OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy in diffuse large B-cell lymphoma.

OX40 enhances the T-cell activation via costimulatory signaling. However, its molecular characteristics and value in predicting response to immunochemotherapy in DLBCL remain largely unexplored. Here, we performed an integrative analysis of sequencing and multiplex immunofluorescence staining, and discovered abnormally higher expression of OX40 in DLBCL patients. Elevated OX40 could activate T cells leading to a higher immune score for tumor immune microenvironment (TiME). OX40 upregulation simultaneously happened with immune-related genes including PD-1, CTLA4 and TIGIT et,al. Patients with high OX40 expression exhibited a lower Ann Arbor stage and IPI score and more easily achieved a complete response/partial response. The analysis of infiltrated T-cell subset revealed that patients with a greater number of CD4+/OX40+ or CD8+/OX40+ T cells had a longer OS. Our findings indicated that OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy, providing insights for the application of OX40 agonist in DLBCL patients.

Diagnosis value of 18F-Fluoro-D-glucose positron emission tomography-computed tomography in pulmonary hamartoma: a retrospective study and systematic review.

PURPOSE: The diagnosis of pulmonary hamartoma (PH) based on computed tomography (CT) is a challenge, especially in patients with atypical imaging characteristics. This study was aimed at summarizing the imaging characteristic of 18F-Fluoro-D-glucose positron emission tomography-computed tomography (18F-FDG PET-CT) in PH and exploring the application value of PET-CT in the diagnosis of PH. DATA AND METHODS: Patients diagnosed with PH who had undergone PET-CT from literature pertaining were retrospectively analyzed, which were cases of publications from the Cochrane Library, PubMed, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI) and Wanfang databases, from 2008 to June 2022. The other 20 cases of the collection were patients from our hospital from 2008 to June 2022. Patients' symptoms, imaging characteristics of chest CT, PET-CT characteristics, the reason for PET-CT and the complications were analyzed. RESULTS: In this retrospective study, a total of 216 patients were diagnosed with PH and had been examined by PET-CT. 20 of the cases were patients of our hospital from January 2008 to June 2022. The other cases were collected from the literature. The mean diameter of most PH lesions is 1.7 ± 1.0 cm. The mean maximum standardized uptake value (SUVmax) of the PH lesions was 1.2 ± 1.1. Most of their SUVmax were lower than internationally recognized cut-off value (SUVmax = 2.5). PET-CT was superior to CT in the diagnosis of PH but there was a correlation of between CT diagnosis and PET-CT diagnosis for the PH lesions. In order to draw the Receiver operating characteristic (ROC), we selected 29 patients with a clear SUVmax value of their PH lesion, and 29 lung cancer patients with clear SUVmax value in our hospital were collected as a control group. ROC curve analysis showed that the area under curve (AUC) of SUVmax was 0.899, and the optimal diagnostic threshold was SUVmax > 2.65. PET-CT could distinguish PH from malignant lesions with a sensitivity of 89.66% by applying a SUVmax of 2.65 as a cut-off in this study. CONCLUSION: PET-CT might be a useful tool to diagnose PH, which shows a better diagnostic sensitivity than CT. But PET-CT can not be used as a single diagnostic approach, which should be combined with other methods and the patients' history to make the most correct diagnosis.

A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma.

Epigenetic modifications contribute to lymphomagenesis. Here, we performed an expression clustering analysis and identified two epigenetic-related clusters (EC1 and EC2). EC1 presented abundant TP53, MYD88, HIST1H1D, HIST1H1C, KMT2D and EZH2 mutations and an inferior prognosis. Pathways involved in the regulation of DNA methylation/demethylation, histone methyltransferase activity, and protein methyltransferase activity were significantly enriched in EC1. However, EC2 was frequently accompanied by B2M, CD70 and MEF2B mutations, which presented with enrichments in DNA damage repair, cytokine-mediated and B-cell activated immune signaling, increased levels of CD8+ T-, γδT- and T helper-cells, as well as immune scores and immunogenic cell death (ICD) modulators. According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2. The novel immune-related epigenetic signature exhibits promising clinical predictive value for diffuse large B-cell lymphoma (DLBCL), particularly for guiding epigenetic therapeutic regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) based combination treatment regimens are suggested.

