Serum PYCARD may become a new diagnostic marker for rheumatoid arthritis patients.

BACKGROUND: The objective of this investigation is to analyze the levels and clinical relevance of serum PYCARD (Pyrin and CARD domain-containing protein, commonly known as ASC-apoptosis-associated speck-like protein containing a caspase activation and recruitment domain), interleukin-38 (IL-38), and interleukin-6 (IL-6) in individuals afflicted with rheumatoid arthritis (RA). METHODS: Our study comprised 88 individuals diagnosed with RA who sought medical attention at the Affiliated Hospital of Chengde Medical University during the period spanning November 2021 to June 2023, constituting the test group. Additionally, a control group of 88 individuals who underwent health assessments at the same hospital during the aforementioned timeframe was included for comparative purposes. The study involved the assessment of IL-38, IL-6, PYCARD, anti-cyclic citrullinated peptide antibody (anti-CCP), and erythrocyte sedimentation rate (ESR) levels in both groups. The research aimed to explore the correlations and diagnostic efficacy of these markers, employing pertinent statistical analyses for comprehensive evaluation. RESULTS: The test group had higher expression levels of PYCARD, IL-6, and IL-38 than the control group (P < 0.05). Based on the correlation analysis, there was a strong relationship between PYCARD and IL-38 (P < 0.01). The receiver operating characteristic (ROC) curve analysis revealed area under the curve (AUC) values of 0.97, 0.96, and 0.96 when using combinations of PYCARD and anti-CCP, IL-38 and anti-CCP, and IL-6 and anti-CCP for predicting RA, respectively. Importantly, all three of these pairs demonstrated superior AUC values compared to PYCARD, IL-38, IL-6, ESR, or anti-CCP used as standalone diagnostic indicators. CONCLUSION: PYCARD, IL-6, and IL-38 exhibit promising potential as novel diagnostic markers and may constitute valuable tools for supporting the diagnosis of RA.

Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke.

BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.

Better Life's Essential 8 contributes to slowing the biological aging process: a cross-sectional study based on NHANES 2007-2010 data.

Objective: To investigate the relationship between Life's Essential 8 (LE8) and Phenotypic Age Acceleration (PhenoAgeAccel) in United States adults and to explore the impact of LE8 on phenotypic biological aging, thereby providing references for public health policies and health education. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2010, this cross-sectional study analyzed 7,339 adults aged 20 and above. Comprehensive assessments of LE8, PhenoAgeAccel, and research covariates were achieved through the integration of Demographics Data, Dietary Data, Laboratory Data, and Questionnaire Data derived from NHANES. Weighted generalized linear regression models and restricted cubic spline plots were employed to analyze the linear and non-linear associations between LE8 and PhenoAgeAccel, along with gender subgroup analysis and interaction effect testing. Results: (1) Dividing the 2007-2010 NHANES cohort into quartiles based on LE8 unveiled significant disparities in age, gender, race, body mass index, education level, marital status, poverty-income ratio, smoking and drinking statuses, diabetes, hypertension, hyperlipidemia, phenotypic age, PhenoAgeAccel, and various biological markers (p < 0.05). Mean cell volume demonstrated no intergroup differences (p > 0.05). (2) The generalized linear regression weighted models revealed a more pronounced negative correlation between higher quartiles of LE8 (Q2, Q3, and Q4) and PhenoAgeAccel compared to the lowest LE8 quartile in both crude and fully adjusted models (p < 0.05). This trend was statistically significant (p < 0.001) in the full adjustment model. Gender subgroup analysis within the fully adjusted models exhibited a significant negative relationship between LE8 and PhenoAgeAccel in both male and female participants, with trend tests demonstrating significant results (p < 0.001 for males and p = 0.001 for females). (3) Restricted cubic spline (RCS) plots elucidated no significant non-linear trends between LE8 and PhenoAgeAccel overall and in gender subgroups (p for non-linear > 0.05). (4) Interaction effect tests denoted no interaction effects between the studied stratified variables such as age, gender, race, education level, and marital status on the relationship between LE8 and PhenoAgeAccel (p for interaction > 0.05). However, body mass index and diabetes manifested interaction effects (p for interaction < 0.05), suggesting that the influence of LE8 on PhenoAgeAccel might vary depending on an individual's BMI and diabetes status. Conclusion: This study, based on NHANES data from 2007-2010, has revealed a significant negative correlation between LE8 and PhenoAgeAccel, emphasizing the importance of maintaining a healthy lifestyle in slowing down the biological aging process. Despite the limitations posed by the study's design and geographical constraints, these findings provide a scientific basis for the development of public health policies focused on healthy lifestyle practices. Future research should further investigate the causal mechanisms underlying the relationship between LE8 and PhenoAgeAccel and consider cross-cultural comparisons to enhance our understanding of healthy aging.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Evaluation of the Mechanism of Yishan Formula in Treating Breast Cancer Based on Network Pharmacology and Experimental Verification.

BACKGROUND: Yishan formula (YSF) has a significant effect on the treatment of breast cancer, which can improve the quality of life and prolong the survival of patients with breast cancer; however, its mechanism of action is unknown. OBJECTIVE: In this study, network pharmacology and molecular docking methods have been used to explore the potential pharmacological effects of the YSF, and the predicted targets have been validated by in vitro experiments. METHODS: Active components and targets of the YSF were obtained from the TCMSP and Swiss target prediction website. Four databases, namely GeneCards, OMIM, TTD, and DisGeNET, were used to search for disease targets. The Cytoscape v3.9.0 software was utilized to draw the network of drug-component-target and selected core targets. DAVID database was used to analyze the biological functions and pathways of key targets. Finally, molecular docking and in vitro experiments have been used to verify the hub genes. RESULTS: Through data collection from the database, 157 active components and 618 genes implicated in breast cancer were obtained and treated using the YSF. After screening, the main active components (kaempferol, quercetin, isorhamnetin, dinatin, luteolin, and tamarixetin) and key genes (AKT1, TP53, TNF, IL6, EGFR, SRC, VEGFA, STAT3, MAPK3, and JUN) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the YSF could affect the progression of breast cancer by regulating biological processes, such as signal transduction, cell proliferation and apoptosis, protein phosphorylation, as well as PI3K-Akt, Rap1, MAPK, FOXO, HIF-1, and other related signaling pathways. Molecular docking suggested that IL6 with isorhamnetin, MAPK3 with kaempferol, and EGFR with luteolin have strong binding energy. The experiment further verified that YSF can control the development of breast cancer by inhibiting the expression of the hub genes. CONCLUSION: This study showed that resistance to breast cancer may be achieved by the synergy of multiple active components, target genes, and signal pathways, which can provide new avenues for breast cancer-targeted therapy.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Poly(ethylene glycol) Hydrogels with the Sustained Release of Hepatocyte Growth Factor for Enhancing Vascular Regeneration.

The surface modification of biologically active factors on tissue-engineering vascular scaffold fails to fulfill the mechanical property and bioactive compounds' sustained release in vivo and results in the inhibition of tissue regeneration of small-diameter vascular grafts in vascular replacement therapies. In this study, biodegradable poly(ε-caprolactone) (PCL) was applied for scaffold preparation, and poly(ethylene glycol) (PG) hydrogel was used to load heparin and hepatocyte growth factor (HGF). In vitro analysis demonstrated that the PCL scaffold could inhibit the heparin release from the PG hydrogel, and the PG hydrogel could inhibit heparin release during the process of PCL degradation. Finally, it results in sustained release of HGF and heparin from the PCL-PG-HGF scaffold. The mechanical property of this hybrid scaffold improved after being coated with the PG hydrogel. In addition, the PCL-PG-HGF scaffold illustrated no inflammatory lesions, organ damage, or biological toxicity in all primary organs, with rapid organization of the endothelial cell layer, smooth muscle regeneration, and extracellular matrix formation. These results indicated that the PCL-PG-HGF scaffold is biocompatible and provides a microenvironment in which a tissue-engineered vascular graft with anticoagulant properties allows regeneration of vascular tissue (Scheme 1). Such findings confirm the feasibility of creating hydrogel scaffolds coated with bioactive factors to prepare novel vascular grafts.

