Long-term trends in lifestyle factors among respondents with dyslipidemia in the United States.

OBJECTIVES: To explore the long-term trends in unhealthy lifestyle factors and the risk sociodemographic subgroups among people with dyslipidemia. METHODS: Data extracted from the 1999 to 2018 National Health and Nutrition Examination Survey (NHANES). Lifestyle factors were smoking status, alcohol drinking, obesity, dietary quality, depression, physical activity, and sedentary behavior. A Joinpoint regression model was used to estimate trends in the log-transformed age-standardized prevalence. Multinomial logistic regression models adjusted for age, sex, and race/ethnicity were used to analyze subgroups by sociodemographic factors. RESULTS: Data for 33,680 respondents were extracted between 1999 and 2018. The prevalence of smoking and poor-quality diet decreased from 1999 to 2018 (P<0.001), while obesity significantly increased (P<0.001). The prevalence of depression marginally increased from 2005 to 2018 (P=0.074). We observed that non-Hispanic Black individuals, Hispanics, males, as well as those with lower family income-to-poverty ratios and education levels, unemployed individuals, or those lacking a spouse/live-in partner, were at elevated risk of unhealthy lifestyle factors when compared to the reference groups. CONCLUSIONS: Among NHANES respondents from 1999 to 2018 with dyslipidemia, significant reductions in the prevalence of current smoking and poor diet were observed, while the prevalence of obesity was markedly increased. There were sociodemographic differences in the management of lifestyle factors. Further initiatives to encourage people with dyslipidemia are required to reduce potential adverse outcomes.

Comprehensive analysis of next generation sequencing and ARMS-PCR for detecting EGFR exon 20 insertion (ex20ins) mutations in Chinese non-small cell lung cancer patients.

Background: Amivantamab (JNJ-372) and mobocertinib (TAK-788) have been reported to have favorable therapeutic effect for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. Thus, accurate detection of EGFR ex20ins mutations is crucial for subsequent individualized therapy. The aim of this study was to compare the two common methods of next generation sequencing (NGS) and amplification refractory mutation system polymerase chain reaction (ARMS-PCR) for detecting EGFR ex20ins mutations in Chinese NSCLC patients. Methods: We retrospectively analyzed EGFR mutations, especially for ex20ins, in 3,606 NSCLC patients detected by NGS and 1,785 patients by ARMS. Results: Among the 3,606 NGS patients, a total of 2,077 EGFR mutations and 95 EGFR ex20ins were identified, accounting for 57.6% and 2.6%, respectively. While 48.4% of EGFR mutations and 1.1% of ex20ins were detected in 1,785 ARMS patients, which were significantly lower than those of NGS (P<0.01). Thirty-four unique ex20ins variants were identified by NGS, and eight of them was reported for the first time. However, ARMS was designed to detect only several known EGFR ex20ins variants, and even did not include the most common variants in Chinese NSCLC patients. Conclusions: NGS is more advantageous and strongly recommended for the detection of EGFR ex20ins mutations. Considering the fast and cost-effective ARMS detection method, it is suggested that the primers design should be updated according to the characteristics of EGFR ex20ins mutations in Chinese NSCLC patients.

Blocking M2-like macrophage polarization using decoy oligodeoxynucleotide-based gene therapy prevents immune evasion for pancreatic cancer treatment.

