Neratinib stimulates senescence of mammary cancer cells by reducing the levels of SIRT1.

Neratinib, a typical small-molecule, pan-human tyrosine kinase inhibitor (TKI), has been licensed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the underlying pharmacological mechanism is still unknown. In the current study, we report a novel function of Neratinib by showing that its treatment stimulates senescence of the mammary cancer AU565 cells. Our results demonstrate that Neratinib induces mitochondrial injury by increasing mitochondrial reactive oxygen species (ROS) and reducing intracellular adenosine triphosphate (ATP). Also, we found that Neratinib induced DNA damage by increasing the levels of 8-Hydroxy-desoxyguanosine (8-OHdG) and γH2AX in AU565 cells. Additionally, Neratinib reduced the levels of telomerase activity after 7 and 14 days incubation. Importantly, the senescence-associated-ß-galactosidase (SA-ß-Gal) assay revealed that Neratinib stimulated senescence of AU565 cells. Neratinib decreased the gene levels of human telomerase reverse transcriptase (hTERT) but increased those of telomeric repeat-binding factor 2 (TERF2) in AU565 cells. Further study displayed that Neratinib upregulated the expression of K382 acetylation of p53 (ac-K382) and p21 but reduced the levels of sirtuin-1 (SIRT1). However, overexpression of SIRT1 abolished the effects of Neratinib in cellular senescence. These findings provide strong preclinical evidence of Neratinib's treatment of breast cancer.

Effectiveness and Safety of Pyrotinib-Based Therapy in the Treatment of HER2-Positive Breast Cancer Patients with Brain Metastases: A Multicenter Real-World Study.

BACKGROUND: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.

Efficacy and safety of Trastuzumab Emtansine in treating human epidermal growth factor receptor 2-positive metastatic breast cancer in Chinese population: a real-world multicenter study.

Background: Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. Materials and methods: This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. Results: During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). Conclusion: This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Saccharomyces cerevisiae cellular engineering for the production of FAME biodiesel.

The unsustainable and widespread utilization of fossil fuels continues to drive the rapid depletion of global supplies. Biodiesel has emerged as one of the most promising alternatives to conventional diesel, leading to growing research interest in its production. Microbes can facilitate the de novo synthesis of a type of biodiesel in the form of fatty acid methyl esters (FAMEs). In this study, Saccharomyces cerevisiae metabolic activity was engineered to facilitate enhanced FAME production. Initially, free fatty acid concentrations were increased by deleting two acetyl-CoA synthetase genes (FAA1, FAA4) and an acyl-CoA oxidase gene (POX1). Intracellular S-adenosylmethionine (SAM) levels were then enhanced via the deletion of an adenosine kinase gene (ADO1) and the overexpression of a SAM synthetase gene (SAM2). Lastly, the S. cerevisiae strain overproducing free fatty acids and SAM were manipulated to express a plasmid encoding the Drosophila melanogaster Juvenile Hormone Acid O-Methyltransferase (DmJHAMT). Using this combination of engineering approaches, a FAME concentration of 5.79 ± 0.56 mg/L was achieved using these cells in the context of shaking flask fermentation. To the best of our knowledge, this is the first detailed study of FAME production in S. cerevisiae. These results will provide a valuable basis for future efforts to engineer S. cerevisiae strains for highly efficient production of biodiesel.

Deep Learning Imaging Reconstruction Algorithm for Carotid Dual Energy CT Angiography: Opportunistic Evaluation of Cervical Intervertebral Discs-A Preliminary Study.