Efficacy of Electronic Reminders in Increasing the Enhanced Recovery After Surgery Protocol Use During Major Breast Surgery: Prospective Cohort Study.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are patient-centered, evidence-based guidelines for peri-, intra-, and postoperative management of surgical candidates that aim to decrease operative complications and facilitate recovery after surgery. Anesthesia providers can use these protocols to guide decision-making and standardize aspects of their anesthetic plan in the operating room. OBJECTIVE: Research across multiple disciplines has demonstrated that clinical decision support systems have the potential to improve protocol adherence by reminding providers about departmental policies and protocols via notifications. There remains a gap in the literature about whether clinical decision support systems can improve patient outcomes by improving anesthesia providers' adherence to protocols. Our hypothesis is that the implementation of an electronic notification system to anesthesia providers the day prior to scheduled breast surgeries will increase the use of the already existing but underused ERAS protocols. METHODS: This was a single-center prospective cohort study conducted between October 2017 and August 2018 at an urban academic medical center. After obtaining approval from the institutional review board, anesthesia providers assigned to major breast surgery cases were identified. Patient data were collected pre- and postimplementation of an electronic notification system that sent the anesthesia providers an email reminder of the ERAS breast protocol the night before scheduled surgeries. Each patient's record was then reviewed to assess the frequency of adherence to the various ERAS protocol elements. RESULTS: Implementation of an electronic notification significantly improved overall protocol adherence and several preoperative markers of ERAS protocol adherence. Protocol adherence increased from 16% (n=14) to 44% (n=44; P<.001), preoperative administration of oral gabapentin (600 mg) increased from 13% (n=11) to 43% (n=43; P<.001), and oral celebrex (400 mg) use increased from 16% (n=14) to 35% (n=35; P=.006). There were no statistically significant differences in the use of scopolamine transdermal patch (P=.05), ketamine (P=.35), and oral acetaminophen (P=.31) between the groups. Secondary outcomes such as intraoperative and postoperative morphine equivalent administered, postanesthesia care unit length of stay, postoperative pain scores, and incidence of postoperative nausea and vomiting did not show statistical significance. CONCLUSIONS: This study examines whether sending automated notifications to anesthesia providers increases the use of ERAS protocols in a single academic medical center. Our analysis exhibited statistically significant increases in overall protocol adherence but failed to show significant differences in secondary outcome measures. Despite the lack of a statistically significant difference in secondary postoperative outcomes, our analysis contributes to the limited literature on the relationship between using push notifications and clinical decision support in guiding perioperative decision-making. A variety of techniques can be implemented, including technological solutions such as automated notifications to providers, to improve awareness and adherence to ERAS protocols.

Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque.

