Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

Around 20–30% of ovarian cancer patients exhibit chemoresistance, but there are currently no methods to predict whether a patient will respond to chemotherapy. Here, we discovered that chemoresistant ovarian cancer cells exhibit enhanced survival in a quiescent state upon experiencing the stress of physical confinement. When immobilized in stiff silica gels, most ovarian cancer cells die within days, but surviving cells exhibit hallmarks of single-cell dormancy. Upon extraction from gels, the cells resume proliferation but demonstrate enhanced viability upon reimmobilization, indicating that initial immobilization selects for cells with a higher propensity to enter dormancy. RNA-seq analysis of the extracted cells shows they have signaling responses similar to cells surviving cisplatin treatment, and in comparison to chemoresistant patient cohorts, they share differentially expressed genes that are associated with platinum-resistance pathways. Furthermore, these extracted cells demonstrate greater resistance to cisplatin and paclitaxel, despite being proliferative. In contrast, serum starvation and hypoxia could not effectively select for chemoresistant cells upon removal of the environmental stress. These findings demonstrate that ovarian cancer chemoresistance and the ability to enter dormancy are linked, and immobilization rapidly distinguishes chemoresistant cells. This platform could be suitable for mechanistic studies, drug development, or as a clinical diagnostic tool.     

Cross-correlation analysis of invasive mango mealybug and its associated natural enemies in relation to meteorological factors: implications for biological control

Damage caused by invasive downey snow line mealybug, Rastrococcus iceryoides Green (Hemiptera: Pseudococcidae) has been reported to vary between 30% to complete crop loss where no control measure is applied. The current studies seek to determine factors influencing R. iceryoides population outbreaks, parasitoid – host and predator–prey relationships as well as predict optimal management strategies through weather modelling over a period of 28 months from 2008 to 2010 in Tanzania. The highest incidence of R. iceryoides was recorded during the dry season coinciding with the major mango fruiting season. The relationship between R. iceryoides and the parasitoid was positive but not significant, which implies the influence on outbreaks was negligible probably due to low percent parasitism (<12%). However, the predator abundance was directly and significantly related to that of R. iceryoides. Average temperature, average relative humidity, rainfall, and R. iceryoides abundance were autocorrelated to each other. Cross-correlation coef?cients vary significantly from ?0.286 to 0.589 for the pair-variable between R. iceryoides, temperature, relative humidity, rainfall, parasitism and predators. Our findings showed that temperature was the key climatic variable that significantly influenced R. iceryoides outbreaks while rainfall was significantly negatively associated with the pest. Time series analyses show R. iceryoides population increased 4 months after an increase in average temperature in all the sites, 11 months after rainfall and 11 months after relative humidity in Kibaha and Dar es Salaam, respectively. Our findings revealed that R. iceryoides is an excellent target for classical biological control. Thus, the importation of promising co-evolved parasitoid specific to R. iceryoides from the aboriginal home is crucial in formulating an efficient and sustainable management approaches against the invasive mealybug pest in mango agro-ecosystems.     

The WHO Maternal Near-Miss Approach and the Maternal Severity Index Model (MSI): Tools for Assessing the Management of Severe Maternal Morbidity

Objectives

To validate the WHO maternal near-miss criteria and develop a benchmark tool for severe maternal morbidity assessments.

Methods

In a multicenter cross-sectional study implemented in 27 referral maternity hospitals in Brazil, a one-year prospective surveillance on severe maternal morbidity and data collection was carried out. Diagnostic accuracy tests were used to assess the validity of the WHO maternal near-miss criteria. Binary logistic regression was used to model the death probability among women with severe maternal complications and benchmark the management of severe maternal morbidity.

Results

Of the 82,388 women having deliveries in the participating health facilities, 9,555 women presented pregnancy-related complications, including 140 maternal deaths and 770 maternal near misses. The WHO maternal near-miss criteria were found to be accurate and highly associated with maternal deaths (Positive likelihood ratio 106.8 (95% CI 99.56–114.6)). The maternal severity index (MSI) model was developed and found to able to describe the relationship between life-threatening conditions and mortality (Area under the ROC curve: 0.951 (95% CI 0.909–0.993)).

Conclusion

The identification of maternal near-miss cases using the WHO list of pregnancy-related life-threatening conditions was validated. The MSI model can be used as a tool for benchmarking the performance of health services managing women with severe maternal complications and provide case-mix adjustment.     

Fusobacterium nucleatum and colorectal cancer: A mechanistic overview

Colorectal cancer (CRC) is the third most prevalent cancer in the world. There are many risk factors involved in CRC. According to recent findings, the tumor microenvironment and feces samples of patients with CRC are enriched by Fusobacterium nucleatum. Thus, F. nucleatum is proposed as one of the risk factors in the initiation and progression of CRC. The most important mechanisms of Fusobacterium nucleatum involved in CRC carcinogenesis are immune modulation (such as increasing myeloid-derived suppressor cells and inhibitory receptors of natural killer cells), virulence factors (such as FadA and Fap2), microRNAs (such as miR-21), and bacteria metabolism. The aim of this review was to evaluate the mechanisms underlying the action of F. nucleatum in CRC.     

