The Association between TRP Channels Expression and Clinicopathological Characteristics of Patients with Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma (PDAC) has low survival rates worldwide due to its tendency to be detected late and its characteristic desmoplastic reaction, which slows the use of targeted therapies. As such, the discovery of new connections between genes and the clinicopathological parameters contribute to the search for new biomarkers or targets for therapy. Transient receptor potential (TRP) channels are promising tools for cancer therapy or markers for PDAC. Therefore, in this study, we selected several genes encoding TRP proteins previously reported in cellular models, namely, Transient Receptor Potential Cation Channel Subfamily V Member 6 (TRPV6), Transient receptor potential ankyrin 1 (TRPA1), and Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), as well as the TRPM8 Channel Associated Factor 1 (TCAF1) and TRPM8 Channel Associated Factor 2 (TCAF2) proteins, as regulatory factors. We analyzed the expression levels of tumors from patients enrolled in public datasets and confirmed the results with a validation cohort of PDAC patients enrolled in the Clinical Institute Fundeni, Romania. We found significantly higher expression levels of TRPA1, TRPM8, and TCAF1/F2 in tumoral tissues compared to normal tissues, but lower expression levels of TRPV6, suggesting that TRP channels have either tumor-suppressive or oncogenic roles. The expression levels were correlated with the tumoral stages and are related to the genes involved in calcium homeostasis (Calbindin 1 or S100A4) or to proteins participating in metastasis (PTPN1). We conclude that the selected TRP proteins provide new insights in the search for targets and biomarkers needed for therapeutic strategies for PDAC treatment.     

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.     

Gut Microbiome Changes in Gestational Diabetes

Gestational diabetes mellitus (GDM), one of the most common endocrine pathologies during pregnancy, is defined as any degree of glucose intolerance with onset or first discovery in the perinatal period. Physiological changes that occur in pregnant women can lead to inflammation, which promotes insulin resistance. In the general context of worldwide increasing obesity in young females of reproductive age, GDM follows the same ascending trend. Changes in the intestinal microbiome play a decisive role in obesity and the development of insulin resistance and chronic inflammation, especially in patients with type 2 diabetes mellitus (T2D). To date, various studies have also associated intestinal dysbiosis with metabolic changes in women with GDM. Although host metabolism in women with GDM has not been fully elucidated, it is of particular importance to analyze the available data and to discuss the actual knowledge regarding microbiome changes with potential impact on the health of pregnant women and newborns. We analyzed peer-reviewed journal articles available in online databases in order to summarize the most recent findings regarding how variations in diet and metabolic status of GDM patients can contribute to alteration of the gut microbiome, in the same way that changes of the gut microbiota can lead to GDM. The most frequently observed alteration in the microbiome of patients with GDM was either an increase of the Firmicutes phylum, respectively, or a decrease of the Bacteroidetes and Actinobacteria phyla. Gut dysbiosis was still present postpartum and can impact the development of the newborn, as shown in several studies. In the evolution of GDM, probiotic supplementation and regular physical activity have the strongest evidence of proper blood glucose control, favoring fetal development and a healthy outcome for the postpartum period. The current review aims to summarize and discuss the most recent findings regarding the correlation between GDM and dysbiosis, and current and future methods for prevention and treatment (lifestyle changes, pre- and probiotics administration). To conclude, by highlighting the role of the gut microbiota, one can change perspectives about the development and progression of GDM and open up new avenues for the development of innovative therapeutic targets in this disease.     

Synthesis and properties of photosensitive poly(urethane‐acrylate) containing anil groups with application in the chemosensors area

Some aspects of the enol‐imine to keto‐enamine photoisomerism and fluorescent behavior of the new monomer with urethane and anil units in its structure, namely, methacryloyloxyethyl‐2‐carbamoyloxy(m‐methyl, o‐hydroxybenziliden)aniline (UAN), were studied comparatively with the corresponding copolymer poly (methacryloyloxyethyl‐2‐carbamoyloxy(m‐methyl, o‐hydroxybenziliden)aniline)‐co‐methyl methacrylate) (COP‐UAN). The structure, thermal properties, and morphology of the anil compounds were investigated by Fourier transform infrared, proton nuclear magnetic resonance, fluorescence spectroscopies, UV spectrophotometry, thermogravimetric analysis, differential scanning calorimetry, and atomic force microscopy. The photochromic behavior of salicylideneanil units was investigated by UV/laser irradiation, and an inspection of their photophysical properties suggested that such structures could function as fluorescent chemosensors for some transition metals, a fluorescence quenching in the presence of different metal cations (Fe³⁺, Fe²⁺, Cu²⁺, and Ni²⁺) being evidenced. The direct observation of an enhancement in the fluorescence emission caused of the presence of Zn²⁺ (solution) or Fe²⁺, Cu²⁺, and Zn²⁺ (thin film) would be rather suitable for the production of turn‐on fluorescent chemosensors. POLYM. ENG. SCI., 2011. © 2011 Society of Plastics Engineers     

FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides

Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface‐adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in‐docking mode to an out‐docking mode, depending on the structure of the antagonist. In this communication, biphenyl α‐D ‐mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell‐free competitive binding assay, a cell‐based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure–activity and structure–property relationships were established for a series of biphenyl α‐D ‐mannosides.     

Iron oxide colloids and their heterogenization by silica sol–gel entrapment: Catalytic and magnetic properties

Fe₃O₄ colloids modified by the chiral ligand cinchonidine were prepared with the goal of obtaining a magnetic and catalytic nano-material and were subsequently embedded in silica to form a heterogeneous catalyst. The systems were characterized by TEM and XRD measurements, while the Mössbauer technique was applied for measuring the magnetic properties of the Fe₃O₄ colloids. The hyperfine magnetic field distribution was consistent with one type of Fe oxide, namely, the magnetite (Fe₃O₄). These colloids, both as ‘quasi-homogenous catalysts’ (or soluble heterogeneous catalysts) and embedded in silica (heterogeneous catalysts) were employed in the selective hydrogenolysis of complex bicyclo[2.2.2]oct-7-enes (bicyclo[2.2.2]oct-2-enes when unsubstituted).     

Normal forms for multi‐input flat systems of minimal differential weight

We present normal forms for nonlinear control systems that are the closest to static feedback linearizable ones, that is, for systems that become feedback linearizable via the simplest dynamic feedback, which is the one‐fold prolongation of a suitably chosen control. They form a particular class of flat systems, namely those of differential weight n + m + 1, where n is the number of states and m is the number of controls. We also show that the dynamic feedback may create singularities in the control space depending on the state and we discuss them. We also address the issue of the normalization of the system only versus that of the system together with a flat output. Finally, we illustrate our results by several examples.     

Complexes With Biologically Active Ligands. Part 7 Synthesis and Fungitoxic Activity of Metal Complexes Containing 1,3,5-tris-(8-Hydroxyquinolino)- Trichlorocyclo-Triphosphazatriene

Complexes containing 1,3,5-tris-(8-hydroxyquinolino)-trichlorocyclotriphosphazatriene, a new cyclophosphazene ligand, and Co(II), Cu(II) and Ni(II) were prepared. The new complexes, having the general formula [MLCl(2)], [ML(2)]Cl(2), (M=Cu, Co, Ni); [NiLAc], [NiL(2)Ac]Ac and [ML(3)]X(3) (M=Ni, Co, X=Cl, Ac) were characterised by elemental analysis, electronic-, IR spectroscopy, and electrical conductivity measurements. Some of them inhibited the growth of several fungi species (Aspergillus and Candida spp.).