BACKGROUND: Umbilical cord (UC) mesenchymal stem cell (MSC) transplantation is a potential therapeutic intervention for atherosclerotic vascular disease. Integrin beta 3 (ITGB3) promotes cell migration in several cell types. However, whether ITGB-modified MSCs can migrate to plaque sites in vivo and play an anti-atherosclerotic role remains unclear. AIM: To investigate whether ITGB3-overexpressing MSCs (MSCsITGB3) would exhibit improved homing efficacy in atherosclerosis. METHODS: UC MSCs were isolated and expanded. Lentiviral vectors encoding ITGB3 or green fluorescent protein (GFP) as control were transfected into MSCs. Sixty male apolipoprotein E-/- mice were acquired from Beijing Vital River Lab Animal Technology Co., Ltd and fed with a high-fat diet (HFD) for 12 wk to induce the formation of atherosclerotic lesions. These HFD-fed mice were randomly separated into three clusters. GFP-labeled MSCs (MSCsGFP) or MSCsITGB3 were transplanted into the mice intravenously via the tail vein. Immunofluorescence staining, Oil red O staining, histological analyses, western blotting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction were used for the analyses. RESULTS: ITGB3 modified MSCs successfully differentiated into the "osteocyte" and "adipocyte" phenotypes and were characterized by positive expression (> 91.3%) of CD29, CD73, and CD105 and negative expression (< 1.35%) of CD34 and Human Leukocyte Antigen-DR. In a transwell assay, MSCsITGB3 showed significantly faster migration than MSCsGFP. ITGB3 overexpression had no effects on MSC viability, differentiation, and secretion. Immunofluorescence staining revealed that ITGB3 overexpression substantially enhanced the homing of MSCs to plaque sites. Oil red O staining and histological analyses further confirmed the therapeutic effects of MSCsITGB3, significantly reducing the plaque area. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction revealed that MSCITGB3 transplantation considerably decreased the inflammatory response in pathological tissues by improving the dynamic equilibrium of pro- and anti-inflammatory cytokines. CONCLUSION: These results showed that ITGB3 overexpression enhanced the MSC homing ability, providing a potential approach for MSC delivery to plaque sites, thereby optimizing their therapeutic effects.

Risk Factors for Stroke Development After Thoracic Aortic Surgery.

OBJECTIVES: Stroke after thoracic aortic surgery is a complication that is associated with poor outcomes. The aim is to characterize the intraoperative risk factors for stroke development. DESIGN: A retrospective analysis. SETTING: Tertiary, high-volume cardiac surgery center. PARTICIPANTS: Patients who had surgical repair of thoracic aortic diseases from January 1, 2017, through December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 704 patients were included, of whom 533 had ascending aortic aneurysms, and 171 had type A aortic dissection. The incidence of postoperative stroke was 4.5% (95% CI 2.9%-6.6%) for ascending aortic aneurysms compared with 12.3% (95% CI 7.8%-18.16%) in type-A aortic dissections. Patients who developed postoperative strokes had significantly lower intraoperative hemoglobin median (7.5 gm/dL [IQR 6.8-8.6] v 8.55 gm/dL [IQR 7.3-10.0]; p < 0.001). The median cardiopulmonary bypass time was 185 minutes (IQR 136-328) in the stroke group versus 156 minutes (IQR 113-206) in the nonstroke group (p = 0.014). Circulatory arrest was used in 57.8% versus 38.5% of the nonstroke patients (p = 0.017). The initial temperature after leaving the operating room was lower, with a median of 35.0°C (IQR 34-35.92) in the stroke group versus 35.5°C (IQR 35-36) in the nonstroke cohort (p = 0.021). CONCLUSIONS: This single-center study highlighted the potential importance of intra-operative factors in preventing stroke. Lower hemoglobin, longer duration of cardiopulmonary bypass, deep hypothermic circulatory arrest, and postoperative hypothermia are potential risk factors for postoperative stroke. Further studies are needed to prevent this significant complication in patients with thoracic aortic diseases.

Robotic-assisted technology does not influence functional outcomes among obese and morbidly obese total knee arthroplasty patients.