Effect of mesenchymal stem cells-derived exosomes on tumor microenvironment: Tumor progression versus tumor suppression

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into different cell types. Owing to their immunosuppressive and anti-inflammatory properties, they are widely used in regenerative medicine, but they have a dual effect on cancer progression and exert both growth-stimulatory or -inhibitory effects on different cancer types. It has been proposed that these controversial effects of MSC in tumor microenvironment (TME) are mediated by their polarization to proinflammatory or anti-inflammatory phenotype. In addition, they can polarize the immune system cells that in turn influence tumor progression. One of the mechanisms involved in the TME communications is extracellular vesicles (EVs). MSCs, as one of cell populations in TME, produce a large amount of EVs that can influence tumor development. Similar to MSC, MSC-EVs can exert both anti- or protumorigenic effects. In the current study, we will investigate the current knowledge related to MSC role in cancer progression with a focus on the MSC-EV content in limiting tumor growth, angiogenesis, and metastasis. We suppose MSC-EVs can be used as safe vehicles for delivering antitumor agents to TME.     

Exploiting yoeB-yefM toxin-antitoxin system of Streptococcus pneumoniae on the selective killing of miR-21 overexpressing breast cancer cell line (MCF-7)

Toxin-antitoxin (TA) systems are two-component genetic modules widespread in bacterial and archaeal genomes, in which the toxin module is rendered inactive under resting conditions by its antitoxin counterpart. Under stress conditions, however, the antitoxin is degraded, freeing the toxin to exert its lethal effects. Although not evolved to function in eukaryotes, some studies have established the lethal activity of these bacterial toxins by inducing apoptosis in mammalian cells, an effect that can be neutralized by its cognate antitoxin. Inspired by the way the toxin can become active in eukaryotes cells, we produced an engrained yoeB-yefM TA system to selectively kill human breast cancer cells expressing a high level of miR-21. Accordingly, we generated an engineered yefM antitoxin gene with eight miR-21 target sites placed in its 3′untranslated region. The resulting TA system acts autonomously in human cells, distinguishing those that overexpress miR-21, killed by YoeB, from those that do not, remaining protected by YefM. Thus, we indicated that microRNA-control of the antitoxin protein of bacterial TA systems constitutes a novel strategy to enhance the selective killing of human cancer cells by the toxin module. The present study provides significant insights for developing novel anticancer strategies avoiding off-target effects, a challenge that has been pursued by many investigators over the years.     

Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach

Peptides are preferred for designing inhibitors because of their high activity and specificity. Seven cyclopentapeptide inhibitors were designed in this study against dengue virus type 2 (DEN-2) NS3-NS2B protease: CKRRC, CGRRC, CRGRC, CRTRC, CTRRC, CKRKC and CRRKC. Docking analysis was performed to study the enzyme-inhibitor binding interactions. The free energy binding and estimated Ki values for all the inhibitors were found to be small (within micromolar range), indicating that the inhibitors bind considerably well to the binding site. The results showed that the cyclopentapeptide CKRKC was the best peptide inhibitor candidate with estimated free binding energy of -8.39 kcal/mol and Ki of 0.707 μM when compared to the standard inhibitor Bz-Nle-Lys-Arg-Arg-H that has been experimentally tested and shown to exhibit Ki value of 5.8 μM. Several modes of weak interactions were observed between the cyclopentapeptide CKRKC and the active site of DEN-2 NS3-NS2B protease. Thus, the cyclopentapeptide is proposed as a potential inhibitor to the NS3-NS2B protease activities of DEN-2. While these preliminary results are promising, further experimental investigation is necessary to validate the results.     

Is miR-144 an effective inhibitor of PTEN mRNA: a controversy in breast cancer

Breast cancer is the first common cancer among women worldwide. One of the major signaling pathways playing a role in the onset and progression of this disease is PI3K/Akt/mTOR, which can be inhibited by PTEN. miRNAs are small non-coding molecules that regulate the expression of their targets by inhibition or suppression, and thus, their dysregulated expression results in the development of cancer. Using various software applications predicting miRNAs and evaluating GEO microarray data, miR-144 was selected as an inhibitor of PTEN. The expression of miR-144 and PTEN was evaluated in 18 triple negative breast cancer (TNBC) clinical samples and cell lines including 4T1, MDA-MB-231, MDA-MB-468, SK-BR-3, and MCF-7 in comparison with normal cells. PTEN and miR-144 expression analysis revealed their elevated expression in MCF-7 cells. MDA-MB-468, SK-BR-3, and MDA-MB-231 cells showed decreased levels of PTEN and increased levels of miR-144. In contrast, 4T1 cells had an increased expression of PTEN and decreased expression of miR-144. In clinical samples, miR-144 was up-regulated in 22% of the cases and PTEN was down-regulated in 78% of the cases. The results showed that the expression of PTEN and miR-144 was inversely correlated in metastatic breast cancer cell lines. However, in TNBC clinical samples, there was no correlation between the expression of miR-144 and PTEN. Literature shows that there are other influencing factors affecting the expression of miRNAs. Therefore, care should be taken in interpreting the results of gene expression studies and its relation with cancer diagnosis/prognosis.