3 (G3, ES<2 segments). Each patient underwent a bilateral ultrasound-guided ESPB with 60 mL of diluted ropivacaine or bupivacaine. RESULTS: Patients within the ERAS cohort reported mild pain (NRS < 3), with no significant NRS variation across G1 to G3 at any time. Sixty-five patients were matched across ERAS and non-ERAS groups. The ERAS group exhibited significantly lower NRS scores from T1 to T3 than the non-ERAS group. Total morphine consumption during hospitalization was 26.7 mg for ERAS and 41.5 mg for non-ERAS patients. The ERAS group resumed water and food intake sooner and had less postoperative nausea and vomiting. CONCLUSIONS: ESPBs can be effectively administered at or near the mid-surgical level to the low thoracic region for lumbar spine surgeries. Given challenges with sonovisualization, a lumbar ESPB may be preferred to minimize the risk of inadvertent pleural injury.

Effect of "Tiaoshen" acupuncture technique on mild depression and its underlying mechanism: A randomized controlled trial study protocol.

Background: Mild depression is not just a mental disease, but also a serious and long-term public health issue. It affects the quality of life of patients and can quickly develop into major depression. There are currently no effective drug treatments with high efficacy and few adverse reactions. Acupuncture may be an alternative treatment option. Preliminary experiments and practices have demonstrated that "Tiaoshen" acupuncture improves symptoms in patients who have depression, however the underlying data and method remain unclear at present. Methods: This is a prospective, single-center, single-blind, randomized controlled trial. We plan to recruit 70 participants and randomly assign them to receive "Tiaoshen" acupuncture or traditional acupuncture at a ratio of 1:1. Then, all the participants will receive the appropriate acupuncture treatment for four weeks. The results of the Hamilton Depression Rating Scale (HDSR-24) will serve as the primary outcome, while the results of the Patient Health Questionnaire-9 (PHQ-9) and the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) will serve as secondary outcomes. Evaluations will be conducted at baseline, 1, 2, and 4 weeks after treatment initiation, and 1 and 3 months after treatment completion. The safety of the intervention will be evaluated every week using the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Treatment Emergent Symptoms Scale (TESS). Serum levels of oxidative stress markers 8-iso-prostaglandin F2α (8-iso-PGF2α), superoxide dismutase (SOD), uric acid (UA), and total bilirubin (TBIL) will be measured at baseline and the end of the treatment. We will conduct a statistical analysis of intention to treat (ITT) and conformance to protocol set (PPS) data. Discussion: This research aims to provide high-quality evidence for the efficacy and safety of "Tiaoshen" acupuncture as a treatment for mild depression. In addition, the mechanism through which acupuncture heals mild depression will be investigated.

Analgesia-nociception index accurately predicts inadequate pectoralis muscle fascia block (PECS) in patients undergoing breast surgery: A prospective observational study.

BACKGROUND: Postoperative opioid administration has been largely replaced by regional anesthesia techniques. We aimed to determine whether intraoperative Analgesia-Nociception Index (ANI) can aid in early evaluation of the effectiveness of regional blocks such as the pectoralis muscle fascia block (PECS, pectoserratus and interpectoral plane blocks) and predicting the need for analgesics postoperatively. METHODS: This prospective observational study enrolled 30 women (age: 20-80 years) undergoing unilateral, non-intubated, breast tumor excision alone or in conjunction with sentinel lymph node biopsy. PECS block was performed following sedation. ANI readings were obtained at 1-min intervals, and polar coordinates were assigned to the distance from the nipple (0.5-cm intervals) and o'clock position (15-min intervals) for each reading. Pain scores were assessed using a numeric rating scale from 0 to 10, and analgesics were administered depending on pain score post-operatively. RESULTS: 8 (27%), 19 (63%), and 3 (10%) patients received morphine, tramadol, and no analgesics, respectively. In total, 954 ANI measurements were obtained. At the proposed cut-off of 50, the sensitivity and specificity of the ANI nadir for need of post-operative opioids were 0.875 and 0.932, respectively. Block effectiveness was most satisfactory in the upper lateral quadrant of the breast with nipple-areolar complex (NAC) sparing effect. Most average ANI measurements for the NAC were <50. No patient experienced postoperative nausea/vomiting, although one reported dizziness. CONCLUSIONS: The intraoperative ANI nadir <50 was strongly correlated with need for postoperative opioids. The ANI may aid in objectively evaluating the effectiveness of pectoralis muscle fascial blocks and predicting postoperative need for analgesics.

Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. METHODS: In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. CONCLUSIONS: The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Clinical implications of hepatitis B virus core antigen-mediated immunopathologic T cell responses in chronic hepatitis B.

Hepatitis B virus (HBV) infection significantly impacts Asian populations. The influences of continuous HBV antigen and inflammatory stimulation to T cells in chronic hepatitis B (CHB) remain unclear. In this study, we first conducted bioinformatics analysis to assess T-cell signaling pathways in CHB patients. In a Taiwanese cohort, we examined the phenotypic features of HBVcore -specific T cells and their correlation with clinical parameters. We used core protein overlapping peptides from the Taiwan prevalent genotype B HBV to investigate the antiviral response and the functional implication of HBV-specific T cells. In line with Taiwanese dominant HLA-alleles, we also evaluated ex vivo HBVcore -specific T cells by pMHC-tetramers targeting epitopes within HBV core protein. Compared to healthy subjects, we disclosed CD8 T cells from CHB patients had higher activation marker CD38 levels but showed an upregulation in the inhibitory receptor PD-1. Our parallel study showed HBV-specific CD8 T cells were more activated with greater PD-1 expression than CMV-specific subset and bulk CD8 T cells. Moreover, our longitudinal study demonstrated a correlation between the PD-1 fluctuation pattern of HBVcore -specific CD8 T cells and liver inflammation in CHB patients. Our research reveals the HBV core antigen-mediated immunopathologic profile of CD8 T cells in chronic HBV infection. Our findings suggest the PD-1 levels of HBVcore -specific CD8 T cells can be used as a valuable indicator of personal immune response for clinical application in hepatitis management.

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD.

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.

"Baihui" (DU20)-penetrating "Qubin" (GB7) acupuncture on blood-brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK II/MLC 2 signaling pathway.

BACKGROUND: Blocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH. METHODS: Scalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point "Baihui"-penetrating "Qubin," and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post-assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging. RESULTS: We found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre-intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7-day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at "Baihui"-penetrating "Qubin" and treatment with fasudil could improve the expression of endothelial-related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats. CONCLUSION: This study found that these experimental data indicated that SA at "Baihui"-penetrating "Qubin" could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell-related proteins.

Subsequent locoregional therapy prolongs survival in progressive hepatocellular carcinoma patients under lenvatinib treatment.