PURPOSE: Despite benefits of total knee arthroplasty (TKA) on function and quality of life, obese patients have less improved functional outcomes following TKA compared to their normal weight counterparts. Furthermore, obesity is a risk factor for aseptic loosening and revision surgery following TKA. With known benefits of robotic-assisted TKA (RaTKA) in precision and patient satisfaction, we aimed to evaluate the differences in patient reported outcome and early complication rates for patients undergoing RaTKA versus conventional TKA among patients of varying BMI groups. METHODS: This study was a retrospective cohort study of patients who underwent conventional versus RaTKA. Patients were grouped by BMI range (< 30 kg/m2, 30-40 kg/m2, and > 40 kg/m2). Patient-reported outcomes were measured by Oxford Knee Scores and 12-Item Short Form Survey scores preoperatively, 6-month, 1-year, and 2-year postoperatively. Mixed-effects linear models were built for each patient-reported outcome to assess the interaction between type of surgery and BMI while adjusting for known confounders such as demographic variables. RESULTS: A total of 350 patients (n = 186 RaTKA, n = 164 conventional TKA) met inclusion criteria. SF-12 physical scores were significantly higher at 2-year follow-up among non-obese patients compared to obese and morbidly obese patients (p = 0.047). There was no statistically significant interaction between the type of surgery performed (RaTKA versus conventional TKA) and obesity regarding their effects on patient reported outcomes. CONCLUSIONS: This study demonstrates no differences in functional outcomes among patients undergoing RaTKA compared to conventional TKA. Furthermore, obesity had no significant effect on this association. LEVEL OF EVIDENCE: III.

Different hydration methods for the prevention of contrast-induced nephropathy in patients with elective percutaneous coronary intervention: a retrospective study.

BACKGROUND: Hydration is currently the main measure to prevent contrast-induced nephropathy (CIN). We aimed to compare the preventive effect of preprocedure and postprocedure hydration on CIN in patients with coronary heart disease undergoing elective percutaneous coronary intervention (PCI). METHODS: A retrospective study included 198 cases of postprocedure hydration and 396 cases of preprocedure hydration using propensity score matching. The incidence of CIN 48 h after PCI and adverse events within 30 days after contrast media exposure were compared between the two groups. Logistic regression analysis was used to analyse the risk factors for CIN. RESULTS: The incidence of CIN in the postprocedure hydration group was 3.54%, while that in the preprocedure hydration group was 4.8%. There was no significant difference between the two groups (p = 0.478). Multivariate logistic regression analysis showed that diabetes mellitus, baseline BNP and cystatin C levels, and contrast agent dosage were independent risk factors for CIN. There was no significant difference in the incidence of major adverse events between the two groups (3.03% vs. 2.02%, p = 0.830). CONCLUSIONS: Postprocedure hydration is equally effective compared to preoperative hydration in the prevention of CIN in patients with coronary heart disease undergoing elective PCI.

Systematic review and meta-analysis: Prognostic impact of time from diagnosis to treatment in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) has been considered an oncologic emergency that requires initiation of chemotherapy immediately after diagnosis. With the introduction of novel targeted therapies, there is a potential benefit associated with delaying definitive treatment for identification of actionable therapeutic targets. Unfortunately, cytogenetic/molecular testing can take >7 days to return, and there is not a consensus regarding the prognostic impact of time from diagnosis to treatment (TDT) in AML. METHODS: A literature review and meta-analysis of studies done to date that evaluate TDT was conducted. Studies that reported baseline characteristics, TDT, and outcomes for patients with AML were selected. Outcomes included overall survival (OS), complete remission (CR), and mortality. Studies that measured CR rates within each TDT range and data to calculate odds ratios were included in the meta-analysis. The remaining outcomes were synthesized descriptively for literature review. RESULTS: Thirteen studies were identified, which comprised a total of 14,946 patients. Median TDT values were between 1 and 8 days. Several studies found a significant association between prolonged TDT and older age and lower proliferation burden. Four of 11 studies did not detect a significant relationship between TDT and OS. No studies found a significant association between TDT and early death. Six of eight studies did not find a significant association between TDT and CR rate. The meta-analysis found a significant association between prolonged TDT and decreased achievement of CR (p < .05). CONCLUSIONS: Results were highly variable but suggest it may be feasible to pursue cytogenetic/molecular testing in patients who are clinically stable, particularly in those aged 60 years and older.

Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant.

Background and Aims: In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach: We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan-Meier method, and correlative studies were calculated using chi-square or Fisher's exact test. Results: Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094-0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%. Conclusions: An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.

Determining the mechanism of action of the Qishan formula against lung adenocarcinoma by integration of network pharmacology, molecular docking, and proteomics.

