Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR

Type 1 diabetes and cardiovascular disease

The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements

Insights for Industry 4.0 Applications into a Hydrogen Advanced Mobility

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T-structures on dg-categories and derived deformations

This paper is a sequel to "t-structures and twisted complexes on derived injectives" by the same authors. We develop the foundations of the infinitesimal derived deformation theory of pretriangulated dg-categories endowed with t-structures. This generalizes the deformation theory of abelian categories developed by the last two authors. We show how deformations of dg-categories of derived injectives yield derived deformations of the associated t-structures.Comment: 56 page

Insights on novel biologically active natural products: 7-isopentenyloxycoumarin.

7-Isopentenyloxycoumarin is a prenyloxyphenylpropanoid derivative found in low concentration in a restricted number of plant families (Apiaceae, Asteraceae, and Rutaceae). Synthetic schemes were recently developed enabling sufficient quantities of the title coumarin to be obtained in order to evidence its valuable biological effects, mainly as an anticancer agent. The aim of this review is to examine the phytochemical and pharmacological properties of this compound

Study on the generalized formulations with the aim to reproduce the viscoelastic dynamic behavior of polymers

Appropriate modelling of the real behavior of viscoelastic materials is of fundamental importance for correct studies and analyses of structures and components where such materials are employed. In this paper, the potential to employ a generalized Maxwell model and the relative fraction derivative model is studied with the aim to reproduce the experimental behavior of viscoelastic materials. For both models, the advantage of using the pole-zero formulation is demonstrated and a specifically constrained identification procedure to obtain the optimum parameters set is illustrated. Particular emphasis is given on the ability of the models to adequately fit the experimental data with a minimum number of parameters, addressing the possible computational issues. The question arises about the minimum number of experimental data necessary to estimate the material behavior in a wide frequency range, demonstrating that accurate results can be obtained by knowing only the data of the upper and low frequency plateaus plus the ones at the loss tangent peak

Rotavirus vaccination as a public health strategy to reduce the burden of hospitalization: The field experience of Italy (2008-2018)

Rotavirus (RV) infection is a leading cause of severe diarrhea among children younger than 5 years old and a considerable cause of RV gastroenteritis (RVGE) hospitalization. This study aimed to evaluate the impact of vaccination in Italy in the reduction of the burden of RV-related disease, estimating the relation between vaccination coverage and hospitalization rates. RVGE-related hospitalizations that occurred in Italy from 2008 to 2018 among children aged 0-35 months were assessed by consulting the Hospital Discharge Record database and including records whose ICD-9-CM diagnosis code was 008.61 in the first or in any diagnosis position. In the 2008-2018 period, a total of 17 535 791 at-risk person-years were considered and 74 211 (423.2 cases x 100 000 per year) RVGE hospitalizations were observed. Higher hospitalization rates occurred in males (456.6 vs. 387.9 x 100 000 per year) and in children aged 1 year (507.8 x 100 000 per year). Poisson regression analysis showed a decrease of -1.25% in hospitalization rates (-1.19% to -1.31%, p < 0.001) per unit increase in vaccination coverage. This is the first study that correlates hospitalization rate reduction with a percentage increase in vaccination coverage. Our findings strongly support RV vaccination as an effective public health strategy for reducing RVGE-related hospitalizations