Reduction of nuclear Y654-p-β-catenin expression through SH3GL2-meditated downregulation of EGFR in chemotolerance TNBC: Clinical and prognostic importance

Triple negative breast cancer (TNBC) originates from a less differentiated ductal cell of breast, which is less sensitive to chemotherapy. The chemotolerance mechanism of TNBC has not yet been studied in detail. For this reason, molecular profiles (expression/genetic/epigenetic) of Y654-p-β-catenin (active) and its kinase epidermal growth factor receptor (EGFR) along with SH3GL2 (regulator of EGFR homeostasis) were compared between neoadjuvant chemotherapy treated (NACT) and pretherapeutic TNBC samples. Reduced nuclear expression of Y654-p-β-catenin protein with low proliferation index and CD44 prevalence showed concordance with reduced expression of EGFR/Y1045-p-EGFR proteins in the NACT samples than the pretherapeutic TNBC samples. Infrequent messenger RNA expression, gene amplification (10–32.5%), and mutation (1%) of EGFR were seen in the TNBC samples irrespective of therapy, suggesting the importance of EGFR protein stabilization in this tumor. The upregulation of SH3GL2 seen in the NACT samples in contrast to the pretherapeutic samples might be due to its promoter hypomethylation, as seen in the quantitative methylation assay. A similar trend of upregulation of SH3GL2 and downregulation of EGFR, Y1045-p-EGFR, Y654-p-β-catenin were seen in the MDA-MB-231 cell line using antharacycline antitumor drugs (doxorubicin/nogalamycin). The NACT patients with reduced expression of Y654-p-β-catenin and/or EGFR and high expression of SH3GL2 showed comparatively better prognosis than the pretherapeutic patients. Thus, our study showed that reduced nuclear expression of Y654-p-β-catenin in NACT samples due to downregulation of EGFR protein through promoter hypomethylation-mediated upregulation of SH3GL2, resulting in low proliferation index/CD44 prevalence with better prognosis of the NACT patients, might have an important role in the chemotolerance of TNBC.     

A Peptide Bond from the Inter-lobe Segment in the Bilobal Lactoferrin Acts as a Preferred Site for Cleavage for Serine Proteases to Generate the Perfect C-lobe: Structure of the Pepsin Hydrolyzed Lactoferrin C-lobe at 2.28 Å Resolution

The Protein Journal - C-lobe represents the C-terminal half of lactoferrin which is a bilobal 80 kDa iron binding glycoprotein. The two lobes are designated as N-lobe (Ser1-Glu333) and...     

A time course study on dose-response relationship between alcohol exposure and its effects on lipid profile and biomarkers of tissue damage

This present research investigated variations in lipid profiles and important biomarkers of tissue damage in response to graded concentrations of alcohol administration in male Wistar rats. Group A (control) received distilled water while group B, C and D received 30%, 40% and 50% (v/v) alcohol respectively. Five rats each from groups A-D were sacrificed after day(s) 1, 7, 14, 21 and 28 of administration. A significant increase was observed at day 28 for serum cholesterol by 79% (group B), 78% (group C) and 47% (group D) together with serum phospholipid 58% (group B), 50% (group C) and 92% (group D). Serum triacylglycerol increased by 71% (group B), 43% (group C) and 16% (group D) at day 21, while concentration of serum albumin decreased at day 28 by 40.9% (group B), 50.2% (group C), 53.3% (group D) respectively when compared with control (group A). Serum aminotransferases and alkaline phosphatase specific activities, as well as creatinine and uric acid concentration increased in a concentration-dependent manner, following alcohol administration. Though most of these effects induced by alcohol were time- and concentration-dependent, 40% alcohol appear to be more stable, giving results consistent with alcohol-induced damages, with minimal mortality. This study therefore further validated dyslipidemia and imbalance in clinical biomarkers as hallmarks of tissue damage induced by excessive alcohol consumption with an insight on the time- and concentration-response relationship between alcohol consumption and its toxicity.     

Piperine suppresses cerebral ischemia–reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model

The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05-0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1β, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death.     

Sucrose regulated enhanced induction of anthraquinone,phenolics, flavonoids biosynthesis and activities of antioxidant enzymes in adventitious root suspension cultures of <Emphasis Type="Italic">Morinda citrifolia</Emphasis> (L.)

The effect of initial sucrose concentration was investigated in root suspension cultures of Morinda citrifolia to improve root growth and secondary metabolites production, i.e. anthraquinone, phenolics and flavonoids. Besides, oxidative stress level, antioxidant enzymes activity and membranes damage under different sucrose concentration were estimated. A 5% sucrose supply was shown to be optimal for the production of root dry mass, but higher sucrose concentrations of 7–9% inhibited the accumulation of root dry weight (DW). However, the maximum production of anthraquinone (251.89 g L⁻¹ DW), phenolics (165.14 g L⁻¹ DW) and flavonoids (163.56 g L⁻¹ DW) were achieved at 1% sucrose-treated culture, which may be a source carbon skeletons for secondary metabolism. At the same time was observed low oxidative damage, which could be associated with high levels of secondary metabolites and the increased activity of catalase. Although, catalase (CAT) activity were stimulated at 7–9% sucrose-treated cultures, high accumulation of hydrogen peroxide (H₂O₂) and peroxidation of lipid (MDA) was induced. The observed high activity of CAT and guaiacol peroxidase (G-POD) were not sufficient enough to mitigate the toxic effect of H₂O₂.     