BACKGROUND: Lung adenocarcinoma (LUAD) is the main pathological type of lung cancer. Qishan formula (QSF) is reportedly efficacious against LUAD. However, its mechanisms of action currently remain elusive. Therefore, network pharmacology, molecular docking techniques and proteomics were used to verify the potential pharmacological effects of QSF in the treatment of LUAD. METHODS: The active ingredients and potential targets of QSF were obtained from the TCMSP, chemical source network and construct a drug-component-target networks using Cytoscape v3.7.2. Data for disease targets were obtained from 5 databases: TCGA, OMIM, DrugBank, DisGeNET, and GeneCards. Drug disease cross targets were used to construct protein-protein interaction networks for selecting the core targets using the STRING database and enrichment pathway networks using the DAVID database. Finally, TMT quantitative proteomics was used to identify the possible core targets and action pathways. Molecular docking to verify the affinity between components and targets. RESULTS: Network pharmacology identified core components of QSF against LUAD included baicalein, methylophiopogonone B, quercetin, kaempferol, isorhamnetin, and luteolin, which can act on 10 key targets (SRC, TP53, PIK3R1, MAPK3, STAT3, MAKP1, HSP90AA1, PIK3CA, HRAS, and AKT1). QSF might play a therapeutic role in LUAD by regulating biological processes such as signal transduction, protein phosphorylation, cell proliferation, and apoptosis, as well as the PI3K/AKT, MAPK, FoxO, and other signaling pathways. Proteomics identified 207 differentially expressed proteins, and by integrating with network pharmacology and molecular docking results we found that 6 core components of QSF may target TP53 against LUAD through the PI3K/AKT signaling pathway. CONCLUSION: QSF is a multitarget recipe potentially exerting pleiotropic effects in LUAD.

A prospective diagnostic and prognostic biomarker for hepatocellular carcinoma that functions in glucose metabolism regulation: Solute carrier family 37 member 3.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Due to the insidious onset of HCC, early diagnosis is relatively difficult. HCC also exhibit strong resistance to first-line therapeutic drugs. Therefore, novel precise diagnostic and prognostic biomarkers for HCC are urgently needed. We employed a combination methods of bioinformatic analysis, cell functional experiments in vitro and a xenograft tumour model in vivo to systematically investigate the role of solute carrier family 37 member 3 (SLC37A3) in HCC progression. First, bioinformatic analysis demonstrated that SLC37A3 expression was significantly increased in HCC tissues compared with normal tissues. SLC37A3 expression was also associated with tumour stages and various clinical and pathological features. Similar trends in SLC37A3 expression levels were verified in HCC cells and by using IHC experiments. Next, survival analysis showed that the overall, 1-year, 3-year and 5-year survival rates were decreased in HCC patients with high SLC37A3 expression compared with HCC patients low SLC37A3 expression. Xenograft tumour experiments also suggested that SLC37A3 knockdown significantly inhibited HCC tumourigenesis in vivo. Cell functional experiments suggested that SLC37A3 knockdown inhibited HCC cell proliferation and metastasis, but promoted apoptosis. Furthermore, RNA-seq analysis of SLC37A3-knockdown HCC cells indicated that the type 1 diabetes mellitus (T1DM)-related signalling pathway was significantly altered. The expression levels of insulin secretion-related and glycolysis/gluconeogenesis-related genes were also altered, suggesting that SLC37A3 might be involved in the regulation of glucose homeostasis. In summary, SLC37A3 represents a prospective diagnostic and prognostic biomarker for HCC that functions in glucose metabolism regulation.

TKIs beyond immunotherapy predict improved survival in advanced HCC.

PURPOSE: For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response. METHODS: We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan-Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis. RESULTS: For all patients, median overall survival (mOS) was 13 months (95% CI 8-19), and median progression-free survival (mPFS) was 6 months (95% CI 4-10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s), p < 0.0001) and mOS (not met vs. 11 vs. 3 months, p < 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months p = 0.133) and mOS (17 vs. 9 months; p = 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months, p = 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (p = 0.0043). CONCLUSION: We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.