Prone position reduces the risk of patients with mild or moderate COVID-19 progressing to severe or even critical cases: a retrospective study.

BACKGROUND: To investigate whether prone position can reduce the risk of patients with mild or moderate COVID-19 who progress to severe or critical illness. METHODS: The prone position group was treated in prone position on the day of admission in addition to conventional treatment. Indicators such as saturation of pulse oximetry (SpO2), heart rate, blood pressure, respiratory rate, and prone position-related adverse events were recorded before prone ventilation, 5 min after prone position and 30 min after prone position. Meanwhile, the cases of severe and critical patients, the percentage of transformation and the final clinical outcome of this group were analyzed. Conversion rates and mortality were calculated for patients with mild or moderate COVID-19 retrieved from the database who received only conventional care without combined prone positioning as control group. RESULTS: (1) A total of 34 patients were included in prone position group. There were significant differences in SpO2 between the first 4 days after admission and the day of discharge (F = 3.17, P < 0.001). (2) The main complications were back and neck muscle soreness (55.9%), followed by abdominal distension (8.9%). (3) In control group, a total of 4873 cases of mild and moderate patients were included from 19 literatures, with an average deterioration rate of 22.7% and mortality rate of 1.7%. (4) In prone position group, there were no severe or critical transformation cases and also no death cases. The prone position group had a significantly lower deterioration rate when compared with the control group (χ2 = 9.962, P < 0.01). CONCLUSION: Prone position improves SpO2 in patients with mild or moderate COVID-19. It can also reduce the percentage of mild or moderate patients progressing to severe or critical patients. The application of prone position is a simple, feasible, safe and effective treatment method in such patients.

Levosimendan Administration May Provide More Benefit for Survival in Patients with Non-Ischemic Cardiomyopathy Experiencing Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure (ADHF) is a life-threatening condition with a high mortality rate. Levosimendan is an effective inotropic agent used to maintain cardiac output and a long-lasting effect. However, only few studies have compared the clinical outcomes, after levosimendan therapy, among etiologies of ADHF. METHODS: Between July 2014 and December 2019, 184 patients received levosimendan therapy for ADHF at our hospital. A total of 143 patients had ischemic cardiomyopathy (ICM), and 41 patients had non-ICM (NICM). Data on comorbidities, echocardiographic findings, laboratory findings, use of mechanical devices, consumption of other inotropic or vasopressor agents, frequency of HF hospitalization, cardiovascular (CV) mortality, and all-cause mortality were compared between the ICM and NICM groups. RESULTS: Patients with ICM were older with higher prevalence of diabetes mellitus when compared to patients with NICM. Patients with NICM had a poorer left ventricular ejection fraction (LVEF) and higher left ventricular end-systolic volume when compared to patients with ICM. At the 30 day follow-up period, a lower CV mortality (ICM vs. NICM: 20.9% vs. 5.1%; log-rank p = 0.033) and lower all-cause mortality (ICM vs. NICM: 28.7% vs. 9.8%; log-rank p = 0.018) was observed in the NICM patients. A significantly lower all-cause mortality was noted at 180 day (ICM vs. NICM: 39.2% vs. 22.0%; log-rank p = 0.043) and 1 year (ICM vs. NICM: 41.3% vs. 24.4%; log-rank p = 0.046) follow up in the NICM subgroup. NICM (hazard ratio (HR): 0.303, 95% confidence interval (CI): 0.108-0.845; p = 0.023) and ECMO use (HR: 2.550, 95% CI: 1.385-4.693; p = 0.003) were significant predictors of 30 day all-cause mortality. CONCLUSIONS: In our study on levosimendan use for ADHF patients, better clinical outcomes were noted in the NICM population when compared to the ICM population. In the patients with cardiogenic shock or ventilator use, significantly lower incidence of 30 day mortality presented in the NICM population when compared with the ICM population.

APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations.

TP53 mutations correlate with inferior survival in many cancers. APR-246 is a compound to shift mutant p53 and exhibits anti-cancer effects. Among its effects, APR-246 facilitates the binding of restored p53 mutants to target genes and their transcription. A set of 2464 DLBCL cases from multiple cohorts including our center, was integrated to identify the type and localization of TP53 mutations and clinical impacts. APR-246 was applied in TP53-mutated DLBCL cells and xenograft mouse models to explore the anti-tumor effect. TP53 mutations frequency was 16% and TP53 mutations correlated with poor overall survival (OS) and progression-free survival (PFS) in all cases, especially in germinal center B-cell-like (GCB) and unclassified (UNC) subtypes. Notably, TP53 single mutations in the DNA binding domain (DBD) led to poor OS and PFS. Specifically, mutations in exon 7 correlated with poorer OS, while mutations in exons 5 and 6 associated with inferior PFS. APR-246 induces p53-dependent ferritinophagy of DLBCL cells with TP53 missense mutation on exon 7 and ferroptosis of DLBCL cells harboring wild-type TP53 and other TP53 mutations. TP53 mutations on exons 5, 6 and 7 are predictors of progression and survival. Targeting mutant p53 by APR-246 is a promising therapeutic approach for DLBCL patients.

Early Levosimendan Administration Improved Weaning Success Rate in Extracorporeal Membrane Oxygenation in Patients With Cardiogenic Shock.

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used in patients with refractory cardiogenic shock (CS) or out-of-hospital cardiac arrest. It is difficult to perform VA-ECMO weaning, which may cause circulatory failure and death. Levosimendan is an effective inotropic agent used to maintain cardiac output, has a long-lasting effect, and may have the potential benefit for VA-ECMO weaning. The study aimed to explore the relationship between the early use of levosimendan and the rate of VA-ECMO weaning failure in patients on VA-ECMO support for circulatory failure. Methods: All patients who underwent VA-ECMO in our hospital for CS between January 2017 and December 2020 were recruited in this cohort study and divided into two groups: without and with levosimendan use. Levosimendan was used as an add-on to other inotropic agents as early as possible after VA-ECMO setting. The primary endpoint was VA-ECMO weaning success, which was defined as survival without events for 24 h after VA-ECMO withdrawl. The secondary outcomes were cardiovascular and all-cause mortality at the 30-day and 180-day follow-up periods post-VA-ECMO initialization. Results: A total of 159 patients were recruited for our study; 113 patients were enrolled in the without levosimendan-use group and 46 patients were enrolled in the levosimendan-use group. In levosimendan-use group, the patients received levosimendan infusion within 24 h after VA-ECMO initialization. Similar hemodynamic parameters were noted between the two groups. Poorer left ventricular ejection fraction and a higher prevalence of intra-aortic balloon pumping were observed in the levosimendan group. An improved weaning rate (without vs. with: 48.7 vs. 82.6%; p < 0.001), lower in-hospital mortality rate (without vs. with: 68.1 vs. 43.5%; p = 0.007), and 180-day cardiovascular mortality (without vs. with: 75.3 vs. 43.2%; p < 0.001) were also noted. Patients administered with levosimendan also presented a lower rate of 30-day (without vs. with: 75.3 vs. 41.3%; p = 0.034) and 180-day (without vs. with: 77.0 vs. 43.2%; p < 0.001) all-cause mortality. Conclusion: Early levosimendan administration may contribute to increasing the success rate of VA-ECMO weaning and may help to decrease CV and all-cause mortality.

Influencing factors of noninvasive positive pressure ventilation in the treatment of respiratory failure: a 10-year study in one single center.