Thus, the aim of this study is to evaluate the performance of deep learning imaging reconstruction (DLIR) algorithm in different image sets derived from carotid dual-energy computed tomography angiography (DECTA) for evaluating cervical intervertebral discs (IVDs) and compare them with those reconstructed using adaptive statistical iterative reconstruction-Veo (ASiR-V). Forty-two patients who underwent carotid DECTA were included in this retrospective analysis. Three types of image sets (70 keV, water-iodine, and water-calcium) were reconstructed using 50% ASiR-V and DLIR at medium and high levels (DLIR-M and DLIR-H). The diagnostic acceptability and conspicuity of IVDs were assessed using a 5-point scale. Hounsfield Units (HU) and water concentration (WC) values of the IVDs; standard deviation (SD); and coefficient of variation (CV) were calculated. Measurement parameters of the 50% ASIR-V, DLIR-M, and DLIR-H groups were compared. The DLIR-H group showed higher scores for diagnostic acceptability and conspicuity, as well as lower SD values for HU and WC than the ASiR-V and DLIR-M groups for the 70 keV and water-iodine image sets (all p < .001). However, there was no significant difference in scores and SD among the three groups for the water-calcium image set (all p > .005). The water-calcium image set showed better diagnostic accuracy for evaluating IVDs compared to the other image sets. The inter-rater agreement using ASiR-V, DLIR-M, and DLIR-H was good for the 70 keV image set, excellent for the water-iodine and water-calcium image sets. DLIR improved the visualization of IVDs in the 70 keV and water-iodine image sets. However, its improvement on color-coded water-calcium image set was limited.

Exosome-Mediated lncRNA LINC01140 Attenuates Breast Cancer Progression by Regulating the Wnt/ß-Catenin Pathway.

Exosome-delivered long non-coding RNAs have a role in the cancer control. It is unknown how exosomal LINC01140 contributes to the breast cancer (BC) growth. The purpose of this investigation is to identify exosomal LINC01140's function in the development of breast cancer. Using quantitative reverse transcripion polymerase chain reaction, the expression of LINC01140 was measured. To investigate how LINC01140 overexpression impacts BC cell proliferation, CCK-8 as well as colony formation assays (CFA) were employed. The expression of apoptosis-related proteins (Bax and Bcl-2) and Wnt/ß-catenin signal pathway-related proteins (Wnt, C-myc, ß-catenin, and p-GSK-3ß) was assessed through Western blotting. Exosomes from BC cells were verified by western blotting to measure CD63 and CD9 levels. To examine how exosomal LINC01140 affects Wnt/ß-catenin signaling pathway and xenograft tumor in nude mice, BC cell exosomes that were overexpressing LINC01140 were obtained and co-cultured with BC cells. In BC, it was discovered that LINC01140 had poor expression. BC cell proliferation was inhibited by overexpressing LINC01140, and the levels of the proteins Bcl-2, ß-catenin, C-myc, and Wnt were lowered while Bax and p-GSK-3 were increased. In addition, exosomal LINC01140 hindered the activation of the Wnt/ß-catenin signaling pathway, leading to a decrease in the growth of breast cancer cells in vivo. The presence of exosomal LINC01140 impedes the initiation of Wnt/ß-catenin and reduces the cancerous characteristics of BC cells.

Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma.

Liver cancer is a common malignancy with high morbidity and mortality rates. Changes in liver metabolism are key factors in the development of primary hepatic carcinoma, and mitochondrial dysfunction is closely related to the occurrence and development of tumours. Accordingly, the study of the metabolic mechanism of mitochondria in primary hepatic carcinomas has gained increasing attention. A growing body of research suggests that defects in mitochondrial respiration are not generally responsible for aerobic glycolysis, nor are they typically selected during tumour evolution. Conversely, the dysfunction of mitochondrial oxidative phosphorylation (OXPHOS) may promote the proliferation, metastasis, and invasion of primary hepatic carcinoma. This review presents the current paradigm of the roles of aerobic glycolysis and OXPHOS in the occurrence and development of hepatocellular carcinoma (HCC). Mitochondrial OXPHOS and cytoplasmic glycolysis cooperate to maintain the energy balance in HCC cells. Our study provides evidence for the targeting of mitochondrial metabolism as a potential therapy for HCC.

Left ventricular strain in patients with Takayasu arteritis with preserved ejection fraction: an analysis using cardiac magnetic resonance imaging feature tracking.