BACKGROUND: Locoregional therapy and multi-kinase inhibitor agent have been the backbone of treatment for hepatocellular carcinoma (HCC) patients. However, the effect of combination or sequential use of locoregional therapy on HCC patients receiving multi-kinase inhibitor remain uncertain. Therefore, we aim to explore whether the subsequent locoregional therapy provides better survival in HCC patients under lenvatinib treatment. METHODS: From March 2018 to April 2020, a total of 78 unresectable HCC patients receiving lenvatinib were recruited. Image response was evaluated by dynamic image using the modified RECIST criteria. Among patients with tumor progression under lenvatinib treatment, whether receiving subsequent locoregional therapy or not were documented. Overall survival between two groups and the predictors for tumor progression were also analyzed. RESULTS: Among the 78 patients receiving lenvatinib, the median age was 67.8 years old, and 69.2 % were male. Forty-four patients (56.4 %) experienced tumor progression with time to progression 5.1 months (95 % confidence interval (CI): 4.7-6.8) months. In multivariable Cox regression analysis, albumin-bilirubin (ALBI) grade II (adjusted HR: 2.883, P = 0.0104), and treatment duration less than three months (adjusted HR: 3.801, P = 0.0014) were the independent predictive factors for tumor progression, while patients achieving objective response under lenvatinib treatment within 12 weeks was the independent protective factor for tumor progression (adjusted HR: 0.144, P = 0.0020). Among the 44 patients with tumor progression, twenty-six (59.1 %) patients received subsequent locoregional therapy after tumor progression. Comparing to those with tumor progression without locoregional treatment, patients who received subsequent locoregional therapy had significantly better survival (1st year cumulative survival rate 70 % vs 27 %, log-rank P = 0.003). CONCLUSION: ALBI grade, treatment duration of lenvatinib, and achieving objective image response within twelve weeks were the independent predictive factors for tumor progression. Furthermore, longer overall survival was observed in tumor progression patients with subsequent locoregional therapy and with better liver preserved function.

Advances in the antitumor mechanisms of tripartite motif-containing protein 3.

The tripartite motif-containing (TRIM) protein family has steadily become a hotspot in tumor-related research. As a member of the E3 ubiquitin ligase family, TRIM is working on many crucial biological processes, including the regulation of tumor cell proliferation, metastasis, apoptosis, and autophagy. Among the diverse TRIM superfamily members, TRIM3 operates via different mechanisms in various types of tumors. This review primarily focuses on the current state of research regarding the antitumor mechanisms of TRIM3 in different cancers. A more in-depth study of TRIM3 may provide new directions for future antitumor treatments. Our review focuses on TRIM3 proteins and cancer. We searched for relevant articles on the mechanisms by which TRIM3 affects tumorigenesis and development from 1997 to 2023 and summarized the latest progress and future directions. Triad-containing motif protein 3 (TRIM3) is an important protein, which plays a key role in the process of tumorigenesis and development. The comprehensive exploration of TRIM3 is anticipated to pave the way for future advancements in antitumor therapy, which is expected to be a new hallmark for cancer detection and a novel target for drug action. TRIM3 is poised to become a significant milestone in cancer detection and a promising focal point for drug intervention. Recent years have witnessed notable progress in research aimed at unraveling the antitumor mechanism of TRIM3, with far-reaching implications for practical tumor diagnosis, treatment protocols, efficacy evaluation, economics, and pharmaceutical utilization.

Extracellular vesicles from Staphylococcus aureus promote the pathogenicity of Pseudomonas aeruginosa.

Co-infections with Staphylococcus aureus and Pseudomonas aeruginosa are common in patients with chronic wounds, but little is known about their synergistic effect mediated by extracellular vesicles (EVs). In this study, we investigated the effect of EVs derived from S. aureus (SaEVs) on the pathogenicity of P. aeruginosa. By using lipophilic dye, we could confirm the fusion between SaEV and P. aeruginosa membranes. However, SaEVs did not alter the growth and antibiotic susceptible pattern of P. aeruginosa. Differential proteomic analysis between SaEV-treated and non-treated P. aeruginosa was performed, and the results revealed that lipopolysaccharide (LPS) biosynthesis protein in P. aeruginosa significantly increased after SaEV-treatment. Regarding this result, we also found that SaEVs promoted LPS production, biofilm formation, and expression of polysaccharide polymerization-related genes in P. aeruginosa. Furthermore, invasion of epithelial cells by SaEV-pretreated P. aeruginosa was enhanced. On the other hand, uptake of P. aeruginosa by RAW 264.7 macrophages was impaired after pretreatment P. aeruginosa with SaEVs. Proteomic analysis SaEVs revealed that SaEVs contain the proteins involving in host cell colonization, inhibition of host immune response, anti-phagocytosis of the macrophages, and protein translocation and iron uptake of S. aureus. In conclusion, SaEVs serve as a mediator that promote P. aeruginosa pathogenicity by enhancing LPS biosynthesis, biofilm formation, epithelial cell invasion, and macrophage uptake impairment.