BACKGROUND: The utilization of noninvasive positive pressure ventilation (NPPV) is becoming more and more common, especially in patients with acute or chronic respiratory failure. The purpose of our study is to analyze the factors that influence the efficacy of NPPV in the treatment of respiratory failure caused by a variety of etiology. METHODS: From May 2011 to April 2020, patients treated with NPPV during hospitalization in the First Affiliated Hospital of Soochow University were enrolled. According to the clinical outcome of NPPV treatment and whether converted to invasive mechanical ventilation, patients were divided into the success group and the failure group. The clinical data and the characteristics of NPPV application were compared between the two groups. RESULTS: A total of 3312 patients were enrolled, including 2025 patients in the success group and 1287 patients in the failure group. Univariate analysis suggested that there were no statistical differences in patients' age, gender, use of analgesia and/or sedation, complicated with barotrauma, inspiratory positive airway pressure and expiratory positive airway pressure between the success and failure groups (P > 0.05). However, there were statistically significant differences in serum albumin levels, Ca2+ concentration, blood glucose levels, duration of NPPV treatment and length of hospital stay between the success and failure groups (P < 0.05). Multivariate logistic regression analysis indicated that serum albumin levels and duration of NPPV treatment had statistical significance on the therapeutic effect of NPPV (P < 0.05). CONCLUSION: Serum albumin levels and duration of NPPV treatment were independent risk factors for the efficacy of NPPV treatment in respiratory failure.

Comparison of three lymph node staging methods for predicting outcome in breast cancer patients with mastectomy.

BACKGROUND: Axillary lymph node (ALN) staging is essential in predicting the clinical outcome of breast cancer (BC) patients. Traditionally, it follows the tumor-node-metastasis (TNM) staging, but its accuracy needs further improvement. METHODS: A total of 9,616 BC patients from the Surveillance, Epidemiology, and End Results (SEER) database and 675 patients from the First Affiliated Hospital of China Medical University underwent mastectomy together with ALN dissection were reviewed. Univariate and multivariate logistic analyses were conducted to find the most meaningful factors relevant to prognosis. RESULTS: After univariate and multivariate analyses, age, race, primary site, radiation, chemotherapy, grade, T-stage, estrogen receptor (ER), progesterone receptor (PR), total number of positive lymph nodes (pN), positive lymph node ratio (LNR) and log odds of positive LNs (LODDS) were found to be significantly associated with overall survival (OS). Using these non-LN risk factors, we further compared the efficacy of three different ALN staging methods in prognosis via nomograms. Harrell's concordance index (C-index) and Akaike Information Criterion (AIC) were used to measure nomogram performance of the ALN staging methods: pN: C-index=0.687 (95% CI: 0.678-0.696), AIC =61,398.24; LNR: C-index =0.691 (95% CI: 0.683-0.701), AIC =61,313.56; and LODDS: C-index =0.691 (95% CI: 0.682-0.700), AIC =61,315.60. We found that the nomogram incorporating LODDS had better predictive ability compared with other two methods. Furthermore, an external validation revealed a C-index of 0.753 (95% CI: 0.690-0.816) for the Asian population, which indicates the nomogram based on LODDS may have universality for both Western and Asian populations. CONCLUSIONS: Compared with pN and LNR, LODDS showed higher homeostasis in LN evaluation, and showed marked efficacy in evaluating survival differences among patients with negative LN staging. We constructed a BC prognosis model by incorporating highly relevant clinical pathological factors and a new method of LN staging, which may greatly aid in guiding postoperative treatment.

Correction: Melatonin attenuated the brain damage and cognitive impairment partially through MT2 melatonin receptor in mice with chronic cerebral hypoperfusion.

[This corrects the article DOI: 10.18632/oncotarget.20382.].

The Undervalued Effects of Polychlorinated Biphenyl Exposure on Breast Cancer.