Background: The alteration of myocardial strain in patients with Takayasu arteritis (TAK) remains unclear. This study aimed to evaluate left ventricular (LV) stain in patients with TAK and preserved left ventricular ejection fraction (pLVEF) using cardiac magnetic resonance imaging feature tracking (CMR-FT) to analyze risk factors for impaired LV strain and to compare the baseline difference of LV strain between patients with reduced and nonreduced LVEF at 6-month follow-up. Methods: In all, 51 patients with TAK and 30 healthy controls were prospectively enrolled. All participants underwent multiple short- and long-axis cine scans with true fast imaging with steady-state precession sequence. In this observational study, LV global and regional longitudinal, circumferential, and radial strain and their strain rates were analyzed with FT on cine images. The relationship between LV strain and clinical data was explored. The baseline LV strain between patients with TAK and reduced and nonreduced LVEF was compared using transthoracic echocardiography (TTE) at the 6-month follow-up. Results: Patients with TAK with pLVEF showed a decline in baseline global longitudinal peak strain (GLS) [TAK (-13.35%±3.11%) vs. controls (-14.77%±1.74%), P=0.021] and circumferential peak strain (GCS) [TAK (-21.46%±2.66%) vs. controls (-22.75%±2.57%), P=0.027] in comparison with normal controls. The longitudinal peak strain (LPS) in the apical (P=0.003) and midventricular regions (P=0.027) and the circumferential peak strain (CPS) in the basal (P=0.021) and midventricular regions (P=0.008) also decreased in patients with TAK. Patients with pulmonary hypertension (PH) or myocardial late gadolinium enhancement (LGE) showed a greater reduction in strain compared with those without PH or LGE. GLS showed a negative association with erythrocyte sedimentation rate (ESR), while GCS showed a positive association with disease duration. In the 30 patients who were followed up, the baseline global and apical circumferential diastolic peak strain rates (DPSR) in patients with reduced LVEF were higher than those in patients without reduced LVEF. Conclusions: In patients with TAK and pLVEF, CMR-FT indicated that both global and segmental myocardial strain decreased. PH, male gender, long disease duration, elevated ESR, and myocardial LGE were associated with declined LV strain. Baseline increased circumferential DPSR may be associated with the decline in LVEF during follow-up.

Myricetin ameliorates experimental autoimmune myocarditis in mice by modulating immune response and inhibiting MCP-1 expression.

Myocarditis is defined as an inflammatory disease of the myocardium, and the autoimmune response specific to myocardium plays an important role in chronic myocarditis. Inhibiting myocardial-specific autoimmune response and inflammation is crucial to treat myocarditis. Myricetin is a plant-derived flavonoid in nature which has potent anti-inflammatory and cardiovascular protective properties. However, the pharmacological effect of myricetin in autoimmune myocarditis is undefined. It is necessary to investigate the role and potential mechanisms of myricetin in autoimmune myocarditis. Therefore, purified cardiac myosin was subcutaneously injected to mice to establish the experimental autoimmune myocarditis (EAM) model. Myricetin was solubilized in normal saline and administered everyday by gavage from the day of immunization. After 21 days of treatment, it was found that myricetin significantly alleviated myocardial injury in EAM mice. The serum anti-cardiac myosin antibody, immunoglobulin (Ig) G, IgM levels and the proportion of T helper 17 (Th17) cells were decreased and the proportion of regulatory T (Treg) cells was increased with the treatment of myricetin in EAM mice. The myosin-specific T cell proliferation was inhibited by myricetin. Meanwhile, myricetin suppressed the expressions of monocyte chemoattractant protein-1 (MCP-1), phospho (p)-p65, p-c-Jun and Act1/TRAF6/TAK1 in H9C2 cells and myocardial tissues of EAM mice. These results revealed that myricetin inhibited the autoimmune response specific to myocardium and the expression of MCP-1 in cardiomyocytes, which suggested that myricetin ameliorated autoimmune myocarditis by modulating immune response and the expression of MCP-1. Therefore, myricetin may be a promising therapeutic strategy for autoimmune myocarditis.

Detection of left atrial appendage thrombus by dual-energy computed tomography-derived imaging biomarkers in patients with atrial fibrillation.

