The Role of Inflammatory and Cytokine Biomarkers in the Pathogenesis of Frailty Syndrome.

Frailty is a conglomerated elderly disorder that includes multiple abnormalities, like anemia, an increased titer of catabolic hormones, and compromised physiology of most of the body systems. Many studies have established the biomarkers that correlate with physical function and immune aging; however, people can age differently, so chronological age is not a sufficient marker of susceptibility to disabilities, morbidities, and mortality. The pathophysiology of frailty is not clearly understood, but a critical role of enhanced inflammation in the body is hypothesized. Many factors contribute to the development of frailty syndrome, such as pro-inflammatory cytokines, inflammatory markers, inflammatory cytokines, and secosteroids, like vitamin D. This review aims to highlight the role of inflammatory and cytokine biomarkers and vitamin D in the pathogenesis of Frailty Syndrome.

Role of Selected miRNAs as Diagnostic and Prognostic Biomarkers in Cardiovascular Diseases, Including Coronary Artery Disease, Myocardial Infarction and Atherosclerosis.

Cardiovascular diseases are the leading cause of death worldwide in different cohorts. It is well known that miRNAs have a crucial role in regulating the development of cardiovascular physiology, thus impacting the pathophysiology of heart diseases. MiRNAs also have been reported to be associated with cardiac reactions, leading to myocardial infarction (MCI) and ultimately heart failure (HF). To prevent these heart diseases, proper and timely diagnosis of cardiac dysfunction is pivotal. Though there are many symptoms associated with an irregular heart condition and though there are some biomarkers available that may indicate heart disease, authentic, specific and sensitive markers are the need of the hour. In recent times, miRNAs have proven to be promising candidates in this regard. They are potent biomarkers as they can be easily detected in body fluids (blood, urine, etc.) due to their remarkable stability and presence in apoptotic bodies and exosomes. Existing studies suggest the role of miRNAs as valuable biomarkers. A single biomarker may be insufficient to diagnose coronary artery disease (CAD) or acute myocardial infarction (AMI); thus, a combination of different miRNAs may prove fruitful. Therefore, this review aims to highlight the role of circulating miRNA as diagnostic and prognostic biomarkers in cardiovascular diseases such as coronary artery disease (CAD), myocardial infarction (MI) and atherosclerosis.

Molecular Evaluation of HIF-1α Gene Variation and Determination of Its Frequency and Association with Breast Cancer Susceptibility in Saudi Arabia.

AIM: Hypoxia-inducible factor 1 (HIF-1α) is responsible in regulating oxygen homeostasis in tissues and is a central effector of the hypoxic response besides its protein overexpression has been shown to have prognostic relevance in several cancers including breast cancer. Several reports indicated that HIF-1α gene variation C1772T (Pro582Ser) is associated with increased breast susceptibility but results remained controversial. Therefore, we performed the molecular evaluation of HIF-1α gene variation and determined its frequency and association with Breast Cancer susceptibility in Saudi Arabia. METHODS: This study was conducted on histologically confirmed Breast cancer patients and gender matched healthy women. HIF-1α C1772T (Pro582Ser) genotyping was done by Amplification refractory mutation system PCR method. The HIF-1α gene genotypes were correlated with different clinicopathological characteristics of breast cancer patients. RESULTS: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro582Ser) between breast cancer cases and gender matched healthy controls (P=0.010). Our findings showed that the HIF- 1α variant was associated with an increased risk of Breast cancer for HIF-1α CC vs CT genotype OR = 2.20, 95% CI = (1.28 -3.77), P = 0.004) in codominant inheritance model. The significant association was reported for HIF1A for genotypes CC vs (CT+ TT) OR = 1.98, 95% CI = (1.17-3.34), P = 0.010) in dominant inheritance model tested. In case of recessive inheritance model, a non-significant association of HIF-1 alpha gene variants was reported for (CC+ CT) vs TT) OR = 1.03, 95% CI = (0. 064-16.79), P = 0.97). During the allelic comparison, a non-significant association was reported between A vs C allele among Breast cancer patients. A significant association of HIF- 1α polymorphism was reported with stage as well as distant metastasis of the disease. CONCLUSION: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro>Ser) between breast cancer cases and gene matched healthy controls (P=0.010). HIF-1α- CT heterozygosity and CC genotype increased the susceptibility .The HIF-1α polymorphism was reported to be significantly associated with the distant metastasis of Breast cancer. Further studies with larger data set and well-designed models are required to validate our findings.

Phosphatidylinositol 3-kinase Glu545Lys and His1047Tyr Mutations are not Associated with T2D.