Holes can be perilous: A rare presentation of intestinal obstruction - Herniation through the broad ligament.

A 57-year-old lady presented with symptoms of intestinal obstruction preceded by a 2-day history of lower abdomen pain. Clinically, she had a distended abdomen with tenderness in her lower abdomen. Laboratory investigations were unremarkable. An abdominal radiograph showed a dilated small bowel with no extensive bowel gas. A computed tomography (CT) scan showed suspected intestinal obstruction secondary to herniation into the right broad ligament. The decision was made to proceed with surgery, and the intraoperative results confirmed the CT results. The literature review is outlined here, and this instance illustrates a surprising discovery.

A novel approach for transforming breast cancer stem cells into endothelial cells.

Tumor vascular endothelial cells play a pivotal in the tumor microenvironment, influencing the proliferation, invasion, and metastasis of tumor progression. The present study investigated a novel method for inducing the transformation of breast cancer stem cells into endothelial cells, providing a cellular model investigating anti-angiogenic mechanisms in vitro. The breast cancer cell line MCF-7 was used, and the expression of CD133 was initially detected using flow cytometry. CD133+ breast cancer cells were purified using immunomagnetic bead sorting technology, yielding an MCF-7CD133+ subpopulation. The proliferation ability of these cells was assessed using an MTT assay, while their microsphere formation ability was evaluated using a microsphere formation assay. Post-transformation in an optimized endothelial cell culture medium, expression of endothelial cell markers CD31 and CD105 were detected using flow cytometry. Endothelial cell tube formation assays and DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL) assays were employed to analyze the endothelial cell function of the MCF-7CD133+ cells. MDM2/CEN12 gene amplification was detected through fluorescence in situ hybridization (FISH). The MCF-7 breast cancer cell line exhibited 1.7±0.3% trace cells expressing the stem cell surface marker CD133. After anti-CD133 immunomagnetic bead sorting, MCF-7CD133+ and MCF-7CD133- subpopulation cells were obtained, with CD133 expression rates of 85.6±2.8 and 0.18±0.08%, respectively. MTT assay results demonstrated that, after 7 days, the proliferation rate of MCF-7CD133+ cells was significantly higher compared with MCF-7CD133- cells. MCF-7CD133+ subpopulation cells displayed strong stem cell characteristics, growing in suspension in serum-free media and forming tumor cell spheres. In contrast, MCF-7CD133- cells failed to form microspheres. After culturing cells in endothelial cell differentiation and maintenance media, the percentage of MCF-7CD133+ cells before and after endothelial cell culture was 0.3±0.16 and 81.4±8.37% for CD31+ cells and 0.2±0.08 and 83.8±7.24% for CD105+ cells, respectively. Vascular-like structure formation and Ac-LDL phagocytosis with red fluorescence in the tube formation assays confirmed endothelial cell function in the MCF-7CD133+ cells. FISH was used to verify MDM2/CEN12 gene amplification in the induced MCF-7CD133+ cells, indicating tumor cell characteristics. The modified endothelial cell transformation medium effectively induced differentiated tumor stem cells to express vascular endothelial cell markers and exhibit endothelial functions, ideal for in vitro anti-angiogenesis research.

Heat Shock Protein SSA1 Enriched in Hypoxic Secretome of Candida albicans Exerts an Immunomodulatory Effect via Regulating Macrophage Function.