Aims: This study aimed to assess the diagnostic performances of dual-energy computed tomography (CT)-derived iodine concentration and effective atomic number (Z eff ) in early-phase cardiac CT in detecting left atrial appendage (LAA) thrombus and differentiating thrombus from spontaneous echo contrast (SEC) in patients with atrial fibrillation using transesophageal echocardiography (TEE) as the reference standard. Methods and results: A total of 389 patients with atrial fibrillation were prospectively recruited. All patients underwent a single-phase cardiac dual-energy CT scan using a third-generation dual-source CT. The iodine concentration, Z eff , and conventional Hounsfield units (HU) in the LAA were measured and normalized to the ascending aorta (AA) of the same slice to calculate the LAA/AA ratio. Of the 389 patients, TEE showed thrombus in 15 (3.9%), SEC in 33 (8.5%), and no abnormality in 341 (87.7%) patients. Using TEE findings as the reference standard, the respective sensitivity, specificity, positive predictive value, and negative predictive value of the LAA/AA HU ratio for detecting LAA thrombus were 100.0, 96.8, 55.6, and 100.0%; those of the LAA/AA iodine concentration ratio were 100.0, 99.2, 83.3, and 100.0%; and those of the LAA/AA Z eff ratio were 100.0, 98.9, 79.0, and 100.0%. The areas under the receiver operator characteristic curve (AUC) of the LAA/AA iodine concentration ratio (0.978; 95% CI 0.945-1.000) and Z eff ratio (0.962; 95% CI 0.913-1.000) were significantly larger than that of the LAA/AA HU ratio (0.828; 95% CI 0.714-0.942) in differentiating the thrombus from the SEC (both P < 0.05). Although the AUC of the LAA/AA iodine concentration ratio was larger than that of the LAA/AA Z eff ratio, no significant difference was found between them (P = 0.259). Conclusion: The dual-energy CT-derived iodine concentration and the Z eff showed better diagnostic performance than the conventional HU in early-phase cardiac CT in detecting LAA thrombus and differentiating the thrombus from the circulatory stasis. However, these results need to be validated in large-cohort studies with late-phase images.

Application of Overlap Gastroduodenostomy in Billroth I Anastomosis after Totally Laparoscopic Distal Gastrectomy for Gastric Cancer.

Delta-shaped gastroduodenostomy (DSGD) and overlap gastroduodenostomy (OGD) are the two most widely used intracorporeal Billroth I anastomosis methods after distal gastrectomy. In this study, we compared the short-term outcomes of DSGD and OGD in total laparoscopic distal gastrectomy (TLDG). In a retrospective cohort study, we examined 92 gastric cancer patients who underwent TLDG performed by the same surgeon between January 2014 and June 2018. All patients underwent Billroth I reconstruction (OGD, n = 45; DSGD, n = 47) and D2 lymph node dissection. We retrospectively reviewed the surgical outcomes, clinical pathological results, and endoscopy results. Laparoscopic surgery was successfully performed in both groups without conversion to open surgery. The demographic and clinical characteristics were similar between the two groups (P > 0.05). There were no significant differences between the two groups in operation time (158.9 ± 13.6 min vs. 158.8 ± 14.8 min, P=0.955), anastomotic time (19.4 ± 3.0 min vs. 18.8 ± 2.9 min, P=0.354), intraoperative blood loss (88.9 ± 25.4 mL vs. 83.7 ± 24.3 mL, P=0.321), number of lymph node dissections (31.0 ± 7.1 vs. 29.2 ± 7.5, P=0.229), length of hospital stay (8.8 ± 2.7 days vs. 9.1 ± 3.0 days, P=0.636), fluid intake time (3.1 ± 0.7 days vs. 3.2 ± 0.7 days, P=0.914), and morbidity of postoperative complications (6.7% [3/45] vs. 10.6% [5/47], P=0.499). Endoscopy performed 6 months postoperatively showed that the residual food (P=0.033), gastritis (P=0.029), and bile (P=0.022) classification score significantly decreased in the OGD group, and there were no significant differences 12 months postoperatively. OGD is a safe and effective reconstruction technique with comparable postoperative surgical outcomes and endoscopy results when compared with those of DSGD.