M2-like macrophages exhibit immunosuppressive activity and promote pancreatic cancer progression. Reactive oxygen species (ROS) affect macrophage polarization; however, the mechanism remains unclear. This study aimed to elucidate the underlying molecular basis and design a gene therapy to inhibit M2-like polarization. Microarray analysis and IF staining were performed in M1-like and M2-like macrophages to ascertain the expression of CYBB, a major intracellular ROS source. Co-culture assay and syngeneic orthotopic pancreatic cancer mouse models were used to study the mechanism of M2-like skewing. Decoy oligodeoxynucleotides (ODNs) were designed to manipulate CYBB transcription to inhibit M2-like polarization and control tumor growth. Lipopolysaccharide (LPS) treatment polarized U937 cells to M1-like macrophages in which CYBB expression was increased. In contrast, co-culture with PANC-1 cells induced M2-like polarization in U937 cells with CYBB downregulation. High CD204 M2-like expression in combination with low CYBB expression was associated with the worst prognosis in pancreatic cancer patients. STAT6 and HDAC2 in U937 cells were activated by cancer cell-derived IL-4 after coculture and then bound to the CYBB promoter to repress CYBB expression, resulting in M2-like polarization. DPI that inhibits ROS production could block this action. Knockdown of STAT6 and HDAC2 also inhibited M2-like polarization and maintained the M1-like phenotype of U937 cells after coculture. Decoy ODNs interrupting the binding of STAT6 to the CYBB promoter counteracted M2-like polarization and tumor growth and triggered antitumor immunity in vivo. Gene therapy using STAT6-CYBB decoy ODNs can inhibit M2-like polarization, representing a potential therapeutic tool for pancreatic cancer.

PCK2 induces gefitinib resistance by suppresses ferroptosis in non-small cell lung cancer.

OBJECTIVES: This study aimed to explore the involvement of phosphoenolpyruvate carboxykinase 2 (PCK2) in gefitinib-resistant non-small cell lung cancer (NSCLC) cells and assess its feasibility as a therapeutic target against gefitinib resistance. METHODS: Gefitinib-resistant cell lines, PC9GR and HCC827GR, were generated through progressive exposure of parental cells to escalating concentrations of gefitinib. Transcriptomic analysis encompassed the treatment of PC9 and PC9GR cells with gefitinib or vehicle, followed by RNA extraction, sequencing, and subsequent bioinformatic analysis. Cell viability was determined via CCK-8 assay, while clonogenic assays assessed colony formation. Apoptosis was detected utilizing the Annexin V-FITC/7AAD kit. Iron ion concentrations were quantified using FerroOrange. mRNA analysis was conducted through quantitative RT-PCR. Western blotting was employed for protein analysis. H&E and immunohistochemical staining were performed on tumor tissue sections. RESULTS: The results revealed that depletion or inhibition of PCK2 significantly enhanced gefitinib's efficacy in inducing cell growth arrest, apoptosis, and ferroptosis in resistant NSCLC. Moreover, PCK2 knockdown led to the downregulation of key ferroptosis-related proteins, GPX4 and SLC7A11, while upregulating ASCL4. Conversely, overexpression of PCK2 in gefitinib-sensitive cells rendered resistance to gefitinib. In vivo experiments using a gefitinib-resistant xenograft model demonstrated that PCK2 silencing not only reduced tumor growth but also considerably increased the anti-tumor effect of gefitinib. CONCLUSIONS: In conclusion, our study presents compelling evidence indicating that PCK2 plays a pivotal role in gefitinib resistance in NSCLC. The modulation of ferroptosis-related proteins and the involvement of Akt activation further elucidate the mechanisms underlying this resistance. Consequently, PCK2 emerges as a promising therapeutic target for overcoming gefitinib resistance in NSCLC, offering a new avenue for the development of more effective treatment strategies.

Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PURPOSE: To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. METHODS: CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. RESULTS: PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 µM). Significantly, treatment with PPI at 1.0 µM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. CONCLUSIONS: We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.

Efficacy and safety analysis of selective hepatic vein occlusion combined with arterial chemoembolization versus conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma.

Background: Transarterial chemoembolization (TACE) is a non-radical treatment. How to improve the local response rate of tumor is the direction we have been exploring. The purpose of this study is to compare the efficacy and safety of occlusion-TACE (O-TACE) versus conventional TACE (C-TACE) in the treatment of patients with early to mid-stage hepatocellular carcinoma (HCC) of lesions being confined to the same hepatic venous drainage area. Methods: In this study, 40 patients with HCC were prospectively enrolled and randomly assigned to the O-TACE and C-TACE groups, and the efficacy of all patients was assessed at 1, 2, and 3 months after the first treatment, and adverse events (AEs) occurring during the treatment period were also recorded. Results: At 1, 2 and 3 months after the first treatment, patients in the O-TACE group had significantly better complete response (CR) rates (35% vs. 5%, P=0.04; 50% vs. 15%, P=0.04; 70% vs. 30%, P=0.02) than those in the C-TACE group. The most common AE was abdominal pain, and the liver function indexes of patients in both groups returned to the baseline level at 1 month after the first treatment, and there was no statistically significant difference in the rate of AEs between the two groups. Conclusions: O-TACE has a better CR rate and a favorable safety profile in patients with early to mid-stage HCC of lesions being confined to the same hepatic venous drainage area.