Candida albicans is an opportunistic pathogenic yeast that can survive in both normoxic and hypoxic environments. The involvement of C. albicans secretome on host biological processes has been demonstrated. However, the immunoregulatory function of C. albicans secretome released under hypoxic condition remains unclear. This study demonstrated the differences in cytokine responses and protein profiles between secretomes prepared under normoxic and hypoxic conditions. Furthermore, the immunoregulatory effects of heat shock protein SSA1(Ssa1), a protein candidate enriched in the hypoxic secretome, were investigated. Stimulation of mouse bone marrow-derived macrophages (BMMs) with Ssa1 resulted in the significant production of interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α as well as the significant expression of M2b macrophage markers (CD86, CD274 and tumor necrosis factor superfamily member 14), suggesting that C. albicans Ssa1 may promote macrophage polarization towards an M2b-like phenotype. Proteomic analysis of Ssa1-treated BMMs also revealed that Ssa1 reduced inflammation-related factors (IL-18-binding protein, IL-1 receptor antagonist protein, OX-2 membrane glycoprotein and cis-aconitate decarboxylase) and enhanced the proteins involved in anti-inflammatory response (CMRF35-like molecule 3 and macrophage colony-stimulating factor 1 receptor). Based on these results, we investigated the effect of Ssa1 on C. albicans infection and showed that Ssa1 inhibited the uptake of C. albicans by BMMs. Taken together, our results suggest that C. albicans alters its secretome, particularly by promoting the release of Ssa1, to modulate host immune response and survive under hypoxic conditions.

Natural Language Processing - A Surveillance Stepping Stone to Identify Child Abuse.

OBJECTIVE: We aimed to refine a natural language processing (NLP) algorithm that identified injuries associated with child abuse and identify areas in which integration into a real-time clinical decision support (CDS) tool may improve clinical care. METHODS: We applied an NLP algorithm in "silent mode" to all emergency department (ED) provider notes between July 2021 and December 2022 (n = 353) at 1 pediatric and 8 general EDs. We refined triggers for the NLP, assessed adherence to clinical guidelines, and evaluated disparities in degree of evaluation by examining associations between demographic variables and abuse evaluation or reporting to child protective services. RESULTS: Seventy-three cases falsely triggered the NLP, often due to errors in interpreting linguistic context. We identified common false-positive scenarios and refined the algorithm to improve NLP specificity. Adherence to recommended evaluation standards for injuries defined by nationally accepted clinical guidelines was 63%. There were significant demographic differences in evaluation and reporting based on presenting ED type, insurance status, and race and ethnicity. CONCLUSIONS: Analysis of an NLP algorithm in "silent mode" allowed for refinement of the algorithm and highlighted areas in which real-time CDS may help ED providers identify and pursue appropriate evaluation of injuries associated with child physical abuse.

Structural analysis of a soluble polysaccharide GSPA-0.3 from the root of Panax ginseng C. A. Meyer and its adjuvant activity with mechanism investigation.

A novel polysaccharide (GSPA-0.3) was isolated and purified from the root of cultivated Panax ginseng C. A. Meyer, and its structure, adjuvant activities, and mechanisms for inducing the maturation of mouse dendritic 2.4 cells (DC2.4) were extensively studied. Fraction GSPA-0.3, mainly composed by the galacturonic acid, galactose, arabinose, glucose, rhamnose, mannose, and xylose, had a molecular weight of 62,722 Da. The main chain of GSPA-0.3 was composed of →3)-α-L-Rhap-(1→, →4)-α-D-GalpA-(1→, and →3, 4)-α-D-GalpA-(1→. Branched chains comprised α-L-Araf-(1→3, 5)-α-L-Araf-(1→5)-α-L-Araf-(1→, α-D-Glcp-(1→6)-α-D-Glcp-(1→6)-α-D-Glcp-(1→, ß-D-Galp-(1→4)-ß-D-Galp-(1→4)-ß-D-Galp-(1→, and α-D-GalpA-(1→ units connected to the C3 position of →3, 4)-α-D-GalpA-(1→. In vivo, GSPA-0.3 was found to stimulate the production of IgG, IgG1, and IgG2a; increase the splenocyte proliferation index; and promote the expression of GATA-3, T-bet, IFN-γ, and IL-4 in H1N1 vaccine-immunized mice. Moreover, GSPA-0.3 significantly increased the levels of neutralizing antibodies in the mice, and its adjuvant activity was found to be superior to aluminum adjuvant (Alum adjuvant). Mechanistic investigations showed that GSPA-0.3 activated the TLR4-dependent pathway by upregulating the expressions of TLR4, MyD88, TRAF-6, and NF-κB proteins and gens. The results presented herein suggested that GSPA-0.3 could significantly promote the efficacy of the H1N1 vaccine by modulating Th1/Th2 response via the TLR4-MyD88-NF-κB signaling pathway.