Aberrant kinesin family member 2A signifies tumor size and invasion, and may help predict prognosis of patients with papillary thyroid carcinoma.

Kinesin family member 2A (KIF2A) has been reported as an oncogene and potential biomarker for the progression of numerous cancer types; however, its role in papillary thyroid carcinoma (PTC) has remained elusive. The present study aimed to assess KIF2A expression in patients with PTC and explore the potential association between KIF2A, clinicopathological features and the prognosis of PTC. A total of 200 patients with PTC who received surgical resection were retrospectively reviewed. KIF2A expression was detected using immunohistochemistry (IHC) in 200 pairs of carcinoma/para-carcinoma tissues and using reverse transcription-quantitative PCR in 91 pairs of carcinoma/para-carcinoma tissues. Clinical and pathological data, disease-free survival (DFS) and overall survival (OS) rates of all patients were obtained. The results of the present study demonstrated that KIF2A protein and mRNA expression were both elevated in carcinoma tissues compared with those in para-carcinoma tissues. KIF2A protein expression in carcinoma tissues was positively associated with increased tumor size and a higher pathologic tumor-nodes-metastasis (pTNM) stage. However, KIF2A mRNA expression in carcinoma tissues was only associated with an increased pTNM stage and not with any other clinicopathological features. In addition, high levels of KIF2A protein expression in carcinoma tissues led to a poor predicted DFS, but were not associated with OS. Following adjustments using a multivariate Cox regression model, high KIF2A protein expression levels were indicated to be independently associated with a decreased DFS. In conclusion, aberrant KIF2A signifies tumor size and invasion, and may help to predict prognosis in patients with PTC.

Clinical value of resting cardiac dual-energy CT in patients suspected of coronary artery disease.

BACKGROUND: Rest/stress myocardial CT perfusion (CTP) has high diagnostic value for coronary artery disease (CAD), but the additional value of resting CTP especially dual-energy CTP (DE-CTP) beyond coronary CT angiography (CCTA) in chest pain triage remains unclear. We aimed to evaluate the diagnostic accuracy of resting myocardial DE-CTP, and additional value in detecting CAD beyond CCTA (obstructive stenosis: ≥ 50%) in patients suspected of CAD. METHODS: In this prespecified subanalysis of 54 patients, we included patients suspected of CAD referred to invasive coronary angiography (ICA). Diagnostic accuracy of resting myocardial DE-CTP in detecting myocardial perfusion defects was assessed using resting 13N-ammonia positron emission tomography (PET) as the gold standard. Diagnostic accuracy of cardiac dual-energy CT in detecting flow-limiting stenoses (justifying revascularization) by CCTA combined with resting myocardial DE-CTP, using ICA plus resting 13N-ammonia PET as the gold standard. The CCTA and DE-CTP datasets derived from a single-phase scan performed with dual-energy mode. RESULTS: For detecting myocardial perfusion defects, DE-CTP demonstrated high diagnostic accuracy with a sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of 95.52%, 85.93%, and 0.907 on a per-segment basis. For detecting flow-limiting stenoses by CCTA alone, sensitivity, specificity, and AUC were 100%, 56.47%, and 0.777 respectively on a per-vessel basis. For detecting flow-limiting stenoses by CCTA combined with resting myocardial DE-CTP, sensitivity, specificity, and AUC were 96.10%, 95.29% and 0.956 respectively on a per-vessel basis. Additionally, CCTA combined with resting myocardial DE-CTP detected five patients (9%) with no obstructive stenosis but with myocardial perfusion defects confirmed by ICA plus 13N-ammonia PET. CONCLUSIONS: Resting cardiac DE-CTP demonstrates a high diagnostic accuracy in detecting myocardial perfusion defects and provides an additional clinical value by reducing rates of false-positive and false-negative patients beyond CCTA in patients suspected of CAD.

Changes in epicardial adipose tissue among women treated with trastuzumab for breast cancer.

