Antibacterial action of an aqueous grape seed polyphenolic extract

The potential of a polyphenolic grape seed extract for use as a natural antibacterial agent was evaluated. Pure catechin (CS) and a previously LC-MS characterized grape seed phenolic extract (PE) were evaluated as antibacterial agents against Escherichia coli and Brevibacterium linens on solid and in liquid culture media. After 48 h incubation on solid medium, PE had a bactericidal effect on the gram positive B. linens and a reduction of the microbial growth for E. coli. The antibacterial agents tested were effective against E. coli for 13 h, after 7 h incubation, but ineffective against B.linens in liquid medium. CS and PE both had an antibacterial effect depending on incubation time.Key words: Catechin, polyphenolic extract, antibacterial activity, Brevibacterium linens, Escherichia coli B41

Dynamics of the intratumoral immune response during progression of high-grade serous ovarian cancer

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC), however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2) expression in the progression of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each). Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018). There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026) and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031). High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012). CONCLUSIONS: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics

Is natural orifice specimen extraction surgery really safe in radical surgery for colorectal cancer?

Scop: Chirurgia rectală robotică este în prezent o procedură nouă pentru cancerele rectale. Extracția eșantionului cu orificiu natural transanal (NOSE) este o tehnică nouă de îndepărtare a specimenului din cavitatea abdominală prin anus, în loc de o incizie suplimentară după o intervenție chirurgicală colorectală laparoscopică sau robotică. Siguranța NOSE rămâne controversată. Acest studiu și-a propus să investigheze siguranța precoce a NOSE transanal în tratamentul cancerului de colon sigmoid și rectal superior din următoarele aspecte: caracteristici clinice și patologice, indicatori inflamatori și imunitari și complicații postoperatorii. Prezentare de caz: O femeie de 61 de ani, diagnosticată anterior cu cancer rectal, cu antecedente de 6 luni de hematochezie și alternanta diaree-constipatie. Diagnosticul de cancer rectal a fost pus pe baza biopsiei colonoscopice care a confirmat un nodul circumferenţial neregulat de adenocarcinom bine diferenţiat la 10 cm de marginea anală. Rezecția anterioară joasă asistata robotic, urmata de extracția specimenului transanal a fost efectuată după obținerea consimțământului informat. Procedura a fost efectuată cu succes și pacienta a avut o evolutie postoperatorie fără complicații. Diagnosticul patologic postoperator a evidențiat un adenocarcinom moderat diferențiat de 4x4x0,6 cm3 și margine circumferențiala libera. Concluzii: Rezectia de rect robotica plus extractia transanala a specimenului pentru cancerul rectal poate fi efectuata în siguranță și poate fi o abordare eficientă în contrast cu abordarea deschisă sau laparoscopică.Background: Robotic rectal surgery is currently a novel procedure for rectal cancers. Transanal natural orifice specimen extraction (NOSE) is a novel technique to remove the specimen from the abdominal cavity through the anus instead of an additional incision following laparoscopic or robotic colorectal surgery. The safety of NOSE remains controversial. This study aimed to investigate the early safety of transanal NOSE in the treatment of sigmoid colon and upper rectal cancer from the follow aspects: clinical and pathological characteristics, inflammatory and immune indicators and postoperative complications. Case presentation: A 61-year-old women, previously diagnosed with rectal cancer with came 6 months history of hematochezia and altered bowel habit. A diagnosis of rectal cancer was made in view of colonoscopic biopsy which confirmed an irregular circumferential lump of well differentiated adenocarcinoma at 10 cm from the anal verge. Robotic low anterior resection (LAR) plus transanal natural orifice specimen extraction (NOSE) was performed after obtaining informed consent. The procedure was performed successfully and the patient convalesced nicely without any complications. The postoperative pathological diagnosis revealed a 4x4x0.6 cm3 moderately differentiated adenocarcinoma and circumferential clearance. Conclusions: Robotic LAR plus transanal NOSE for rectal cancer can be performed safely and may be an effective approach in contrast to open or laparoscopic approach

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101

Microguards and micromessengers of the genome

The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as ‘transcription dynamics’. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term ‘microguarding’. An additional emerging role for miRNAs is as ‘micromessengers’—through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic

BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis

BACKGROUND BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal/ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. METHODS 2636 participants' data across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinico-pathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were two-sided. RESULTS 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, HR = 1.01, 95% CI = 0.87-1.16, P=0.98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87-1.18, P=0.96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2 intact (BRCA1/2 wild type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific PCR and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66-0.97, P=0.02; OS: HR = 0.80, 95% CI = 0.63-1.00, P=0.05) on mixed-effects modelling. CONCLUSION BRCA1-methylated OC displays similar clinico-pathological features to BRCA1-mutated OC, but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes

WAP four-disulfide core domain protein 2 gene(WFDC2) is a target of estrogen in ovarian cancer cells

BACKGROUND: WAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer. METHODS: We investigated the role of estradiol (E2) on cell growth in estrogen-sensitive or estrogen-insensitive ovarian cancer cell lines. Real-time (RT)-PCR and western blotting were used to examine the expression of WFDC2 at RNA and protein levels. Growth traits of cells transfected with WFDC2-shRNA or blank control were assessed using MMT arrays. Cell apoptosis was analyzed using annexin V-FITC/PI and flow cytometry. Estrogen receptor expression was evaluated using RT-PCR and flow cytometry. Apoptosis-related proteins induced by E2 directly and indirectly were determined using an antibody array comparing cells transfected with WFDC2- shRNA or a blank control. RESULTS: High-dose (625 ng/ml) E2 increased the expression of WFDC2 in HO8910 cells at both the mRNA and protein levels. However, E2 had no effect on WFDC2 expression in estrogen-insensitive SKOV3 cells. Of interest, knockdown of WFDC2 enabled a considerable estrogen response in SKOV3 cells in terms of proliferation, similar to estrogen-responsive HO8910 cells. This transformation of SKOV3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor beta (ERß) and an effect on cell apoptosis under E2 treatment by regulating genes related to cell proliferation and apoptosis. CONCLUSIONS: We postulate that increased WFDC2 expression plays an important role in altering the estrogen pathway in ovarian cancer, and the identification of WFDC2 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13048-015-0210-y) contains supplementary material, which is available to authorized users

Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.

Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes

Milk exosomes: beyond dietary microRNAs

Extracellular vesicles deliver a variety of cargos to recipient cells, including the delivery of cargos in dietary vesicles from bovine milk to non-bovine species. The rate of discovery in this important line of research is slowed by a controversy whether the delivery and bioactivity of a single class of vesicle cargos, microRNAs, are real or not. This opinion paper argues that the evidence in support of the bioavailability of microRNAs encapsulated in dietary exosomes outweighs the evidence produced by scholars doubting that phenomenon is real. Importantly, this paper posits that the time is ripe to look beyond microRNA cargos and pursue innovative pathways through which dietary exosomes alter metabolism. Here, we highlight potentially fruitful lines of exploration