Nothing in excess - lessons learned from the expression of high-mobility group proteins type A in non-cancer and cancer cells

High-mobility group A (HMGA) proteins are major transcription regulators which are abundantly and ubiquitously expressed in undifferentiated cells but present at a low level in somatic cells of adult organisms. Up-regulation of HMGA expression is a frequent finding in cancer, either via direct stimulation of expression by constitutively expressed proto-oncogenic factors such as MYC and JUN or by rearrangements rendering the expression of the HMGA proteins not suppressible by inhibitory factors such as miRNAs. Rearrangements of the HMGA genomic loci resulting in disabling of the control mechanisms of their expression are often seen in tumours of various origin. A direct relationship between the level of expression of HMGA in mitochondria and the level of accumulation of oxidative damage in cancer cells has been recently noted. On the other hand, mammalian cells deficient in HMGA1 expression are also deficient in utilization of glucose and show the impairment in expression of the insulin receptor and the high levels of oxidative damage of DNA characteristic of diabetes type 2 and the related condition metabolic syndrome. Insulin resistance and metabolic syndrome could be viewed as a premalignant state in which DNA damage is slowly accumulating until the repair machinery of the cell cannot withstand the constant oxidative barrage and surrenders to neoplastic transformation

Repair, abort, ignore? Strategies for dealing with UV damage

DNA repair is a prominent member of the nuclear transactions triad (replication, transcription, and repair). Sophisticated mechanisms govern the cellular process of decision-making (to repair or not to repair, to proceed with cell cycle or not and, eventually, to let the cell survive or die) and the temporal and spatial distribution of the DNA repair activities. UV radiation is a very common and virtually unavoidable mutagen whose carcinogenic potential seems to accumulate over time. Various strategies have been developed to avoid or decrease UV damage to cellular DNA, based on prevention of exposure as well as on post-irradiation measures. It is, however, important to acknowledge that the individual capacity for DNA repair varies during the life of the individual and must, therefore, be assessed so as to determine whether the individual is coping with environmental UV damage. Assessment of individual repair capacity might greatly modify the existing therapeutic strategies for common cancers and ought to become a routine part of health prophylaxis

On a break with the X: the role of repair of double-stranded DNA breaks in X-linked disease

The problem of managing free reactive DNA ends in eukaryotic cells has resulted in the development of a number of mechanisms in order to ensure that free ends are rendered non-reactive, or that the double-strand DNA breaks generating the free ends are promptly repaired; or that if the cell requires the introduction of double-strand breaks in its DNA at some point in its life cycle, the generated free DNA ends would be subject to strictest management. Different mechanisms for dealing with double-strand breaks in DNA exist, contributing to the maintenance of the exquisite balance between entering an evolutionary dead end resulting from extremely faithful DNA repair and genome instability resulting from relaxed control of repair. Recombination-based mechanisms related to the mechanism for repair of double-strand breaks and template slippage during replication are believed to be able to account for multiplication of parts of the genome, generating regions of homology which may serve as sites for mispairing during meiotic and mitotic recombination, and resulting, in turn, in translocations, deletions and inversions. This is especially true for the X chromosome, which engages in homologous recombination with the partnering X chromosome in female meiosis, but will participate in only limited partial genomic exchange with the Y chromosome in male meiosis, providing ample opportunities for mispairing and non-allelic recombination. Several X-linked monogeneous diseases and even some chromosome diseases such as variants of Turner syndrome have been found to be related to non-allelic homologous recombination during male meiosis, resulting in various rearrangements of the X chromosome. Apparently, the mechanisms which protect the mammalian genomes from stagnation or, alternatively, from hypermutability, may not always perform adequately. The genome rearrangement disorders may be unfortunate manifestations of the ongoing process of reorganization of genetic architecture in the eukaryotic genomes, which is inherent to evolution

ATM in focus:a damage sensor and cancer target

The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways

Correction to the pathogenic alternative splicing, caused by the common GNB3 c.825C>T allele, using a novel, antisense morpholino

The very common GNB3 c.825C>T polymorphism (rs5443), is present in approximately half of all human chromosomes. Significantly the presence of the GNB3 825T allele has been strongly associated, with predisposition to essential hypertension. Paradoxically the presence of the GNB3 825T allele, in exon 10, introduces a pathogenic alternative RNA splice site into the middle of exon 9. To attempt to correct this pathogenic aberrant splicing, we therefore bioinformatically designed, using a Gene Tools® algorithm, a GNB3 specific, antisense morpholino. It was hoped that this morpholino would behave in vitro as either a potential “ splice blocker and/or exon skipper, to both bind and inhibit/reduce the aberrant splicing of the GNB3, 825T allele. On transfecting a human lymphoblast cell line homozygous for the 825T allele, with this antisense morpholino, we encouragingly observed both a significant reduction (from ~58% to ~5%) in the production of the aberrant smaller GNB3 transcript, and a subsequent increase in the normal GNB3 transcript (from ~42% to ~95%). Our results demonstrate the potential use of a GNB3 specific antisense morpholino, as a pharmacogenetic therapy for essential hypertension

Targeted Triple Drug Regimen for the Treatment of Prostate Cancer

Prostate cancer is the most common amongst men. According to ACS 2018 statistics, about 164,690 new cases appear and 29,430 deaths occur. Nearly 6 in 10 cases are diagnosed in men over 50 years of age and often there are no early symptoms. The treatment options include surgery, chemotherapy, hormonal therapy and/or radiation and it can often be treated successfully. However, the poor management and adverse effects demanded ways to find better treatment option. Towards the development of a personalized medicine for prostate cancer treatment, we proposed to design prostate cancer targeting magnetic nanoplatform. This integrates various key components such as combination of drugs, imaging agents, targeting ligands and targeted delivery of these cargos in high concentrations to tumor. A triple drug regimen of Oxaliplatin, Irinotecan and 5-Fluorouracil was used, which was already known to be effective in the treatment of colorectal cancer and pancreatic cancer. These three drugs were encapsulated in folate conjugated magnetic nanoparticles and tremendous effect of cell death via oxidative stress in LNCaP cells was observed. The synthesis of magnetic nanoparticles, surface conjugation with folic acid using “Click” chemistry, encapsulations of cargos and their characterization were discussed in detail. Having folate conjugated magnetic nanomedicine, the drug delivery was targeted to prostate cancer and had no to minimal toxic effects on the healthy cells. Individual mechanism of the drugs and their synergistic effect in the treatment was evaluated by performing optical microscopy, magnetic resonance imaging experiments as well as cell-based assays such as ROS, apoptosis and necrosis, cytotoxicity, migration, and comet. This study showed us the targeted nanoformulation which we designed was successful in exhibiting the toxic effects on a tumor cell

On the high strain rate behavior of 63-37 Sn-Pb eutectic solders with temperature effects

This study presents experimental results performed on samples of Eutectic solder material (63 wt. % Sn 37 wt. % Pb) loaded at high strain rates and elevated temperatures. The tests were performed at high strain rates using Split Hopkinson Pressure Bar (SHPB). The strain rates were in the range of 400 s-1to 1300 s-1. Heating unit was added to conventional SHPB to vary sample' s initial temperature conditions. Tests were conducted at three initial temperatures, i.e. room temperature, 60 °C and 120 °C for compressive mode. The effects of temperature on the behavior of material were compared. Transient temperature changes during dynamic loading conditions are calculated by an analytical approach using measured stress-strain data for plastic work. Test results were fitted into the Johnson-Cook model (JC model). In addition, dynamic tests were performed in tension mode using Split Hopkinson Tensile Bar (SHTB) at room temperature

Predictive Modeling of FMOL Health System Utilization Using Machine Learning Algorithms and Retrospective Study of COVID Tested Patients

Overutilization of Emergency Departments (ED) is a major problem among the health care providers in the United States. In this research, a machine learning-based predictive model for predicting ED high utilizers will be designed based on a set of existing and proposed facilities and the population and social determinant of health (SDOH) factors influencing utilization. The purpose of the model will be to alert the healthcare systems and government organizations by identifying the reasons for overutilization of the medical services among the people in a particular community. Also, the novel coronavirus disease 2019 (COVID-19) developed in Whunan city, China has spread quickly to the other parts of the world. It has become a serious health threat to the United States. Moreover, in this research study, the clinical and social characteristics that are responsible for the quick spread of COVID-19 disease across the Louisiana state will be identified. The purpose of this study is to identify what kind of population gets COVID 19 and providing real time care decisions to minimize the risk of an individual acquiring COVID-19. The patient data from Electronic Health Records (EHR) of Francis Missionaries of our Lady Health System (FMOLHS) is geocoded and mapped into ArcGIS software. The socioeconomic factors and social vulnerability Index (SVI) variables available from various online sources are joined to the geocoded patient data with the help of spatial joining techniques available in the ArcGIS software. Correlation analysis between the dependent variables and factors will be conducted

Political Corruption in India: Coalition Dharma?!

This article, while drawing a distinction between three kinds of corruption– transactional, constitutional and political, dwells on an analysis of the latter with particular reference to the time stemming out of the call for confidence by the Manmohan Singh coalition government in India in 2008. It also makes a case for controlling the proliferation of parties, while acknowledging the need for political parties for a successful working of a democracy. The plea is to stop small, splinter parties based on individual personalities rather than any ideology, and provide proper political conduct devoid of opportunism