BACKGROUND: Epicardial adipose tissue (EAT) as an endocrine organ, secreting hormones, and inflammatory cytokines is associated with adverse cardiovascular outcomes and may have a role in trastuzumab-induced cardiotoxicity (TIC). We sought to assess changes in EAT volume and radiodensity after receiving trastuzumab and if they are associated with TIC. METHODS: A total of 185 women treated with trastuzumab for human epidermal growth factor receptor 2-positive breast cancer were retrospectively recruited. All patients underwent echocardiography and CT before and during trastuzumab therapy. The time interval between CT and echocardiography was <10 days. EAT volume and density were quantified by CT. TIC was defined as a left ventricular ejection fraction (LVEF) decrease of >10% and < 53%. RESULTS: Of the 185 patients, 18 (9.7%) experienced TIC. After receiving trastuzumab, EAT volume and radiodensity were increased, despite similar BMI. TIC group showed a significantly higher increment of EAT volume (21.2 ± 6.3 vs. 11.7 ± 10.5 ml, p < 0.001) and radiodensity (2.7 ± 1.8 vs. 1.5 ± 2.0HU, p < 0.05) than no TIC group. There was a high negative correlation between changes in EAT volume and LVEF (r = -0.70; p < 0.001) and a moderately negative correlation between changes in EAT radiodensity and LVEF (r = -0.50; p < 0.001). Increased EAT volume, but not radiodensity appeared to be a good imaging biomarker for TIC (AUC: 0.79 vs. 0.65, p < 0.05). CONCLUSIONS: EAT volume and radiodensity were increased after receiving trastuzumab particularly in the TIC patients despite similar BMI. Notably, the increased EAT volume rather than radiodensity was strongly negatively associated with LVEF and appeared to be a good imaging biomarker of TIC.

Cardiac Involvement in Human Immunodeficiency Virus Infected Patients: An Observational Cardiac Magnetic Resonance Study.

Objectives: To investigate the subclinical imaging changes in terms of myocardial inflammation and fibrosis and to explore the risk factors associated with myocardial fibrosis by cardiac magnetic resonance (CMR) approach in a Chinese HIV/AIDS cohort. Methods: We evaluated myocardial function (cine), myocardial inflammation (T1, T2), and myocardial fibrosis (through extracellular volume fraction [ECV] and late gadolinium enhancement [LGE]) by a multiparametric CMR scan protocol in a total of 68 participants, including 47 HIV-infected individuals, who were divided into two groups: asymptomatic HIV (HIV+) (n = 30), and acquired immunodeficiency syndrome (AIDS) (n = 17), and 21 healthy controls. Results: HIV-infected patients had lower left (55.3 ± 6.5 vs. 63.0 ± 7.9%, P < 0.001) and right ventricular systolic function (35.9 ± 15.7 vs. 50.8 ± 9.3%, P < 0.001). Radial systolic strain (30.7 ± 9.3 vs. 39.3 ± 9.4%, P = 0.001), circumferential systolic strain (-17.5 ± 2.6 vs. -19.4 ± 2.7%, P = 0.008), and longitudinal systolic strain (-9.4 ± 5.7 vs. -12.8 ± 3.1%, P = 0.012) were also decreased in HIV. Native T1 relaxation time (1,337.2 ± 70.2 vs. 1,249.5 ± 47.0 ms, P < 0.001), ECV value (33.5 ± 6.2 vs. 28.5 ± 2.9 ms, P = 0.026), and T2 relaxation time (45.2 ± 3.5 vs. 42.0 ± 2.6 ms, P = 0.001) were higher in HIV-infected patients compared with controls. Myocardial fibrosis, predominantly in the mid-inferior wall, was detected in 24.4% of the HIV-infected patients. HIV+ had a significantly lower value of ECV [29.1 (26.1, 31.8) vs. 35.2 (31.8, 41.9) %, P < 0.001] and frequency of LGE [3/25 (8%) vs. 7/16 (43.8%), P = 0.014)] compared with AIDS. AIDS was associated with myocardial fibrosis. Conclusions: HIV-infected patients were associated with changes in myocardial function and higher rates of subclinical myocardial inflammation and fibrosis, which were more abnormal with greater severity of the disease. AIDS was associated with myocardial fibrosis, where the observations supported earlier initiation of antiretroviral therapy in the Chinese HIV/AIDS cohort.