The M2 Macrophages Derived Migrasomes From the Surface of Titania Nanotubes Array as a New Concept for Enhancing Osteogenesis.

As newly discovered substrate anchored extracellular vesicles, migrasomes (Migs) may bring a new opportunity for manipulating target cells bioactivities. In this study, the M2 macrophages derived Migs are obtained by titania nanotubes surface (NTs). Due to the benefits of nanostructuring, the NTs surface is not only able to induce RAW264.7 for M2 polarization but also to generate more Migs formation, which can be internalized by following seeded mesenchymal stem cells (MSCs). Then, the NTs surface induced Migs are collected by density-gradient centrifugation for MSCs treatment. As indicated by immunofluorescence staining, alkaline phosphatase activity, and alizarin red staining, the osteogenic differentiation capacity of MSCs is significantly enhanced by Migs treatment, in line with the dosage. By RNA-sequence analysis, the enhancement of osteogenic differentiation is correlated with PI3K-AKT pathway activation that may originate from the M2 polarization state of donor cells. Finally, the Migs are coated onto Ti surface for therapeutic application. Both the in vitro and in vivo analysis reveal that the Migs coated Ti implant shows significant enhancement of osteogenesis. In conclusion, this study suggests that the nanosurface may be a favorable platform for Migs production, which may bring a new concept for tissue regeneration.

CD204-positive M2-like tumor-associated macrophages increase migration of gastric cancer cells by upregulating miR-210 to reduce NTN4 expression.

BACKGROUND: Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment and portend poor prognosis. However, the molecular mechanisms underlying the tumor promotion of TAMs have not been fully elucidated. METHODS: Coculture of gastric cancer cells with U937 cells was performed to investigate the impact of TAMs on cancer cell behavior. MicroRNA (miRNA) microarray and bioinformatics were applied to identify the involved miRNAs and the functional target genes. The regulation of the miRNA on its target gene was studied using anti-miRNA and miRNA mimic. RESULTS: Coculture with CD204+ M2-like TAMs increased proliferation, migration, and epithelial-mesenchymal transition of gastric cancer cells. MiR-210 was the most upregulated miRNA in cancer cells identified by miRNA microarray after coculture. In gastric cancer tissues, miR-210 expression was positively correlated with CD204+ M2-like TAM infiltration. Inactivation of miR-210 by antimir attenuated CD204+ M2-like TAMs-induced cancer cell migration. Using pharmacological inhibitors and neutralizing antibodies, CD204+ M2-like TAMs-secreted TNFα was found to upregulate miR-210 through NF-κB/HIF-1α signaling. Bioinformatics analysis showed netrin-4 (NTN4) as a potential target of miR-210 to suppress gastric cancer cell migration. We also found an inverse expression between miR-210 and NTN4 in cancer cells after coculture or in tumor xenografts. Anti-miR-210 increased NTN4 expression, while miR-210 mimics downregulated NTN4 in cancer cells. Reporter luciferase assays showed that MiR-210 mimics suppressed NTN4 3' untranslated region-driven luciferase activity in cancer cells, but this effect was blocked after mutating miR-210 binding site. CONCLUSIONS: CD204+ M2-like TAMs can utilize the TNF-α/NF-κB/HIF-1α/miR-210/NTN4 pathway to facilitate gastric cancer progression.

From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.

Protocol for the PORT study: short-term perioperative rehabilitation to improve outcomes in cardiac valvular surgery - a randomised control trial.

INTRODUCTION: Perioperative rehabilitation (PORT) has shown a positive effect on patients undergoing cardiac surgery. However, there are minimal data on the impact of short-term PORT in cardiac surgery, which is associated with higher postoperative morbidity and mortality. The trial will assess the efficacy of short-term PORT in reducing in-hospital mortality, postoperative pulmonary complications and length of stay, compared with the usual care in cardiac surgical patients. METHODS AND ANALYSIS: This is a single-centre prospective, randomised, open, controlled trial with a 1:1 ratio. Consecutive 800 adult patients undergoing elective valve surgery will be randomised to either usual care or in-hospital short-term PORT that consists of education, inspiratory muscle training, active cycle of breathing techniques and early mobilisation. The primary outcome of this study will be a composite of in-hospital all-cause mortality, incidence of postoperative pulmonary complications and the ratio of postoperative hospitalisation >7 days. ETHICS AND DISSEMINATION: The PORT study was granted by the Medical Research Ethics Committee of Guangdong Provincial People's Hospital in August 2018. Findings will be disseminated to patients, clinicians and commissioning groups through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03709511.

Prognosis value of EAS index in patients with obstructive coronary artery disease.

Background: EAS index is reported to be an adjunctive tool for risk stratification in addition to left ventricular ejection fraction (LVEF). This study aimed to verify the predictive value of EAS index among coronary artery disease (CAD) patients with different cardiac systolic function levels. Methods: A total of 477 patients with obstructive CAD were included in the exploratory analysis of a prospective cohort between October 2017 and January 2018 at Guangdong Provincial People's Hospital. EAS index, e'/(a' × s'), is a novel parameter assessed by tissue Doppler imaging (TDI) indicating combined diastolic and systolic performance. Any occurrence of major adverse cardiovascular event (MACE) was recorded, including first onset of myocardial infarction, stroke, readmission for heart failure, coronary revascularization, or cardiovascular death that occurred within 6 months of the first admission. Kaplan-Meier survival and Cox regression analyses were applied to testify the predictive value of EAS index for cardiovascular outcome. Results: A total of 415 patients (87.2%) completed the follow-up (median, 25.9 months) and experienced 101 (24.3%) MACEs, 17 (4.0%) deaths, and 139 (33.4%) composite events. Elevated EAS index was significantly associated with a higher incidence of MACE, even after adjustment for age, sex, body mass index, N-terminal pro brain natriuretic peptide, high-sensitivity troponin T, high-density lipoprotein, stenosis degree, and other TDI parameters [Model 3, hazard ratio: 1.81, 95% confidence interval (CI): 1.15-2.85]. For different levels of cardiac function, Kaplan-Meier survival analysis revealed that elevated EAS index was associated with higher MACE incidence only in patients with LVEF ≥50% (P<0.05). Conclusions: EAS index is an independent predictor of MACE in patients with obstructive CAD, which could be utilized as a tool for risk stratification in CAD patients or incorporated into a prediction model to improve efficacy.

Case report: Unveiling the unforeseen: a catastrophic encounter of giant aortic aneurysm rupture during re-sternotomy in a patient with bicuspid aortic valve and previous surgical aortic valve replacement.

Due to structural abnormalities in the leaflets, patients with bicuspid aortic valve (BAV) may develop isolated aortic valve disease, such as aortic regurgitation, aortic stenosis, or a combination of both. In addition to valvular pathology, numerous studies have indicated that approximately 40% of BAV patients exhibit aortic pathologies characterized by aortic dilatation. According to guidelines for valvular diseases, patients with BAV who require surgical aortic valve replacement (SAVR) and have a diameter of the aortic sinuses or ascending aorta ≥4.5 cm are recommended to undergo concomitant replacement of the aortic sinuses or ascending aorta. However, we encountered a case in 2020 involving a patient with severe aortic regurgitation due to BAV and an ascending aortic diameter of 4.2 cm. This patient underwent SAVR and ascending aortoplasty surgery at our center. Remarkably, three years postoperatively, the patient's aortic diameter rapidly expanded by nearly threefold, which also suggests the risk of encountering a giant aortic root aneurysm during reoperation. Unfortunately, a fatal rupture of a giant aortic root aneurysm was encountered during re-sternotomy. Fortunately, with adequate preoperative planning, we successfully managed to avert this perilous situation. The patient recovered without complications and was discharged on the 8th day. Individualized surgical plans were formulated based on a comprehensive evaluation of the perioperative conditions.

New insights into the role of adipocytes in pancreatic cancer progression: paving the way towards novel therapeutic targets.

Pancreatic cancer (PC) remains one of the most lethal malignancies across the world, which is due to delayed diagnosis and resistance to current therapies. The interactions between pancreatic tumor cells and their tumor microenvironment (TME) allow cancer cells to escape from anti-cancer therapies, leading to difficulties in treating PC. With endocrine function and lipid storage capacity, adipose tissue can maintain energy homeostasis. Direct or indirect interaction between adipocytes and PC cells leads to adipocyte dysfunction characterized by morphological change, fat loss, abnormal adipokine secretion, and fibroblast-like transformation. Various adipokines released from dysfunctional adipocytes have been reported to promote proliferation, invasion, metastasis, stemness, and chemoresistance of PC cells via different mechanisms. Additional lipid outflow from adipocytes can be taken into the TME and thus alter the metabolism in PC cells and surrounding stromal cells. Besides, the trans-differentiation potential enables adipocytes to turn into various cell types, which may give rise to an inflammatory response as well as extracellular matrix reorganization to modulate tumor burden. Understanding the molecular basis behind the protumor functions of adipocytes in PC may offer new therapeutic targets.

Advanced applications of DNA nanostructures dominated by DNA origami in antitumor drug delivery.

DNA origami is a cutting-edge DNA self-assembly technique that neatly folds DNA strands and creates specific structures based on the complementary base pairing principle. These innovative DNA origami nanostructures provide numerous benefits, including lower biotoxicity, increased stability, and superior adaptability, making them an excellent choice for transporting anti-tumor agents. Furthermore, they can considerably reduce side effects and improve therapy success by offering precise, targeted, and multifunctional drug delivery system. This comprehensive review looks into the principles and design strategies of DNA origami, providing valuable insights into this technology's latest research achievements and development trends in the field of anti-tumor drug delivery. Additionally, we review the key function and major benefits of DNA origami in cancer treatment, some of these approaches also involve aspects related to DNA tetrahedra, aiming to provide novel ideas and effective solutions to address drug delivery challenges in cancer therapy.

Hippo-YAP/TAZ signaling in osteogenesis and macrophage polarization: Therapeutic implications in bone defect repair.

Bone defects caused by diseases or surgery are a common clinical problem. Researchers are devoted to finding biological mechanisms that accelerate bone defect repair, which is a complex and continuous process controlled by many factors. As members of transcriptional costimulatory molecules, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play an important regulatory role in osteogenesis, and they affect cell function by regulating the expression of osteogenic genes in osteogenesis-related cells. Macrophages are an important group of cells whose function is regulated by YAP/TAZ. Currently, the relationship between YAP/TAZ and macrophage polarization has attracted increasing attention. In bone tissue, YAP/TAZ can realize diverse osteogenic regulation by mediating macrophage polarization. Macrophages polarize into M1 and M2 phenotypes under different stimuli. M1 macrophages dominate the inflammatory response by releasing a number of inflammatory mediators in the early phase of bone defect repair, while massive aggregation of M2 macrophages is beneficial for inflammation resolution and tissue repair, as they secrete many anti-inflammatory and osteogenesis-related cytokines. The mechanism of YAP/TAZ-mediated macrophage polarization during osteogenesis warrants further study and it is likely to be a promising strategy for bone defect repair. In this article, we review the effect of Hippo-YAP/TAZ signaling and macrophage polarization on bone defect repair, and highlight the regulation of macrophage polarization by YAP/TAZ.

Imaging biomarkers on Angio-CT for predicting the efficacy of transarterial chemoembolization in hepatocellular carcinoma.

