BRCA1 and BRCA2 genes mutations among high risk breast cancer patients in Jordan.

Familial breast cancer is estimated to account for 15-20% of all cases of breast cancer. Surveillance for familial breast cancer is well-established world-wide. However, this service does not exist in Jordan, due to the scarcity of information with regard to the genetic profiling of these patients, and therefore lack of recommendations for policy-makers.

Analgesic Effects and Impairment in Locomotor Activity Induced by Cannabinoid/Opioid Combinations in Rat Models of Chronic Pain.

Both opioids and cannabinoids have well-known antinociceptive effects in different animal models of chronic pain. However, unwanted side effects limit their use. The aim of this study is to evaluate the antinociceptive effect of combining synthetic cannabinoids with subtherapeutic doses of opioids, and to evaluate the effects of these drugs/combinations on rat's locomotor activity.

Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents.

Background: Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes.

The desensitization of the transient receptor potential vanilloid 1 by nonpungent agonists and its resensitization by bradykinin.

Transient receptor potential vanilloid type-1 (TRPV1) channels have crucial roles in inflammatory hyperalgesia. Different inflammatory mediators can modulate TRPV1 sensitization. Bradykinin is an algogenic substance released at the site of inflammation.

Enteric anendocrinosis attributable to a novel Neurogenin-3 variant.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that often present with severe diarrhea in the first weeks of life. Enteric anendocrinosis (EA), an extremely rare cause of CODE, is characterized by a marked reduction of intestinal enteroendocrine cells (EC). EA is associated with recessively inherited variants in Neurogenin-3 (NEUROG3) gene.

Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy.

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage.

Genotoxicity of cisplatin and carboplatin in cultured human lymphocytes: a comparative study.

Cisplatin and carboplatin are integral parts of many antineoplastic management regimens. Both platinum analogues are potent DNA alkylating agents that robustly induce genomic instability and promote apoptosis in tumor cells. Although the mechanism of action of both drugs is similar, cisplatin appears to be more cytotoxic.

Extending the spectrum of CLRN1- and ABCA4-associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing.

Background: Inherited retinal dystrophies (IRDs) are characterized by extreme genetic and clinical heterogeneity. There are many genes that are known to cause IRD which makes the identification of the underlying genetic causes quite challenging. And in view of the emergence of therapeutic options, it is essential to combine molecular and clinical data to correctly diagnose IRD patients.

The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families.

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders that are characterized by progressive skeletal muscle weakness and dystrophic changes on muscle biopsy. The broad genetic and clinical heterogeneity of MDs make the accurate diagnosis difficult via conventional approaches. This study investigated 23 patients from eight unrelated consanguineous families with MDs.

Associations of CYP2A6 Gene Polymorphism with Smoking Status Among Jordanians: Gender-Related Differences.

Background: Cytochrome P450 2A6 enzyme (CYP2A6), an essential hepatic enzyme involved in the metabolism of drugs, is responsible for a major metabolic pathway of nicotine. Variation in the activity of polymorphic CYP2A6 alleles has been implicated in inter-individual differences in nicotine metabolism.

Aims: The objective of the current study was to assess the association between the smoking status and the cytochrome P450 2A6 enzyme (CYP2A6) genotype in Jordanians.

Effects of Dual Peroxisome Proliferator-Activated Receptors and Activation in Two Rat Models of Neuropathic Pain.

Neuropathic pain is a growing healthcare problem causing a global burden. Currently used analgesics such as opioids are associated with adverse effects; urging the need for safer alternatives. Here we aimed to investigate the potential analgesic effects of tesaglitazar; dual peroxisome proliferator-activated receptors and (PPAR and ) agonist in rat models of neuropathic pain.

The frequency of NOTCH1 variants in T-acute lymphoblastic leukemia/lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma among Jordanian patients.

The transmembrane receptor NOTCH1 is thought to be associated with the development and progression of T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma (T-LBL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The current study aimed to characterize NOTCH1 expression and elucidate the variants in the functional PEST domain of the receptor in T-ALL/LBL and CLL/SLL. The nuclear expression of NOTCH1 protein was detected in 25% and 5% of cases of T-ALL/LBL and CLL/SLL, respectively, whereas cytoplasmic expression was detected in 33.

The role of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptors-α in mediating the antinociceptive effects of palmitoylethanolamine in rats.

Palmitoylethanolamine (PEA) is a ligand at peroxisome proliferator-activated receptors-α (PPARα), a nuclear receptor that has anti-inflammatory effects. Herein, complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats and in-vitro calcium imaging studies were used to evaluate the mechanisms that underlie the antinociceptive effects of PEA, including modulating the activity of the transient receptor potential vanilloid receptor 1, which is a key receptor involved in the development of inflammatory pain. Adult male Sprague-Dawley rats (180-250 g) received subcutaneous injections of CFA (0.

PKM2 and HIF-1α regulation in prostate cancer cell lines.

Prostate cancer (PCA) is one of the most common cancer types in men, with cancer progression being linked to hypoxia and the induction of hypoxia-inducible factor (HIF).We investigated the expression of pyruvate kinase M2 (PKM2), its regulation by HIF isoforms 1α and 2α, and its role in HIF stabilization. We additionally examined cell survival in the prostate cancer cell lines PC3 and LNCaP under severe hypoxic (0.

Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disorder that result as a consequence of a deficiency in the lysosomal hydrolase, a-L-iduronidase enzyme encoded by IDUA gene. Over a hundred causative variants in IDUA have been identified, which result in a progressive multi-systemic disease with a broad range of severity and disease progression reported across affected individuals. The aim of this study was the detection and interpretation of IDUA mutation in a family with two children affected with lethal MPS I.

Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline.

Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity.

Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV).

Few options are available for treating patients with advanced prostate cancer (PC). As PC is a slow growing disease and accessible by ultrasound, gene therapy could provide a viable option for this neoplasm. Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating PC.

Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24.

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.

Targeted apoptotic effects of thymoquinone and tamoxifen on XIAP mediated Akt regulation in breast cancer.

X-linked inhibitor of apoptosis protein (XIAP) is constitutively expressed endogenous inhibitor of apoptosis, exhibit its antiapoptotic effect by inactivating key caspases such as caspase-3, caspase-7 and caspase-9 and also play pivotal role in rendering cancer chemoresistance. Our studies showed the coadministration of TQ and TAM resulting in a substantial increase in breast cancer cell apoptosis and marked inhibition of cell growth both in vitro and in vivo. Anti-angiogenic and anti-invasive potential of TQ and TAM was assessed through in vitro studies.

MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells.

Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.

Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma.

MDA-9/syntenin: a positive gatekeeper of melanoma metastasis.

Melanoma differentiation associated gene-9 (MDA-9), synonymous with syntenin, is an adapter protein that provides a central role in regulating cell-cell and cell-matrix adhesion. MDA-9/syntenin transduces signals from the cell-surface to the interior through its interaction with a plethora of additional proteins and actively participates in intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies demarcate a seminal role of MDA-9/syntenin in cancer metastasis.

Targeting Mcl-1 for the therapy of cancer.

Introduction: Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers.