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Evidence for somatic gene conversion and deletion in bipolar disorder, Crohn's disease, coronary artery disease, hypertension, rheumatoid arthritis, type-1 diabetes, and type-2 diabetes
Kenneth Ross
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-12
Abstract: A novel analysis technique is proposed for detecting the signature of somatic gene conversion from SNP microarray data. The Wellcome Trust Case Control Consortium has gathered SNP microarray data for two control populations and cohorts for bipolar disorder (BD), cardiovascular disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), type-1 diabetes (T1D) and type-2 diabetes (T2D). Using the new analysis technique, the seven disease cohorts are analyzed to identify cohort-specific SNPs at which conversion is predicted. The quality of the predictions is assessed by identifying known disease associations for genes in the homologous duplicons, and comparing the frequency of such associations with background rates.Of 28 disease/locus pairs meeting stringent conditions, 22 show various degrees of disease association, compared with only 8 of 70 in a mock study designed to measure the background association rate (P < 10-9). Additional candidate genes are identified using less stringent filtering conditions. In some cases, somatic deletions appear likely. RA has a distinctive pattern of events relative to other diseases. Similarities in patterns are apparent between BD and HT.The associations derived represent the first evidence that somatic gene conversion could be a significant causative factor in each of the seven diseases. The specific genes provide potential insights about disease mechanisms, and are strong candidates for further study. Please see Commentary: http://www.biomedcentral.com/1741-7015/9/13/abstract webcite.Gene conversion is a process in which genetic information is transferred unidirectionally between highly homologous but non-allelic regions of DNA [1]. The genome contains many pairs of homologous regions, reflecting frequent gene duplication during evolution. Gene conversion is usually triggered by a double strand break (DSB), which can occur during meiosis or mitosis [1]. The DSB is repaired using the homologous sequence as the
Ana Stankovi?,Nikola ?ivkovi?
Acta Medica Medianae , 2011,
Abstract: There is a growing body of evidence that the observed characteristics in pharmacokinetics and pharmacodynamics of drugs are genetically determined and that they primarily include drug metabolism and transport processes. Current acknowledge-ments, based on collected evidence, clearly show that an early adjustment of therapy regime to genetic characteristics of patients may help to avoid side effects. Such an approach stands for an individualized, optimal therapeutic use of drugs, based on the dose regime adjusted to an individual genotype. Gene therapy is the intentional transfer of genetic material into human somatic cells in prophylactic, therapeutic or diagnostic purposes. While the gene transfer technology is very advanced, ethical principles related to this procedure are still the subject of discussion. The goal of gene therapy is to correct genetic defects and to establish a normal cell functioning. Most of the techniques of gene therapy should enable the replacement of defective genes by those that function normally. The ideal vector should influence specific target cells, without stimulating the inflammatory response in the host cell. In addition, it should facilitate the transfer of genes of different length (the length of the code gene therapeutic sequences vary considerably and there should be a possibility of inserting regulatory sequences in transduction and expression) and integrate into the host cell chromosome at the exact location or to stay in the form of an episome within the nucleus (it should not be installed randomly in the chromosomes of the host, since it would mean a disturbed control of expression). The existing vector systems can be briefly divided into viral and non-viral. The paper presents the basic principles of the application of genes in the therapy of atherosclerosis, hereditary lung disease and cancer.
Post-natal somatic cell gene therapy.  [cached]
Culver K
Journal of Postgraduate Medicine , 1994,
Genetic Diversification by Somatic Gene Conversion  [PDF]
Kohei Kurosawa,Kunihiro Ohta
Genes , 2011, DOI: 10.3390/genes2010048
Abstract: Gene conversion is a type of homologous recombination that leads to transfer of genetic information among homologous DNA sequences. It can be categorized into two classes: homogenizing and diversifying gene conversions. The former class results in neutralization and homogenization of any sequence variation among repetitive DNA sequences, and thus is important for concerted evolution. On the other hand, the latter functions to increase genetic diversity at the recombination-recipient loci. Thus, these two types of gene conversion play opposite roles in genome dynamics. Diversifying gene conversion is observed in the immunoglobulin (Ig) loci of chicken, rabbit, and other animals, and directs the diversification of Ig variable segments and acquisition of functional Ig repertoires. This type of gene conversion is initiated by the biased occurrence of recombination initiation events (e.g., DNA single- or double-strand breaks) on the recipient DNA site followed by unidirectional homologous recombination from multiple template sequences. Transcription and DNA accessibility is also important in the regulation of biased recombination initiation. In this review, we will discuss the biological significance and possible mechanisms of diversifying gene conversion in somatic cells of?eukaryotes.