BACKGROUND: Insulin resistance initiated in peripheral tissues induces type 2 diabetes (T2D). It occurs when insulin signaling is impaired. INTRODUCTION: Phosphatidylinositol 3-kinases (PI3K) are important for insulin signaling. Single nucleotide polymorphisms of the PI3K gene have been associated with T2D. METHODS: We have investigated the association of Glu545Lys and His1047Tyr mutations of phosphatidylinositol- 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene with T2D. We have screened 103 T2D patients and 132 controls for Glu545Lys mutation, and 101 T2D patients and 103 controls for the His1047Tyr mutation from a Saudi cohort using AS-PCR. RESULTS: Our results indicated that there is no association between the GA genotype of rs104886003 (Glu545Lys) and T2D, OR= 0.15 (95% CI: 0.007-3.28), RR= 0.29(0.02-3.72), P value= 0.23. The A allele is also not associated with T2D diabetes, OR= 1.01(95% CI: 0.70-1.46), RR=1.00(0.85-1.18), P value=0.91. Results showed that CT genotype of rs121913281 (His1047Tyr) was not associated with T2D, OR=0.94(95% CI: 0.23-3.9), RR= 0.97(0.48-1.97), P-value = 0.94, and T allele was also not associated with T2D, OR=1.06 (95% CI: 0.71-1.56), RR= 1.02(0.84-1.24), P-value =0.76. CONCLUSION: We conclude that the A allele of rs104886003 may not be associated with T2D. The T allele of rs121913281 may also not associated with T2D. However, future studies with larger sample sizes and in different populations are recommended.

Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders.

The impact of neurodegenerative disorders in humans has multiple consequences because of the progressive decline in cognitive and physical performances. These disorders have diverse manifestations and are influenced by genetic and lifestyle factors, concurrent health conditions as well as un-modifiable predisposing risk factors, including gender and advanced age. Accumulating evidence indicates a gender-dependent natural bias of neurodegenerative diseases, such as, Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple sclerosis, with the ratio of male to female prevalence as well as the severity of the disease differing significantly between the two sexes. This observation has recently garnered much attention and it is now being realized that understanding the sex as a biological variable in the etiology of the neurodegenerative diseases may advance the status of the pathophysiology and treatment strategies while improving the associated decline in cognitive and functional abilities. This review highlights the influence of gender in neurodegenerative disorders and further discusses the sex-specific pre-determined microenvironments that are critical in predisposing the individuals to such disorders.

Sero-prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) specific antibodies in dromedary camels in Tabuk, Saudi Arabia.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a novel Coronavirus which was responsible of the first case of human acute respiratory syndrome in the Kingdom of Saudi Arabia (KSA), 2012. Dromedary camels are considered as potential reservoirs for the virus and seem to be the only animal host which may transmit the infection to human. Further studies are required to better understand the animal sources of zoonotic transmission route and the risks of this infection. A primary sero-prevalence study of MERS-CoV preexisting neutralizing antibodies in Dromedary camel serum was conducted in Tabuk, western north region of KSA, in order to assess the seopositivity of these animals and to explain their possible role in the transmission of the infection to Human. One hundred seventy one (171) serum samples were collected from healthy dromedary camels with different ages and genders in Tabuk city and tested for specific serum IgG by ELISA using the receptor-binding S1 subunits of spike proteins of MERS-CoV. 144 (84,21%) of the total camel sera shown the presence of protein-specific antibodies against MERS-CoV. These results may provide evidence that MERS-CoV has previously infected dromedary camels in Tabuk and may support the possible role of camels in the human infection.

Sequencing, analysis, and annotation of expressed sequence tags for Camelus dromedarius.

Despite its economical, cultural, and biological importance, there has not been a large scale sequencing project to date for Camelus dromedarius. With the goal of sequencing complete DNA of the organism, we first established and sequenced camel EST libraries, generating 70,272 reads. Following trimming, chimera check, repeat masking, cluster and assembly, we obtained 23,602 putative gene sequences, out of which over 4,500 potentially novel or fast evolving gene sequences do not carry any homology to other available genomes. Functional annotation of sequences with similarities in nucleotide and protein databases has been obtained using Gene Ontology classification. Comparison to available full length cDNA sequences and Open Reading Frame (ORF) analysis of camel sequences that exhibit homology to known genes show more than 80% of the contigs with an ORF>300 bp and approximately 40% hits extending to the start codons of full length cDNAs suggesting successful characterization of camel genes. Similarity analyses are done separately for different organisms including human, mouse, bovine, and rat. Accompanying web portal, CAGBASE (http://camel.kacst.edu.sa/), hosts a relational database containing annotated EST sequences and analysis tools with possibility to add sequences from public domain. We anticipate our results to provide a home base for genomic studies of camel and other comparative studies enabling a starting point for whole genome sequencing of the organism.

Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias.

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.

Mutational analysis of class III receptor tyrosine kinases (C-KIT, C-FMS, FLT3) in idiopathic myelofibrosis.

Genomic DNA from patients with idiopathic myelofibrosis (IMF) was screened by polymerase chain reaction (PCR) and conformation sensitive gel electrophoresis (CSGE) for mutations in the C-KIT gene (60 patients), as well as the C-FMS and FLT3 genes (40 patients). Intronic primers were used to amplify the entire coding region of both the C-KIT and C-FMS genes, and selected regions of the FLT3 gene. CSGE and direct DNA sequencing detected all previously reported as well as several novel polymorphisms in each of the genes. A novel c-fms exon 9 mutation (Gly413Ser) was detected in two patients. Its functional significance remains to be determined. The c-kit mutation Asp52Asn, previously described in two of six IMF patients in Japan, was not detected in this study. In addition, the reported c-fms mutations involving codons 301 and 969 were not identified. Therefore, in contrast to acute myeloid leukaemia, mutations in RTKs class III do not appear to play a significant pathogenetic role in idiopathic myelofibrosis.