The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment

Combination light-based therapies to treat pancreatic cancer: A proof of concept

Pancreatic ductal adenocarcinoma remains one of the worst types of cancers mainly due to its late diagnosis, lack of effective therapies for advance disease and high chemoresistance. Novel therapeutic options that could improve patient quality of life and overall survival are therefore imperative. In this study, we describe the use of an original strategy based on photochemical internalisation (PCI) technology for pancreatic cancer treatment. Subcellular localisation of the photosensitiser meso-tetraphenylporphine-disulfonate (TPPS2a) was performed in PANC-1 cells, showing its preferential accumulation in lysosomes. Treatments with increasing concentrations of the ribosome-inactivating protein saporin or TPPS2a alone were compared with PCI-saporin. Metabolic activity and cell viability of PANC-1 cells were determined 96h post-illumination by MTT and trypan blue assays, respectively. Our results show that PCI using the photosensitiser TPPS2a, synergistically enhances the cytotoxic effects of saporin in PANC-1 cells and could offer more effective treatment options for pancreatic cancer

Student performance assessment using clustering techniques

The application of informatics in the university system management allows managers to count with a great amount of data which, rationally treated, can offer significant help for the student programming monitoring. This research proposes the use of clustering techniques as a useful tool of management strategy to evaluate the progression of the students’ behavior by dividing the population into homogeneous groups according to their characteristics and skills. These applications can help both the teacher and the student to improve the quality of education. The selected method is the data grouping analysis by means of fuzzy logic using the Fuzzy C-means algorithm to achieve a standard indicator called Grade, through an expert system to enable segmentation.Universidad de la Costa, 2 Universidad Nacional Experimental Politécnica “Antonio José de Sucre”, Universidad Simón Bolívar, Corporación Universitaria Latinoamericana, Corporación Universitaria Minuto de Dios

Multimodal use of the porphyrin TMPyP: From cancer therapy to antimicrobial applications

The cationic porphyrin meso-tetra(4-N-methylpyridyl)porphine (TMPyP) has a high yield of singlet oxygen generation upon light activation and a strong affinity for DNA. These advantageous properties have turned it into a promising photosensitizer for use in photodynamic therapy (PDT). In this review, we have summarized the current state-of-the-art applications of TMPyP for the treatment of cancer as well as its implementation in antimicrobial PDT. The most relevant studies reporting its pharmacokinetics, subcellular localization, mechanism of action, tissue biodistribution and dosimetry are discussed. Combination strategies using TMPyP-PDT together with other photosensitizers and chemotherapeutic agents to achieve synergistic anti-tumor effects and reduce resistance to therapy are also explored. Finally, we have addressed emerging applications of this porphyrin, including nanoparticle-mediated delivery, controlled drug release, biosensing and G-quadruplex stabilization for tumor growth inhibition. Altogether, this work highlights the great potential and versatility that TMPyP can offer in different fields of biomedicine such us cancer treatment or antimicrobial therapy

Antioxidant and Anti-Inflammatory Activity of Cynanchum acutum L. Isolated Flavonoids Using Experimentally Induced Type 2 Diabetes Mellitus: Biological and In Silico Investigation for NF-κB Pathway/miR-146a Expression Modulation

Cynanchum acutum L. is a climbing vine that belongs to the family Apocynaceae. Using different chromatographic techniques, seven compounds were isolated from the methanolic extract of the plant. The isolated compounds include six flavonoid compounds identified as rutin (1), quercetin-3-O-neohesperidoside (2), quercetin-3-O-β-galactoside (3), isoquercitrin (4), quercetin (5), and kaempferol 3-O-β-glucoside (6), in addition to a coumarin, scopoletin (7). The structures of the compounds were elucidated based on 1D NMR spectroscopy and high-resolution mass spectrometry (HR-MS), and by comparison with data reported in the literature. The first five compounds were selected for in vivo investigation of their anti-inflammatory and antioxidant properties in a rat model of type 2 diabetes. All tested compounds significantly reduced oxidative stress and increased erythrocyte lysate levels of antioxidant enzymes, along with the amelioration of the serum levels of inflammatory markers. Upregulation of miR-146a expression and downregulation of nuclear factor kappa B (NF-κB) expression were detected in the liver and adipose tissue of rats treated with the isolated flavonoids. Results from the biological investigation and those from the validated molecular modeling approach on two biological targets of the NF-κB pathway managed to highlight the superior anti-inflammatory activity of quercetin-3-O-galactoside (3) and quercetin (5), as compared to other bioactive metabolites

Influence of high altitude on cerebrovascular and ventilatory responsiveness to CO2

An altered acid–base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO2 sensitivity at high altitude. Likewise, if [H+] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO2 (termed cerebrovascular CO2 reactivity). However, the effect altered acid–base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO2 remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O2 and CO2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg−1; P < 0.01) and CO2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min−1 mmHg−1; P < 0.01). Likewise, the hypocapnic MCAv CO2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg−1; P < 0.01). The hypercapnic MCAv CO2 reactivity correlated with resting pH at high altitude (R2= 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R2= 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO2 reactivity and central chemoreflex may be partly attributed to an acid–base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid–base balance in the regulation in CBF and ventilatory control