ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients.

Objective-To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry. Methods and Results-A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (PϽ10 Ϫ2) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; Pϭ2ϫ10 Ϫ3) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (Pϭ1ϫ10 Key Words: myocardial infarction Ⅲ 9p21 Ⅲ Pakistanis Ⅲ risk factor Ⅲ South Asia Ⅲ meta-analysis V ariants at the 9p21.3 locus have been established as among the strongest common genetic factors associated with the risk of coronary artery disease (CAD) in people of European continental ancestry. [1][2][3][4][5] These variants are in highlinkage disequilibrium (LD) and span a 58-kb region that has multiple neighboring genes (CDKN2A, CDNK2B, and MTAP), without annotating to any single protein sequence. 5 An RNA coding gene, ANRIL, that overlaps with the risk To our knowledge, we report the first large-scale study of variants at the 9p21 locus in relation to risk of acute myocardial infarction (MI) in Pakistanis. This study involved 1851 patients with confirmed diagnoses of first-ever MI and 1903 control subjects from the Pakistan Risk of Myocardial Infarction Study 8 (PROMIS). Genotyping was conducted on 89 tagging single-nucleotide polymorphisms (SNPs) at the 9p21.3 locus, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium in association with CAD. 1,2 To place our findings in context, we also report a literaturebased meta-analysis of relevant studies, encompassing information on 23 variants at the 9p21 locus in up to 38 250 CAD cases and 84 820 controls. The current meta-analysis substantially updates a previous relevant review, 5 involving data from an additional 82 117 participants and 20 additional variants. Methods Study DesignThis article follows the reporting recommendations of STrengthening the REporting of Genetic Association studies. 9 PROMIS is a casecontrol study of acute first-ever MI in urban Pakistan. 8 Patients with MI experienced the following: (1) symptoms within 24 hours of hospital presentation, (2) typical ECG characteristics (eg, Ն1-mm ST elevation in any Ն2 contiguous limb leads or new-onset left bundle branch block), and (3) a positive troponin test result (Ͼ1 ng/mL). Controls were indi...

BackgroundDespite being born with a significant number of primordial cells which representing the ancestor cells of the germ-line, women experience a depletion of ovarian reserve and sub-fertility mid-way into their healthy lives. The poor ovarian response is a substantial limiting factor amplified with higher maternal age and associated with a considerably lower likelihood of pregnancy.MethodsA present analytical prospective cross-sectional study was conducted to explore whether infertile women below the age of 40 years have low ovarian reserve than fertile women of same age, assessed by Antral follicle count (AFC) and anti-Müllerian hormone (AMH), at tertiary care infertility center: Lahore Institute of Fertility and Endocrinology, Hameed Latif Hospital. The study population including 423 infertile and 388 fertile female patients from June 2013 to November 2016. Patients and controls were aged between 25 and 39 years. Serum levels of FSH, LH, AMH were assessed, and AFC was measured by transvaginal sonography on cycle days 2 or 3.ResultsA total of 35.6% of infertile women stated a menstrual cycle length shorter than 21 days, while 21% had a regular cycle length between 24 and 38 days, and 43.2%, longer than 38 days. Overall, the two cohorts did not significantly differ on cycle length. The age-specific reduction of the ovarian reserve was similar in both cohorts; serum AMH concentration decreased by 6% (95% Cl: 5–8%) and AFC decline by 4.5% (95% Cl: 5–7%) per year with increased age. Aged patients (36–39 years) had a 5.3% (95% Cl, 1.5; 7.2) higher risk ratio of having an AMH level < 0.7 ng/ml than women of younger age groups (Kruskal-Wallis test, p < 0.01).ConclusionThis study indicates that the possible common observation of low respondent in ART might not be a result of over-representation of patients with an early age-specific decline in the ovarian reserve, but rather primarily as a consequence of age-specific depletion in the stock of developing follicles at the time of recruitment and selection.

PDGF is a growth factor and is extensively involved in multi-dimensional cellular dynamics. It switches on a plethora of molecules other than its classical pathway. It is engaged in various transitions of development; however, if the unleashed potentials lead astray, it brings forth tumourigenesis. Conventionally, it has been assumed that the components of this signalling pathway show fidelity and act with a high degree of autonomy. However, as illustrated by the PDGF signal transduction, reinterpretation of recent data suggests that machinery is often shared between multiple pathways, and other components crosstalk to each other through multiple mechanisms. It is important to note that metastatic cascade is an intricate process that we have only begun to understand in recent years. Many of the early steps of this PDGF cascade are not readily targetable in the clinic. In this review, we will unravel the paradoxes with reference to mitrons and cellular plasticity and discuss how disruption of signalling cascade triggers cellular proliferation phase transition and metastasis. We will also focus on the therapeutic interventions to counteract resultant molecular disorders.