The incidence of breast cancer across the world has been on the rise in recent decades. Because identified risk factors can only explain a relatively small portion of the cases, environmental exposure to organic pollutants is suspected to play a role in breast cancer etiology. Polychlorinated biphenyls (PCBs) are among the most abundant pollutants, and the impact of their exposure on breast cancer risk has been extensively studied in recent decades. However, the results of most epidemiologic studies do not support an association between PCB exposure and breast cancer risk. We hypothesized that the effects of PCBs on breast cancer might have been undervalued for reasons such as insufficient recognition of the confounding effects of several factors and lack of attention on the innate heterogeneity of PCB mixtures or breast cancer. After reviewing the evidence in the existing literature, we concluded that early life exposure, known risk factors of breast cancer, and impact of exposure to other pollutants are the main sources of confounding effects and have potentially masked the associations between PCBs and breast cancer. Because PCBs are mixtures of congeners with varied properties, and because breast cancers of different subtypes are etiologically distinct diseases, the absence of stratified subgroup analysis on individual PCBs and patients with specific biological subtypes and insufficient attention paid to the results of these subgroup analyses may result in an underestimation of the correlations between PCBs and breast cancer. In future studies, these factors must be taken into consideration when exploring the effect of PCB exposure on breast cancer risk.

Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer.

A potential strategy for patients with estrogen receptor (ER)-positive breast cancer is necessary to replace neoadjuvant chemotherapy which has limited benefit. Neoadjuvant endocrine therapy (NAE) has been indicated to be a favorable alternate approach to downstage large or locally advanced breast cancer in ER-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) patients, especially postmenopausal women. Previous studies have demonstrated the efficacy of various endocrine agents in NAE. Aromatase inhibitors (AIs) have proven superiority over tamoxifen as a suitable choice to optimize treatment efficacy. Fulvestrant was recently reported as an effective agent, similar to AIs. Furthermore, the addition of targeted agents exerts synergistic antiproliferative effects with endocrine agents and rapidly improves response rates in both endocrine sensitive and resistant tumors. The neoadjuvant platform provides a unique opportunity to define the appropriate strategy and address the mechanisms of endocrine resistance. In addition, the predictive value of biomarkers and genomic assays in NAE is under investigation to evaluate individual effects and validate biomarker-based strategies. In this review, we discuss the most relevant evidence on the potential of NAE for ER+ breast cancer. The current understanding also offers new insights into the identification of the optimal settings and valuable predictive tools of NAE to guide clinical treatment decisions and achieve beneficial therapeutic effects.

Development of prognostic signature and nomogram for patients with breast cancer.

To identify prognostic signature that could predict the survival of patients with breast cancer (BC).Breast cancer samples and normal breast tissues in the TCGA-BRCA and GSE7390 were included. Differentially expressed genes (DEGs) were identified using the "limma" method. Overall survival (OS) associated with DEGs were obtained using univariate and multivariable Cox proportional-hazards regression analysis, and the corresponding prognostic signature and nomogram were constructed. Calibration analysis and decision curve analysis (DCA) were performed.In all, 742 DEGs were identified, 19 of which were independently correlated with the OS of BC patients. The OS of patients in the 19-gene signature low-risk group was significantly better than that in high-risk group (hazard ratio [HR] 0.3506, 95% confidence interval [CI] 0.2488-0.4939), and the 19-gene based signature was demonstrated to be an independent prognostic factor in patient with BC in the TCGA-BRCA cohort (HR 1.501, 95% CI 1.374-1.640) and validation cohort GSE7392 ((HR 0.3557, 95% CI 0.2155-0.5871, P < .0001)). The primary and internally validated C-indexes for the 19-gene signature-based nomogram were 0.817 and 8.013, respectively. The results of calibration analysis and DCA analysis confirmed the robustness and the clinical usability of the nomogram.We constructed a prognostic signature and nomogram for patient with BC, which showed good application prospect.

Combined effects of GSTM1 and GSTT1 polymorphisms on breast cancer risk: A MOOSE-compliant meta-analysis and false-positive report probabilities test.

Many molecular epidemiology studies have reported an association between the combined effects of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms on breast cancer risk. However, the results have been controversial.A meta-analysis was performed to clarify this issue.Meta-analysis of observational studies in epidemiology guidelines was used. Pooled the crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model or fixed-effects model. Several subgroup analyses were conducted by ethnicity, source of control, matching, and menopausal status. In addition, we also performed sensitivity analysis and publication bias. Moreover, a false-positive report probability (FPRP) test was applied to assess positive results.A significantly increased breast cancer risk was observed in overall population (GSTM1 null/GSTT1 present [- +] vs GSTM1 present/GSTT1 present [+ +]: OR = 1.19, 95% CI: 1.03-1.36, GSTM1 null/GSTT1 null [- -] vs + +: OR = 1.63, 95% CI: 1.29-2.06, (- +) + GSTM1 present/GSTT1 null (+ -) vs + +: OR = 1.17, 95% CI: 1.05-1.31, (- +) + (+ -) + (- -) vs + +: OR = 1.27, 95% CI: 1.12-1.44, and - - vs (- +) + (+ -) + (+ +): OR = 1.39, 95% CI: 1.17-1.66) and several subgroup analyses, such as Caucasians, Indians, postmenopausal women, and so on. However, positive results were only considered noteworthy in overall population (- - vs + +: FPRP = 0.150 and (- +) + (+ -) + (- -) vs + +: FPRP = 0.162). Moreover, no significant association was observed when we used the trim and fill method to adjust the pooled data from all populations. Further, none of positive results of sensitivity analysis were considered noteworthy (FPRP >0.2).These positive findings should be interpreted with caution and indicate that an increased breast cancer risk may most likely result from false-positive results, rather than from true associations or biological factors on the combined effects of GSTM1 and GSTT1. Future studies should be based on sample sizes well-powered and attention needs to be paid to study design to further identify this issue.

Entresto therapy effectively protects heart and lung against transverse aortic constriction induced cardiopulmonary syndrome injury in rat.

This study tested the hypothesis that entresto therapy effectively protected heart and lung against cardiopulmonary syndrome (CPS) caused by transverse aortic constriction (TAC) in rat. Adult-Male SD rats (n = 36) were equally categorized into group 1 [sham-operated control (SC)], group 2 [SC + enalapril (7 mg/kg/day) since day-28 after TAC induction], group 3 [SC + entresto (30 mg/kg/day) since day-14 after TAC induction], group 4 (TAC only), group 5 (TAC + enalapril) and group 6 (TAC + entresto) and euthanized at day 60 after TAC induction. By day 60, the left-ventricular (LV) ejection fraction was significantly lower in group 4 than in other groups and significantly lower in groups 5 and 6 than in groups 1 to 3, whereas the ratios of heart and lung weights to tibial-length as well as the right-ventricular-systolic blood pressure exhibited an opposite pattern among the groups (all P<0.001). The sarcomere-length (SL), LV fibrotic area, cardiomyocyte size, and lung injury score were highest in group 4, lowest in groups 1 to 3 and significantly lower in group 6 than in group 5 (all P<0.0001). The protein expressions of fibrotic (Smad3/TGF-ß), apoptotic (mitochondrial-Bax/cleaved-caspase3/PARP) and DNA-damaged (γ-H2AX) markers in lung and LV myocardium as well as oxidative (NOX-1/NOX2/oxidized protein) in LV myocardium exhibited an identical pattern of SL (all P<0.0001). The protein expressions of pressure/volume overload (BNP/MHC-ß) mitochondrial-damaged (cytosolic cytochrome-C) of LV myocardium exhibited an identical pattern of SL (all P<0.001). In conclusion, Entresto is non-inferior to enalapril for protecting the heart-lung against CPS.

Study of Microbiomes in Aseptically Collected Samples of Human Breast Tissue Using Needle Biopsy and the Potential Role of in situ Tissue Microbiomes for Promoting Malignancy.

