Investigating the role of microRNAs and extracellular vesicles in cisplatin resistance in ovarian cancer

Ovarian cancer claims the lives of more than 150000 women worldwide annually. One of the contributors to this high mortality is resistance to cisplatin chemotherapy. Resistance to cisplatin is multifactorial involving various networks and tiers of regulation and is not completely understood yet. Among the regulatory molecules in the body, microRNAs have a prominent role in physiological and pathological conditions. Extracellular Vesicle (EV) communication between cells could also play a noteworthy role in cisplatin resistance. The main aim was to identify microRNAs involved in cisplatin resistance in ovarian cancers whose role in this aspect has not been documented yet and to ascertain and validate possible targets. MicroRNAs exhibiting differential levels of expression in sensitive and resistant ovarian cancer cell lines were identified. Gain or loss of function experiments in cell lines validated their involvement in cisplatin resistance; possible targets were confirmed by transient knockdown experiments in ovarian cancer cell lines. miR-21* and miR-31 functionally increased cisplatin resistance in ovarian cancer cells; NAV3 and KCNMA were validated as their respective targets and shown to modulate cisplatin resistance in ovarian cancer cell lines. A second aim was to explore the role of EVs in cisplatin resistance – to investigate if cisplatin resistance could be transferred between cell lines and to investigate the consequences of preventing EV uptake within a population of cisplatin treated cells. EVs extracted from a cisplatin resistant cell line were transferred onto a cisplatin sensitive cell line; results showed that these EVs could increase cisplatin resistance in the recipient cell line. The response of ovarian cancer cells to cisplatin was analysed following prevention of EV uptake by using heparin, amiloride or dynasore - known inhibitors of EV uptake; results indicate that inhibition of EV uptake increases cisplatin sensitivity significantly. These results open up future avenues for research regarding the role of microRNAs and EVs in cisplatin resistance with possible therapeutic potential

Study on Self-Esteem among the College Students in Trichirappalli District

The correlate of self-esteem among the college students in Trichy District is a study on a sample of 120 respondents in three colleges in Trichy district namely Bishop Heber, ChristhuRaj and Government arts colleges.  For the selection of these respective colleges researcher used the simple random sampling (lottery method) from the Final year Under Graduate Students only who is pursuing currently in the Arts and Science College. After that, the researcher had selected 20 from the Arts Section and 20 from the Science Section. Hence the Sampling method for this study is Disproportionate Stratified random sampling method is adopted. This study investigated in the three dimensions of self-esteem like performance, social and Appearance self-esteem. The relationship among the selected variables as well as their association with socio demographic background variables of the respondents was also investigated.  The hypothesis generated based on the objectives to find out the relationship between the subject variables. A self-prepared interview schedule and standardized scales were used for the collection of data. Statistical techniques such as mean, standard deviation, median, chi-square, “z” test, Karl Pearson’s coefficient of correlation. Major findings of the study and the conclusions drawn from them indicate that self-esteem is in moderate level among the college students. The study also revealed that there was a significant relationship between the subject variables. Suggestions of the study with general recommendations are given. Keywords: Self-esteem, performance, social and appearanc

The diagnostic and prognostic potential of miRNAs in epithelial ovarian carcinoma

​Ovarian cancer causes more than 100,000 deaths globally per year. Despite intensive research efforts, there has been little improvement in the overall survival of patients over the past three decades. Most patients are not diagnosed until the cancer is at an advanced stage, by which time their chances of still being alive after 5 years are appallingly low. Attempts to extend life in these patients have been, for the most part, unsuccessful. This owes partly to the lack of suitable biomarkers for stratifying patients at the molecular level, into responders and non-responders. This would lead to more drugs being shown to have a clinical benefit and being approved for use in subgroups of patients. There is also a desperate need for improved biomarkers for earlier detection of ovarian cancer; if the disease is detected sooner there is a significantly improved outlook. In this review, we outline the evidence that microRNAs are deregulated in ovarian cancer, what this can tell us about tumour progression and how it could be used to improve patient stratification in clinical trials. We also describe the potential for circulating microRNAs, both associated with proteins or carried in vesicles, to be used as diagnostics for earlier detection or as biomarkers for informing clinicians on the prognosis and best treatment of ovarian cancer

Mechanisms of drug resistance in cancer: the role of extracellular vesicles

Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long non-coding RNA and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. Whilst further characterisation of the vesiculome and the mechanisms of EV function is still required, EVs offer an exciting opportunity in the fight against cancer

Depression and Oxidative Stress: Results From a Meta-Analysis of Observational Studies

To perform a systematic review and meta-analysis that quantitatively tests and summarizes the hypothesis that depression results in elevated oxidative stress and lower antioxidant levels

Detecting ovarian cancer using extracellular vesicles: Progress and possibilities

Ovarian cancer (OC) is the deadliest gynecological malignancy. Most patients are diagnosed when they are already in the later stages of the disease. Earlier detection of OC dramatically improves the overall survival, but this is rarely achieved as there is a lack of clinically implemented biomarkers of early disease. Extracellular vesicles (EVs) are small cell-derived vesicles that have been extensively studied in recent years. They contribute to various aspects of cancer pathology, including tumour growth, angiogenesis and metastasis. EVs are released from all cell types and the macromolecular cargo they carry reflects the content of the cells from which they were derived. Cancer cells release EVs with altered cargo into biofluids, and so they represent an excellent potential source of novel biomarkers for the disease. In this review we describe the latest developments in EVs as potential biomarkers for earlier detection of OC. The field is still relatively young, but a number of studies have shown that EVs and the cargo they carry, including miRNAs and proteins, can be used to detect OC. They could also give insight into the stage of the disease and predict the likely therapeutic outcome. There remain a number of challenges to the use of EVs as biomarkers, but through ongoing research and innovation in this exciting field there is great potential for the development of diagnostic assays in the clinic that could improve patient outcome

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Monitoring the electroactive cargo of extracellular vesicles can differentiate various cancer cell lines

Extracellular vesicles (EVs) are pivotal in cell-to-cell communication due to the array of cargo contained within these vesicles. EVs are considered important biomarkers for identification of disease, however most measurement approaches have focused on monitoring specific surface macromolecular targets. Our study focuses on exploring the electroactive component present within cargo from EVs obtained from various cancer and non-cancer cell lines using a disk carbon fiber microelectrode. Variations in the presence of oxidizable components were observed when the total cargo from EVs were measured, with the highest current detected in EVs from MCF7 cells. There were differences observed in the types of oxidizable species present within EVs from MCF7 and A549 cells. Single entity measurements showed clear spikes due to the detection of oxidizable cargo within EVs from MCF7 and A549 cells. These studies highlight the promise of monitoring EVs through the presence of varying electroactive components within the cargo and can drive a wave of new strategies towards specific detection of EVs for diagnosis and prognosis of various diseases

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study.

BACKGROUND: Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). METHODS AND FINDINGS: Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. CONCLUSIONS: In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults

Nanovesicles displaying functional linear and branched oligomannose self-assembled from sequence-defined Janus glycodendrimers

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine “click”-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar “raft-like” nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity. © 2020 National Academy of Sciences. All rights reserved