Osmoregulation in decapod crustaceans: physiological and genomic perspectives

Aquatic plants may face resource constraints or anthropogenic pollution, and effects might be heightened under multiple stress conditions. We investigated if arsenate effects on Myriophyllum spicatum L. would be stronger under CO₂ limitation and low phosphorus availability. In a factorial design, we exposed sediment-grown plants to either CO₂ (high carbon or HC) or bicarbonate (low carbon or LC) and four levels of arsenate. We observed strong effects of arsenate exposure on growth, biomass allocation (leaf, stem and root mass fractions), pigments and phenolic compounds. CO₂ availability strongly affected the content in phenolic compounds and a few other response variables, yet overall effects were less pronounced than expected. Strong interactive effects of CO₂ availability and arsenic concentration were only observed for carotenoids, the carotenoid/chlorophyll ratio and phenolic compounds in leaves. Only the carbon content declined with increasing arsenic concentration, otherwise leaf elemental content and stoichiometry were not affected by arsenic or CO₂ availability, suggesting that plants strived to maintain leaf functions. The observed effects on biomass allocation and plant quality, specifically dry matter content and phenolic compound content of M. spicatum not only show direct changes in plant performance but suggest also indirect effects on ecological interactions such as competition or herbivory.     

Improvement of Early Maturing and Climate Resilient Chickpea (<i>Cicer arietinum</i> L.) Cultivars Suitable for Multiple Environments in Bangladesh

Ensuring food security for the rapidly increasing population and changing climatic scenarios are requisites for exploiting the genetic divergence of food crops. A study was undertaken to sort out an early maturing chickpea variety for fitting easily between rice-rice cropping systems in the Eastern Indo-Gangetic Plain of Bangladesh. The trial was comprised of eight elite lines of chickpea and executed at various localities in Bangladesh from 2014– 15 to 2017–18. The result explored the chickpea genotype, BARI Chola-11 remained superior to the rest of the elite genotypes for having a short maturity period (100–106 days), and lesser days to 50% flowering (47– 55 days). The same genotype was recorded to have robust vegetative and reproductive yield attributes including plant height (49–57 cm), podsplant⁻¹ (37–50), and optimum 100 seed weight (19.5–20.6 g). Owing to better yield attributes, BARI Chola-11 resulted in the maximum seed yield (1200–1500 kg ha⁻¹ ) of chickpea and might be recommended for general adoption in the region for boosting nutritional security status through improved productivity under changing climate.     

Association between Alcohol Consumption and Pancreatic Cancer Risk: A Case-Control Study

Purpose

Evidence is inconsistent regarding alcohol and pancreatic cancer risk, although heavy drinking may increase risk.

Methods

A population-based case-control study was conducted using 345 pancreas cancer cases diagnosed 2011–2012 and 1,285 frequency-matched controls from Ontario, Canada. Logistic regression was used to evaluate alcohol consumption and pancreatic cancer risk; data was also stratified by sex and smoking status to assess interaction.

Results

Alcohol consumption was not associated with pancreatic cancer risk (age-adjusted odds ratio=0.78, 95% CI: 0.58, 1.05 for 1 - 3 drinks/week; age-adjusted odds ratio=0.86, 95% CI: 0.63, 1.17 for 4 - 20 drinks/week), however there was a non-significant increased risk for heavy drinkers consuming ≥21 drinks/week (age-adjusted odds ratio=1.35, 95% CI: 0.81, 2.27). Cigarette smoking modified the alcohol-cancer relationship; among current smokers, heavy alcohol consumption was associated with a significantly increased pancreatic cancer risk (age-adjusted odds ratio=4.04, 95% CI: 1.58, 10.37), whereas this significant association with heavy drinking was not observed among non-smokers (age-adjusted odds ratio=2.01, 95% CI: 0.50, 8.18). Furthermore, light – moderate alcohol intake was associated with increased pancreas cancer risk among current smokers.

Conclusions

While alcohol was not significantly associated with pancreatic cancer risk, smoking status modified this relationship such that among current smokers, alcohol intake was associated with a greater than two-fold increased risk of pancreatic cancer. The results should be interpreted with caution due to small sample sizes within subgroups and correction for multiple comparisons should be considered. These findings should be replicated in larger studies where more precise estimates of risk can be obtained.     

Defining the Minimal Important Difference for the Visual Analogue Scale Assessing Dyspnea in Patients with Malignant Pleural Effusions

Background

The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established.

Methods

Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale.

Findings

The mean decrease in VASD in patients with a MPE reporting a ‘small but just worthwhile decrease’ in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml.

Interpretation

The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies.