Regulation of Metastatic Tumor Dormancy and Emerging Opportunities for Therapeutic Intervention

Cancer recurrence and metastasis, following successful treatment, constitutes a critical threat in clinical oncology and are the leading causes of death amongst cancer patients. This phenomenon is largely attributed to metastatic tumor dormancy, a rate-limiting stage during cancer progression, in which disseminated cancer cells remain in a viable, yet not proliferating state for a prolonged period. Dormant cancer cells are characterized by their entry into cell cycle arrest and survival in a quiescence state to adapt to their new microenvironment through the acquisition of mutations and epigenetic modifications, rendering them resistant to anti-cancer treatment and immune surveillance. Under favorable conditions, disseminated dormant tumor cells ‘re-awake’, resume their proliferation and thus colonize distant sites. Due to their rarity, detection of dormant cells using current diagnostic tools is challenging and, thus, therapeutic targets are hard to be identified. Therefore, unraveling the underlying mechanisms required for keeping disseminating tumor cells dormant, along with signals that stimulate their “re-awakening” are crucial for the discovery of novel pharmacological treatments. In this review, we shed light into the main mechanisms that control dormancy induction and escape as well as emerging therapeutic strategies for the eradication of metastatic dormant cells, including dormancy maintenance, direct targeting of dormant cells and re-awakening dormant cells. Studies on the ability of the metastatic cancer cells to cease proliferation and survive in a quiescent state before re-initiating proliferation and colonization years after successful treatment, will pave the way toward developing innovative therapeutic strategies against dormancy-mediated metastatic outgrowth.     

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)—known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis—was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion^®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.     

Alicyclobacillus acidoterrestris in fruit juices and its control by nisin

Summary The acid-tolerant and heat-resistant bacterium Alicyclobacillus acidoterrestris is a spoilage problem in pasteurized and heat-treated fruit juices. In this study it was shown to grow in orange juice, grapefruit juice and apple juice to produce detectable taint at levels of about 10⁴–10⁵ c.f.u. ml⁻¹. Decimal reduction times were determined at 80 °, 90 ° and 95 °C in each juice and confirmed the heat-resistant nature of the spores under normal juice pasteurization conditions. They also confirmed that heat sensitivity increased with decreasing pH but that this effect was less pronounced at higher temperatures. The organism was, however, sensitive to the bacteriocin food preservative nisin. The presence of nisin during heating decreased the D value by up to 40% and the MIC for nisin against spores at 25 °C was only 5 International Units (IU) ml⁻¹. The results indicate that use of nisin is a potentially useful way of controlling this organism in fruit juices and fruit juice-containing products.     

Molecular Advances in Preeclampsia and HELLP Syndrome

Preeclampsia (PE) constitutes one of the principal reasons for maternal and perinatal morbidity and mortality worldwide. The circumstance typically implicates formerly healthful normotensive women, after 20 weeks of gestation, typically withinside the third trimester, without regarded threat elements or past deliveries. PE can be further complicated with hemolysis and thrombocytopenia, leading to the emergence of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low platelets). Both conditions are classified as hypertensive diseases of pregnancy (HDP), and their pathogenesis has been linked to an excessive maternal inflammatory response, accompanied by enhanced endothelial activation. Several studies have found that in pregnancies affected by PE/HELLP, von Willebrand factor (vWF) antigen levels (vWF:Ag) are significantly elevated, while its cleaving protease (ADAMTS-13, A Disintegrin-like and Metalloprotease with Thrombospondin type 1 motif, member 13) activity is normal to decreased. Furthermore, the higher urine excretion of the terminal complement complex C5b-9, as well as its greater deposition in the placental surface in preeclamptic women, imply that the utero-placental unit’s distinctive deficits are intimately tied to disproportionate complement activation. The goal of this updated evaluation is to provide the most up-to-date molecular advances in the pathophysiology of PE/HELLP syndromes. Recent medical data on vWF:Ag levels in patients with PE, ADAMTS-13, and dysregulation of the complement system, are highlighted and evaluated. Furthermore, we discuss the relationship between those entities and the progression of the disease, as well as their significance in the diagnostic process. Finally, considering the difficulties in analyzing and controlling those symptoms in pregnant women, we can provide a current diagnostic and therapeutic algorithm.     

Experimental investigations of non‐Newtonian/Newtonian liquid‐liquid flows in microchannels

The plug flow of a non‐Newtonian and a Newtonian liquid was experimentally investigated in a quartz microchannel (200‐µm internal diameter). Two aqueous glycerol solutions containing xanthan gum at 1000 and 2000 ppm were the non‐Newtonian fluids and 0.0046 Pa s silicone oil was the Newtonian phase forming the dispersed plugs. Two‐color particle image velocimetry was used to obtain the hydrodynamic characteristics and the velocity profiles in both phases under different fluid flow rates. The experimental results revealed that the increase in xanthan gum concentration produced longer, bullet‐shaped plugs, and increased the thickness of the film surrounding them. From the shear rate and viscosity profiles, it was found that the polymer solution was in the shear‐thinning region while the viscosity was higher in the middle of the channel compared to the region close to the wall. Circulation times in the aqueous phase increased with the concentration of xanthan gum. © 2017 The Authors AIChE Journal published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers AIChE J, 63: 3599–3609, 2017     

Effect of moisture on salmonella spp. heat resistance in cocoa and hazelnut shells

The heat resistance of food-poisoning outbreak and non-outbreak associated strains of Salmonella (S. Enteritidis, S. Montevideo, S. Napoli, S. Oranienburg, S. Poona, S. Senftenberg and S. Typhimurium) was established in confectionery-related materials such as crushed cocoa bean and hazelnut shells at low moisture contents (≤ 4% w/w). The two most heat resistant strains in cocoa and hazelnut shells at ca. 4% w/w moisture were S. Oranienburg and S. Enteritidis PT30. Both strains were associated with outbreaks from dried materials. Their D_100°C values were ca. 2.5 min in crushed cocoa bean shells and 7–11 min in crushed hazelnut shells. Addition of moisture to ca. 7% w/w markedly reduced D-values (D_80°C of 2–4.5 min) for both strains in the two matrices.     

Effects of chromium (VI) addition on the activated sludge process

The effect of hexavalent chromium, Cr(VI), addition on various operating parameters of activated sludge process was evaluated. To accomplish this, two parallel lab-scale continuous-flow activated sludge plants were operated. One was used as a control plant, while the other received Cr(VI) concentrations equal to 0.5, 1, 3 and 5 mgl(-1). Cr(VI) concentrations of 0.5 mgl(-1) caused significant inhibition of the nitrification process (up to 74% decrease in ammonia removal efficiency). On the contrary, the effect of Cr(VI) on organic substrate removal was minor for concentrations up to 5 mgl(-1), indicating that heterotrophic microorganisms are less sensitive to Cr(VI) than nitrifiers. Activated sludge floc size and structure characterization showed that Cr(VI) concentrations higher than 1 mgl(-1) reduced the filaments abundance, causing the appearance of pin-point flocs and free-dispersed bacteria. Additionally, the variability of protozoa and rotifers was reduced. As a result of disperse growth, effluent quality deteriorated, since significant amounts of suspended solids escaped with the effluent. Termination of Cr(VI) addition led to a partial recovery of the nitrification process (up to 57% recovery). Similar recovery signs were not observed for activated sludge floc size and structure. Finally, shock loading to the control plant with 5 mgl(-1) Cr(VI) for 2 days resulted in a significant inhibition of the nitrification process and a reduction in filamentous microorganisms abundance.