Mounting evidence suggests that changes in microbiome are linked to development of cancer and its aggressiveness. Microbiome profiles in human breast tissue previously presumed to be sterile, have recently been characterized using high-throughput technologies. Recent findings of microbiome variation between benign and malignant disease provides a rationale for exploring microbiomes associated with cancer during tumor progression. We assessed microbiomes of aseptically collected human breast tissue samples in this study, using needle biopsy from patients with benign and malignant tumors of different histological grading, using 16S rRNA gene amplicon sequencing. This is consistent with previous studies, and our results identified distinct microbiome profiles in breast tissues from women with cancer as compared to women with benign breast disease in Chinese cohorts. The enriched microbial biomarkers in malignant tissue included genus Propionicimonas and families Micrococcaceae, Caulobacteraceae, Rhodobacteraceae, Nocardioidaceae, Methylobacteriaceae, which appeared to be ethno-specific. Further, we compared microbiome profiles in malignant tissues of three different histological grades. The relative abundance of family Bacteroidaceae decreased and that of genus Agrococcus increased with the development of malignancy. KEGG pathways inferred by PICRUSt showed that biotin and glycerophospholipid metabolism had significant differences in all three grades. Glycerophospholipid and ribosome biogenesis increased in grade III tissue as compared to grades I and II. Flavonoid biosynthesis significantly decreased in grade III tissue. The specific correlation of these potential microbial biomarkers and indicated pathways with advanced disease could have broad implications in the diagnosis and staging of breast cancer. Further large-cohort investigation of the breast cancer microbiome and its potential mechanism in breast cancer development are essential.

The Five-Year Clinical and Angiographic Follow-Up Outcomes of Intracoronary Transfusion of Circulation-Derived CD34+ Cells for Patients With End-Stage Diffuse Coronary Artery Disease Unsuitable for Coronary Intervention-Phase I Clinical Trial.

OBJECTIVES: This study investigated the clinical and angiographic long-term outcomes of intracoronary transfusion of circulation-derived CD34+ cells for patients with end-stage diffuse coronary artery disease unsuitable for coronary intervention. DESIGN AND SETTING: A single-center prospective randomized double-blinded phase I clinical trial. Thirty-eight patients undergoing CD34+ cell therapy were allocated into groups 1 (1.0 × 10 cells/each vessel; n = 18) and 2 (3.0 × 10 cells/each vessel; n = 20). PATIENTS: Those with end-stage diffuse coronary artery disease were unsuitable for percutaneous and surgical coronary revascularization. INTERVENTIONS: Intracoronary delivery of circulation-derived CD34+ cells. MEASUREMENTS AND MAIN RESULTS: We prospectively evaluated long-term clinical and echocardiographic/angiographic outcomes between survivors and nonsurvivors. By the end of 5-year follow-up, the survival rate and major adverse cardio/cerebrovascular event were 78.9% (30/38) and 36.8% (14/38), respectively. During follow-up period, 31.6% patients (12/38) received coronary stenting for reason of sufficient target vessel size grown-up after the treatment. Endothelial function was significantly reduced in the nonsurvivors than the survivors (p = 0.039). Wimasis image analysis of angiographic findings showed that the angiogenesis was significantly and progressively increased from baseline to 1 and 5 years (all p < 0.001). The 3D echocardiography showed left ventricular ejection fraction increased from baseline to 1 year and then remained stable up to 5 years, whereas left ventricular chamber diameter exhibited an opposite pattern to left ventricular ejection fraction among the survivors. The clinical scores for angina and heart failure were significantly progressively reduced from baseline to 1 and 5 years (all p < 0.001). CONCLUSIONS: CD34+ cell therapy for end-stage diffuse coronary artery disease patients might contribute to persistently long-term effects on improvement of left ventricular function, angina/heart failure, and amelioration of left ventricular remodeling.