Antioxidant Effects of Roasted Licorice in a Zebrafish Model and Its Mechanisms.

Licorice (Gan-Cao, licorice) is a natural antioxidant and roasted licorice is the most common processing specification used in traditional Chinese medicine prescriptions. Traditional Chinese medicine theory deems that the honey-roasting process can promote the efficacy of licorice, including tonifying the spleen and augmenting "Qi" (energy). The antioxidant activity and mechanisms underlying roasted licorice have not yet been reported. In this study, we found that roasted licorice could relieve the oxidative stress injury induced by metronidazole (MTZ) and could restrain the production of excessive reactive oxygen species (ROS) induced by 2,2'-azobis (2-methylpropionamidine) dihydrochloride (AAPH) in a zebrafish model. It was further found that roasted licorice could exert its oxidative activity by upregulating the expression of key genes such as heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) in the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway both in vivo and in vitro. Furthermore, consistent results were obtained showing that rat serum containing roasted licorice was estimated to reduce cell apoptosis induced by H2O2. Then, the UHPLC-Q-Exactive Orbitrap MS analysis results elucidated the chemical composition of rat plasma containing roasted licorice extracts, including ten prototype chemical components and five metabolic components. Among them, six compounds were found to have binding activity with Kelch-like ECH-associated protein 1 (KEAP1), which plays a crucial role in the transcriptional activity of NRF2, using a molecular docking simulation. The results also showed that liquiritigenin had the strongest binding ability with KEAP1. Immunofluorescence further confirmed that liquiritigenin could induce the nuclear translocation of NRF2. In summary, this study provides a better understanding of the antioxidant effect and mechanisms of roasted licorice, and lays a theoretical foundation for the development of a potential antioxidant for use in clinical practice.

An investigation into gender bias in the evaluation of orthopedic trainee arthroscopic skills.

BACKGROUND: Women surgeons receive lower compensation, hold fewer academic positions, and hold fewer leadership positions than men, particularly in orthopedic surgery. Gender bias at the trainee level has been demonstrated in various surgical subspecialties, but there is a lack of information on gender bias within the orthopedic training environment. This study investigated whether implicit gender bias is present in the subjective evaluation of orthopedic trainee arthroscopic skills. METHODS: After institutional review board approval, a web-based survey was sent to American Shoulder and Elbow Surgeons (ASES) members via the society's email listserve. Study participants were informed that the study was being done to develop a systematic evaluation method for trainees. The survey randomized participants to view and evaluate a prefellowship and a postfellowship video of "Rachel" (she/her) or "Charles" (he/him) performing a 15-point diagnostic shoulder arthroscopy. The videos for Rachel and Charles were identical except for the pronouns used in the video. Participants evaluated the trainee's skill level using questions from the Arthroscopic Surgical Skill Evaluation Tool (ASSET). Blinded and deidentified additional comments regarding the trainee's skill were classified as positive, negative, or neutral. Statistical analyses were used to compare scores and comments between Rachel and Charles. RESULTS: Of 1115 active ASES members, 181 ASES members started the survey and 106 watched both videos and were included in the analysis. Of the 106 participants completing the survey, 96 (91%) were men and 10 (9%) were women with a median (interquartile range) age of 44 (38-51). A teaching role was reported by 84 of 106 participants (79%). There was no significant difference between prefellowship scores (P = .87) or between postfellowship scores (P = .84) for the woman and man fellow. The numbers of comments classified as positive, negative, or neutral were not significantly different between the man and woman fellow (P = .19). Participants in teaching roles gave significantly lower scores to both fellows at both time points (P = .04), and participants who had fellow trainees were more likely to give negative comments to both fellows (P = .02). DISCUSSION: Trainee gender did not influence the ratings and comments participants gave for trainee arthroscopic skills, suggesting that gender bias may not play a major role in the evaluation of arthroscopic skill during orthopedic training.