Long non-coding RNA NORAD inhibition upregulates microRNA-323a-3p to suppress tumorigenesis and development of breast cancer through the PUM1/eIF2 axis.

Long non-coding RNAs (lncRNAs) are known to competitively bind with microRNAs (miRNAs) to participate in human cancers. We aim to explore the role of non-coding RNA activated by DNA damage (NORAD) binding to miR-323a-3p in breast cancer (BC) with the involvement of pumilio RNA-binding family member 1 (PUM1)/eukaryotic initiation factor 2 (eIF2) axis. Expression of NORAD, miR-323a-3p and PUM1 in tissues and cell lines was detected, and the correlation between NORAD expression and clinicopathological features of BC patients was analyzed. The screened cell line was respectively transfected with altered NORAD or miR-323a-3p to reveal their roles in viability, migration, invasion and apoptosis of BC cells in vitro. The tumor growth in vivo was observed in nude mice. The binding relationships among NORAD, miR-323a-3p and PUM1 were analyzed, and the regulatory role of NORAD and miR-323a-3p in the eIF2 signaling pathway was assessed. NORAD and PUM1 were upregulated and miR-323a-3p was downregulated in BC. High NORAD expression indicated a poor prognosis of BC patients. NORAD inhibition or miR-323a-3p elevation inhibited malignant behaviors of BC cells. The in vivo assay revealed that NORAD inhibition or miR-323a-3p elevation inhibited tumor growth as well. MiR-323a-3p inhibition reversed the role of NORAD knockdown in the biological functions of BC cells while silencing PUM1 reversed the influence of NORAD overexpression on BC cells. NORAD bound with miR-323a-3p and miR-323a-3p targeted PUM1. NORAD and miR-323a-3p functioned through the PUM1/eIF2 axis. NORAD inhibition or miR-323a-3p elevation suppresses the development of BC through the PUM1/eIF2 axis.

Clinically applicable 53-Gene prognostic assay predicts chemotherapy benefit in gastric cancer: A multicenter study.

BACKGROUND: We previously established a 53-gene prognostic signature for overall survival (OS) of gastric cancer patients. This retrospective multi-center study aimed to develop a clinically applicable gene expression detection assay and to investigate the prognostic value of this signature. METHODS: A TCGA gastric adenocarcinoma cohort (TCGA-STAD) was used for comparing 53-gene signature with other gene signatures. A high-throughput mRNA hybridization gene expression assay was developed to quantify the expression of 53-genes in formalin-fixed paraffin-embedded tissues of 540 patients enrolled from three hospitals. 180 patents were randomly selected from two hospitals to build a prognostic prediction model based on the 53-gene signature using leave-p-out (one-third out) cross-validation method together with Cox regression and Kaplan-Meier analysis, and the model was assessed on three validation cohorts. FINDINGS: In the evaluation phase, studies based on TCGA-STAD showed that the 53-gene signature was significantly superior to other three prognostic signatures and was independent of TCGA molecular subtypes and clinical factors. For clinical validation and utility, the prognostic scores were generated using the newly developed assay, which was reliable and sensitive, in 100 sampling training sets and were significantly associated with OS in 100 sampling validation sets. The scores were significantly associated with OS in three independent and combined validation cohorts, and in patients with stages II and III/IV. The multivariate Cox regression demonstrated that the prognostic power of the score was independent of clinical factors, consistent with those findings in the TCGA dataset. Finally, patients with good prognostic scores exhibited significantly a better 5-year OS rate from adjuvant FOLFOX chemotherapy after surgery than from other chemotherapies. INTERPRETATION: The 53-gene prognostic score system is clinically applicable for predicting the OS of patients independent of clinical factors in gastric cancers, which could also be a promising predictive biomarker for FOLFOX regimen. FUNDING: Chinese National Science and Technology, National Natural Science Foundation and Natural Science Foundation of Jiangsu Province.