Melatonin attenuated the brain damage and cognitive impairment partially through MT2 melatonin receptor in mice with chronic cerebral hypoperfusion.

BACKGROUND: Vascular cognitive impairment (VCI) is a spectrum of cognitive impairment caused by various chronic diseases including aging, hypertension, and diabetes mellitus. Oxidative and inflammatory reactions induced by chronic cerebral hypoperfusion (CHP) are believed to cause VCI. Melatonin is reported to possess anti-oxidation and anti-inflammation effects. This study was designed to investigate the effect and mechanisms of melatonin in CHP mice model. RESULTS: The behavioral function results revealed that CHP mice were significantly impaired when compared with the control. Melatonin improved the cognitive function, but the addition of MT2 receptor antagonist reversed the improvement. The IHC staining showed melatonin significantly improved WM lesions and gliosis in CHP mice. Again, the addition of MT2 receptor antagonist to melatonin worsened the WM lesion and gliosis. Similar results were also found for mRNA and protein expressions of oxidative reaction and inflammatory cytokines. MATERIALS AND METHOD: Forty C57BL/6 mice were divided into four groups: Group 1: sham control; Group 2: CHP mice; Group 3: CHP with melatonin treatment; Group 4: CHP-melatonin and MT2 receptor antagonist (all groups n = 10). Working memory was assessed with Y-arm test at day-28 post-BCAS (bilateral carotid artery stenosis). All mice were sacrificed at day-30 post-BCAS. The immunohistochemical (IHC) staining was used for white matter (WM) damage and gliosis. The expression of mRNA and proteins about inflammatory and oxidative reaction were measured and compared between groups. CONCLUSIONS: Partially through MT2 receptor, melatonin is effective for CHP-induced brain damage.

Impact of Double Loading Regimen of Clopidogrel on Final Angiographic Results, Incidence of Upper Gastrointestinal Bleeding and Clinical Outcomes in Patients with STEMI Undergoing Primary Coronary Intervention.

This study tested the therapeutic impact of double-loading dose (i.e., 600 mg) versus standard-loading dose (i.e., 300 mg) of clopidogrel on ST-segment-elevation-myocardial-infarction (STEMI) patients undergoing primary-coronary-intervention (PCI).Between January 2005 and December 2013, a total of 1461 STEMI patients undergoing PCI were consecutively enrolled into the study and categorized into group 1 (600 mg/clopidogrel; n = 508) and group 2 (300 mg/clopidogrel; n = 953). We assessed angiographic thrombolysis-in-myocardial-infarction (TIMI) flow in the infarct-related-artery, 30-day mortality and upper-gastrointestinal-bleeding (UGIB) within 30 days as primary-endpoints and later incidents of UGIB as secondary-endpoints.The results showed that the incidences of advanced Killip score (defined as ≥ score 3) upon presentation (23.8% versus 24.6%) and advanced heart failure (defined as ≥ NYHAFc-3) (10.2% versus 10.4%) did not differ between groups 1 and 2 (all P > 0.4). Primary-endpoints, which were final TIM-3 flow (91.3% versus 91.7%) in the infarct-related-artery, incidences of 30-day mortality (5.8% vs. 7.1%), and UGIB ≤ 30 day (7.8% versus 8.9%) did not differ between group 1 and group 2 (all P > 0.33). The secondary-endpoints which were incidences of ≥ 30-day < one-year (5.2% versus 4.7) and > one-year (8.9% versus 10.1%) UGIB did not differ between groups 1 and 2 (all P > 0.45). One-year mortality did not differ between two groups (10.74% versus 12.9%) (P > 0.25). Multiple-stepwise-logistic-regression analysis showed that age and advanced-Killip score were independently predictive of 30-day mortality (all P < 0.001).Double-loading dose of clopidogrel did not confer an additional benefit to the final angiograph results, 30-day/one-year clinical outcomes; and age and advanced Killip-score were powerful predictors of 30-day mortality.