Background: This study aimed to evaluate whether the lipiodol deposition pattern on intraprocedural Angio-CT could predict tumor treatment response in hepatocellular carcinoma (HCC) patients treated with conventional transarterial chemoembolization (c-TACE). Methods: This retrospective study enrolled intermediated and advanced HCC nodules treated with c-TACE and Angio-CT from June 2021 to June 2022. The therapeutic efficacy was evaluated according to the mRECIST standards. First, Angio-CT was used to determine lipiodol deposition at the end of c-TACE, redefined as complete, partial-complete, and incomplete groups. Second, the mean CT value of lipiodol deposition and its association with therapeutic efficacy were calculated in the complete model. Finally, the relationship between imaging biomarkers and efficacy was evaluated. Results: A total of 45 patients with 72 HCC nodules were enrolled with 28 nodules in the complete group, 31 nodules in the partial-complete group, and 13 nodules in the incomplete group. The complete response (CR) proportion was significantly higher in patients with good lipiodol deposition compared with patients with poor lipiodol deposition (P<0.0001). There was no significantly different CR rate between CT value ≥800 and <800 HU (P=0.119) in the complete group. Meanwhile, the non-CR rate in cases with hepatic vein development was significantly higher than that in cases with no hepatic vein development in the arterial phase (P<0.0001). Conclusions: Complete lipiodol deposition on Angio-CT during c-TACE was a predictive factor for therapeutic response to TACE. For HCC nodules with well-deposited lipiodol, hepatic vein development on Angio-CT in the arterial phase was strongly associated with poor efficacy of TACE.

Deep learning to automatically evaluate HER2 gene amplification status from fluorescence in situ hybridization images.

Human epidermal growth factor receptor 2 (HER2) gene amplification helps identify breast cancer patients who may respond to targeted anti-HER2 therapy. This study aims to develop an automated method for quantifying HER2 fluorescence in situ hybridization (FISH) signals and improve the working efficiency of pathologists. An Aitrox artificial intelligence (AI) model based on deep learning was constructed, and a comparison between the AI model and traditional manual counting was performed. In total, 918 FISH images from 320 consecutive invasive breast cancers were analysed and automatically classified into 5 groups according to the 2018 ASCO/CAP guidelines. The overall classification accuracy was 85.33% (157/184) with a mean average precision of 0.735. In Group 5, the most common group, the consistency was as high as 95.90% (117/122), while the consistency was low in the other groups due to the limited number of cases. The causes of this inconsistency, including clustered HER2 signals, coarse CEP17 signals and some section quality problems, were analysed. The developed AI model is a reliable tool for evaluating HER2 amplification statuses, especially for breast cancer in Group 5; additional cases from multiple centres could further improve the accuracy achieved for other groups.

Trends in unhealthy lifestyle factors in US NHANES respondents with cardiovascular disease for the period between 1999 and 2018.

Objectives: To examine national trends in unhealthy lifestyle factors among adults with cardiovascular disease (CVD) in the United States (US) between 1999 and 2018. Methods: We analyzed data from National Health and Nutrition Examination Survey (NHANES), a nationally representative survey of participants with CVD who were aged ≥20 years, which was conducted between 1999 and 2000 and 2017-2018. CVD was defined as a self-report of congestive heart failure, coronary heart disease, angina, heart attack, or stroke. The prevalence rate of each unhealthy lifestyle factor was calculated among adults with CVD for each of the 2-year cycle surveys. Regression analyses were used to assess the impact of sociodemographic characteristics (age, sex, race/ethnicity, family income, education level, marital status, and employment status). Results: The final sample included 5610 NHANES respondents with CVD. The prevalence rate of their current smoking status remained stable among respondents with CVD between 1999 and 2000 and 2017-2018. During the same period, there was a decreasing trend in the age-adjusted prevalence rate of poor diet [primary American Heart Association (AHA) score <20; 47.5% (37.9%-57.0%) to 37.5% (25.7%-49.3%), p < 0.01]. Physical inactivity marginally increased before decreasing, with no statistical significance. The prevalence rate of sedentary behavior increased from 2007 to 2014 but subsequently returned to its original level in 2018 with no statistical significance. The age-adjusted prevalence rate of obesity increased from 32% (27.2%-36.8%) in 1999-2000 to 47.9% (39.9%-55.8%) in 2017-2018 (p < 0.001). The age-adjusted prevalence rate of depression increased from 7% (4.2%-9.9%) in 1999-2000 to 13.9% (10.2%-17.6%) in 2017-2018 (p = 0.056). Trends in mean for each unhealthy lifestyle factor were similar after adjustment for age. We found that respondents who had low education and income levels were at a higher risk of being exposed to unhealthy lifestyle factors (i.e., smoking, poor diet, and physical inactivity) than those who had high education and income levels. Conclusions: There is a significant reduction in the prevalence rate of poor diet among US adults with CVD between 1999 and 2018, while the prevalence rate of obesity showed increasing trends over this period. The prevalence rate of current smoking status, sedentary behavior, and depression was either stable or showed an insignificant increase. These findings suggest that there is an urgent need for health policy interventions targeting unhealthy lifestyles among adults with CVD.