Short- and long-term outcomes of laparoscopic complete mesocolic excision for colon cancer in the elderly: A retrospective cohort study.

PURPOSE: Laparoscopic complete mesorectal excision (CME) can be used for the treatment of colon cancer. This study was designed to assess short-term and long-term outcomes of laparoscopic CME in elderly colon cancer patients. METHODS: We retrospectively reviewed colon cancer patients who underwent laparoscopic CME at a single medical center between January 2014 and January 2019. Short-term surgical outcomes and long-term survival outcomes were analyzed, including overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 152 patients were included in the study, of which 54 were classified as elderly group (≥70 years) and 98 were classified as younger group (<70 years). The elderly group had more Charlson comorbidity index (CCI) scores >3. The short-term results of the two groups were similar. The overall complication and major complication rates were comparable between the two groups. The 5-year OS rates of the elderly and younger groups were 67% and 71%, respectively (p=0.846). The 5-year DFS rates in the elderly and younger groups were 59% and 62%, respectively (p=0.995). CONCLUSION: Compared with younger patients, laparoscopic CME in elderly colon cancer patients can achieve similar short-term and long-term outcomes. For elderly colon cancer patients, age is not a contraindication to laparoscopic CME.

Prognostic Value of Enolase Gene Family in Colon Cancer.

BACKGROUND Colorectal cancer (CRC), the most common gastrointestinal cancer, is associated with high mortality rates. Enolase is a major enzyme present in the glycolytic pathway. However, the functional significance of the enolase (ENO) gene family in the pathogenesis of CRC has been unclear. MATERIAL AND METHODS The data associated with 438 CRC patients from The Cancer Genome Atlas database were extracted for analysis. Survival analyses with Cox regression was performed to construct a prognostic signature. We investigated the processes that underlies the correlation between ENO genes and overall survival (OS) using gene set enrichment analysis (GSEA). We then developed a connectivity map to identify candidate target drugs for CRC. RESULTS The multivariate survival analysis showed that low expression of ENO2 and ENO3 had a significant correlation with longer OS. The joint-effects survival analysis indicated that the combined low expression of ENO2 and ENO3 was highly correlated with favorable OS. As indicated by the gene set enrichment analysis (GSEA), the ENO gene is involved in various biological pathways and has multiple roles. Potential pharmacological targets of ENO2 and ENO3 were constructed as well. CONCLUSIONS Low expression levels of both ENO2 and ENO3 were linked to a positive prognosis for CRC. Both ENO2 and ENO3 show promise as prognostic biomarkers for colon cancer patients.

Short- And medium-term outcomes of reduced-port laparoscopic surgery in elderly patients with upper rectal cancer: A retrospective cohort study.

BACKGROUND: To investigate the short- and medium-term outcomes of using a reduced-port laparoscopic surgery (RPLS), compared to multi-port laparoscopic surgery (MPLS), for the treatment of upper rectal cancer (URC) among elderly patients. METHODS: We conducted a retrospective analysis of the clinical and follow-up data of 181 elderly patients with URC, who underwent radical laparoscopic surgery at our hospital, between January 2015 and January 2019. Among these 181 cases, 62 underwent RPLS and 119 MPLS. RESULTS: Compared to MPLS, RPLS decreased the length of surgical incision, lower pain on postoperative days 1 and 2, decreased the time to first flatus after surgery, as well as the time to mobilization after surgery. There was no difference between the short-term outcomes between the two laparoscopic approaches, and no difference in the 3-year disease-free and overall survival rate. CONCLUSION: Compared to MPLS, RPLS provides several advantages for the treatment of URC among elderly individuals, including a shorter length of surgical incision, reduced postoperative pain, shorter time to first flatus after surgery, earlier mobilization, and better cosmetic outcomes. These advantages are achieved with no difference in the length of surgery, nor in the 3-year disease-free and overall survival rate, compared to MPLS.