Anti-cancer activity and cellular uptake of 7,3',4'- and 7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions.

Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The anti-cancer effects of soybean isoflavones daidzein derivatives 7,3',4'-trihydroxyisoflavone (734THIF) and 7,8,4'-trihydroxyisoflavone (784THIF) were evaluated under hypoxic microenvironments. Molecular docking of these isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor 2 (VEGFR2) was assessed. About 40 µM of 734THIF and 784THIF have the best effect on inhibiting the proliferation of HepG2 cells under hypoxic conditions. At a concentration of 40 µM, 784THIF significantly inhibits COX-2 expression in pre-hypoxia conditions compared to 734THIF, with an inhibition rate of 67.73%. Additionally, 40 µM 784THIF downregulates the expression of hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative stress, and inhibits the expression of anti-apoptotic proteins. The uptake by HepG2 confirmed higher 784THIF level and slower degradation characteristics under post- or pre-hypoxic conditions. In conclusion, our results showed that 784THIF had better anti-cancer effects and cellular uptake than 734THIF.

A combination of locoregional treatment with systemic therapy after atezolizumab plus bevacizumab failure for unresectable hepatocellular carcinoma provides survival benefit.

Atezolizumab plus bevacizumab (A+B) is used to treat unresectable hepatocellular carcinoma (HCC), but the optimal rescue therapy after A+B remains unclear. Combining locoregional therapy (LRT) with systemic treatment has been shown to improve tumor control, but the role in patients who fail A+B is unknown. We retrospectively enrolled patients who experienced radiological progression after A+B. Objective response rate (ORR), disease control rate (DCR), post progression survival (PPS), and secondary progression-free survival (PFS) were evaluated by modified RECIST. Inverse probability weighting (IPW) was used to balance baseline clinical features. A total of 61 patients were enrolled with a median age of 60.7 years, 83.6% male, 88.5% viral hepatitis-related, and 60.7% without prior systemic treatment before A+B. Patients receiving sequential therapies had significantly longer PPS than supportive care (10.5 vs. 2.3 months, P<0.0001). Among 37 patients received sequential systemic treatment, 18 received combined LRT. The median follow-up after post A+B failure was 6.6 months. The combined LRT group had higher ORR (27.8 vs. 0%, P=0.0197) and DCR (72.2 vs. 26.3%, P=0.0052) than systemic alone group. The median PPS and secondary PFS were significantly longer in combined LRT group (PPS: 12.2 vs. 5.8 months, P=0.0070; PFS: 5.0 vs. 2.6 months, P=0.0134) than systemic alone group. After IPW analysis, patients with combined LRT had superior PPS and secondary PFS. The incidence rates of AEs were higher in LRT combination compared to systemic alone (any grade AEs: 94.4 vs. 63.2%, P=0.0422; severe AEs: 33.3 vs. 5.3%, P=0.0422). No significant albumin-bilirubin index changed in the first 3 months in combined LRT group (0.966 [0.647-1.443], P=0.867) though a trend of deterioration in systemic alone group. In conclusion, sequential systemic therapy provides survival benefits after A+B failure. Furthermore, combining LRT with systemic treatment could provide better tumor responses and survival benefits with acceptable toxicity than systemic therapy alone.

Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122.

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.