Combination therapy in hypertension: An update
Sanjay Kalra, Bharti Kalra, Navneet Agrawal
Diabetology & Metabolic Syndrome , 2010, DOI: 10.1186/1758-5996-2-44
Abstract: Achieving recommended goal of blood pressure (BP) {< 140/90 mmHg in all hypertensives, < 130/80 mm Hg in hypertensives with diabetes mellitus (DM) [1]} is difficult in majority of patients with hypertension [2]. Various studies have shown that tight control of BP is required to produce the maximum reduction in clinical cardiovascular end points [3,4]. The Framingham Heart Study[5] indicated that a 2-mm Hg reduction in average diastolic blood pressure (DBP) could result in a 14% decrease in the risk of stroke and transient ischemic attacks and a 6% reduction in the risk of coronary artery disease. A meta-analysis of 9 major prospective observational studies also showed that prolonged reduction in DBP of 5, 7.5, and 10 mm Hg were associated with 34%, 46%, and 56% fewer strokes and 21%, 29%, and 37% lower incidences of coronary heart disease respectively [6]. These data suggest that more aggressive BP lowering might be beneficial. Though single drug treatment may be effective in some, more than 50% will require more than one drug for appropriate control of their BP.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and European Society of Hypertension (ESH) guidelines recommend that therapy with more than one antihypertensive agent be considered in patients with systolic blood pressure (SBP) more than 20 mm Hg or DBP more than 10 mm Hg above goal and among patients at high cardiovascular risk, as determined by elevated BP level and the presence of other risk factors [7,8]. The approach of combination therapy may be theoretically favored by the fact that multiple factors contribute to the hypertension and achieving control of BP with single agent that acts through one particular mechanism may be unrealistic. Combining the second agent may lead to better control, acting by complimentary mechanism.This review focuses the need and basis of combination therapy, different classes of combinatio
"3Y" Problem and Principle in Gene Therapy
基因治疗的“3Y”问题与原则 “3Y” Problem and Principle in Gene Therapy

Chun-Song Hu,

遗传 , 2003,
Abstract: Somatic gene therapy based on nonviral and viral vectors is an attractive approach for treatment of human diseases. However,the application of gene therapy to human disease is currently hampered by potential hazards of methods of gene delivery,the relatively low efficiency and intracellular stability of target gene. Therefore,we summarized them as the "3Y" problems----(safety,efficacy and stability) and also think people should abide the "3Y" principles in gene therapy.
Mihaela Blaj,Ioana Grigora?
Jurnalul de Chirurgie , 2011,
Abstract: Intravenous fluid administration is a common therapy in critically patients; the fluid loading is the first step in the resuscitation protocols of hemodynamic unstable patients. Inappropriate intravenous fluid therapy is a significant cause of patient morbidity and mortality and may result from either incorrect volume (too much or too little) or incorrect type of fluid. Uncorrected hypovolemia leading to inadequate organ perfusion and inappropriate infusions of vasopressor agents that may increase organ hypoperfusion and ischemia. Multiple studies demonstrated a clear positive association between the mean cumulative daily fluid balance and mortality .Fluid over-resuscitation has been shown to promote general oedema and intraabdominal hypertension (IAH) that is an independent predictor for mortality. In all patients that receive massive fluid resuscitation is necessary to monitor intraabdominal pressure (IAP) and abdominal perfusion pressure (APP) and to addapt the hemodynamic parameters according to IAP values. The maine concern regarding the nonsurgical management of patients with IAH and abdominal compartment syndrom (ACS) is to decrease fluid overload for improve outcome.
Combination therapy in hypertension
B Rayner
South African Family Practice , 2007,
Abstract: Hypertension is one of the most important risk factors for death, heart failure, ischaemic heart disease, stroke and chronic kidney disease. Treatment of hypertension, particularly to goal blood pressure (BP), prevents these complications. In South Africa the reported control rates for treated hypertensives using a goal BP South African Family Practice Vol. 49 (2) 2007: pp. 22-26
Somatic Cell Therapy: A Genetic Rescue for a Tattered Immune System?  [cached]
Williams-Jones, Bryn
BioéthiqueOnline , 2012,
Abstract: The case of Andrew Gobea, the first child to receive experimental gene therapy for SCID, and a reflection on the associated ethical implications of gene therapy research.
The Mechanism of Gene Targeting in Human Somatic Cells  [PDF]
Yinan Kan,Brian Ruis,Sherry Lin,Eric A. Hendrickson
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004251
Abstract: Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells.
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