The effect of ROS-YAP crosstalk on osteoimmune response orchestrating osteogenesis.

Bone defect repair is a common medical concern. In spite of various existing treatments, its management still requires improvement. Here we show that YAP, a downstream signaling of Hippo pathway, might interplay with redox oxygen species (ROS) and modulate osteoimmunology, which refers to the interaction between immune and skeletal system during bone defect repair. We modulated the ROS level of RAW264.7 cells and found YAP level was reversely regulated. Meanwhile, we detected the feedback of YAP on oxidation level. The results demonstrated that the antioxidant enzyme expression was in proportion to the YAP level of RAW264.7 cells. Additionally, indirect coculture system was applied and it indicated that RAW264.7 cells under oxidative stress could impede proliferation and migration ability of MC3T3-E1 pre-osteoblasts. Consistently, in vivo experiment verified high oxidant level slowed down mice osteogenesis during bone defect repair, while antioxidant and upregulation of YAP accelerated this process. Additionally, we established a mouse model with YAP conditional knockout in macrophages. The results identified that deficiency of YAP in macrophages negatively affected bone defect repair in vivo. In summary, our study indicated that ROS and YAP could jointly modulate osteogenesis via their effect on osteoimmunology.ABBREVIATIONS: GPX4, glutathione peroxidase 4; NAC, N-Acetyl-L-cysteine; qRT-PCR, real-time quantitative PCR; ROS, reactive oxygen species; Tb.N, trabecular number; Tb.Sp, trabecular separation.

Comparison of quantitative volumetric analysis and linear measurement for predicting the survival of Barcelona Clinic Liver Cancer 0- and A stage hepatocellular carcinoma after radiofrequency ablation.

PURPOSE: The prognostic role of the tumor volume in patients with hepatocellular carcinoma (HCC) at the Barcelona Clinic Liver Cancer (BCLC) 0 and A stages remains unclear. This study aims to compare the volumetric measurement with linear measurement in early HCC burden profile and clarify the optimal cut-off value of the tumor volume. METHODS: The consecutive patients diagnosed with HCC who underwent initial and curative-intent radiofrequency ablation (RFA) were included retrospectively. The segmentation was performed semi-automatically, and enhanced tumor volume (ETV) as well as total tumor volume (TTV) were obtained. The patients were categorized into high- and low-tumor burden groups according to various cutoff values derived from commonly used diameter values, X-tile software, and decision-tree analysis. The inter- and intra-reviewer agreements were measured using the intra-class correlation coefficient. Univariate and multivariate time-to-event Cox regression analyses were performed to identify the prognostic factors of overall survival. RESULTS: A total of 73 patients with 81 lesions were analyzed in the whole cohort with a median follow-up of 31.0 (interquartile range: 16.0­36.3). In tumor segmentation, excellent consistency was observed in intra- and inter-reviewer assessments. There was a strong correlation between diameter-derived spherical volume and ETV as well as ETV and TTV. As opposed to all linear candidates and 4,188 mm3 (sphere equivalent to 2 cm in diameter), ETV >14,137 mm3 (sphere equivalent to 3 cm in diameter) or 23,000 mm3 (sphere equivalent to 3.5 cm in diameter) was identified as an independent risk factor of survival. Considering the value of hazard ratio and convenience to use, when ETV was at 23,000 mm3, it was regarded as the optimal volumetric cut-off value in differentiating survival risk. CONCLUSION: The volumetric measurement outperforms linear measurement on tumor burden evaluation for survival stratification in patients at BCLC 0 and A stages HCC after RFA.