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Yousef M Al-saraireh,1 Fatemah OFO Alshammari,2 Ahmed MM youssef,3 Sameeh Al-Sarayreh,4 Ghadeer H Almuhaisen,5 Nedal Alnawaiseh,6 Jehad M Al-Shuneigat,4 Hamzeh M Alrawashdeh7 1Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 2Department of Medical Laboratory Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh, Kuwait; 3Department of Pharmacology, Faculty of Pharmacy, Mutah University, Al-Karak, Jordan; 4Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 5Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, Al- Karak, Jordan; 6Department of Public Health, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 7Department of Ophthalmology, Sharif Eye Centers, Irbid, JordanCorrespondence: Yousef M Al-sarairehDepartment of Pharmacology, Faculty of Medicine, Mutah University, PO. Box: 7, Al-Karak, 61710, JordanTel +962799172658Email Yousef.sar@mutah.edu.joPurpose: Colon cancer is a leading cause of mortality worldwide. It has a relatively poor prognosis; therefore, new therapies are needed. One of the tumour-related enzymes that has gained considerable interest is CYP4Z1. This enzyme has been expressed in many tumours and has been hypothesized as a potential biomarker or target for novel anticancer therapies.Patients and Methods: CYP4Z1 overexpression was immunohistochemically examined in a large panel of colon tissue types including normal, benign, primary and metastatic ones, and the enzyme’s relation to histopathological features and patient survival was evaluated.Results: A high CYP4Z1 expression was observed in benign, primary and metastatic colon tissues compared to a weak or lack of expression in normal tissues. Importantly, there was a significant differential in CYP4Z1 expression where it was stronger in metastatic, primary and benign, respectively (p < 0.05). A significantly high rate of CYP4Z1 expression was found in high histological grades and late stages of the disease, where its expression was more evident in patients with metastasis in the lymph nodes (p < 0.05). Interestingly, CYP4Z1 expression was identified an independent prognostic predictor of poor overall survival of colon cancer patients (p = 0.003).Conclusion: CYP4Z1 was distinctly overexpressed in benign, primary and metastatic colon tissues compared to corresponding normal tissues. This differential in CYP4Z1 expression across different types of colon tissues strongly supports CYP4Z1 as potential biomarker and target for novel anticancer therapy development.Keywords: cancer, colon cancer, cytochrome P450, cytochrome 4Z1, immunohistochemistry

Fatemah OFO Alshammari,1 Yousef M Al-Saraireh,2 Ahmed MM Youssef,3 Yahya M AL-sarayra,4 Hamzeh Mohammad Alrawashdeh5 1Department of Medical Lab technology, Faculty of health sciences, The Public Authority for Applied Education and Training, Kuwait, Kuwait; 2Department of Pharmacology, Faculty of Medicine, Mutah University, Al-karak, Jordan; 3Department of Pharmacology, Faculty of Pharmacy, Mutah University, Al-karak, Jordan; 4Al-karak Governmental hospital, Al-Karak, Jordan; 5Department of Ophthalmology, Sharif Eye Centers, Irbid, JordanCorrespondence: Yousef M Al-SarairehDepartment of Pharmacology, Faculty of Medicine, Mutah University, PO. Box: 7, Al-karak, 61710, JordanTel +962 799172658Email Yousef.sar@mutah.edu.joPurpose: Treatment of metastatic breast cancer patients is challenging and remains a major underlying cause of female mortality. Understanding molecular alterations in tumor development is critical to identify novel biomarkers and targets for cancer diagnosis and therapy. One of the aberrant cancer expressions gaining recent research interest is glypican-1. Several studies reported strong glypican-1 expression in various types of human cancers. However, none of these investigated glypican-1 expression in a large cohort of breast cancer histopathological subtypes.Patients and Methods: Immunohistochemistry was used to assess glypican-1 expression in 220 breast cancer patients and its relation to demographic and clinical features, as well as important prognostic immunohistochemical markers for breast cancer.Results: Intense glypican-1 expression was recognized in all breast cancer histopathological subtypes. Normal, healthy breast tissue displayed a heterogeneous low expression (20%). Importantly, a strong differential in glypican-1 expression was determined between normal and malignant breast tissues. Moreover, there was a significantly high rate of glypican-1 expression in advanced grades of breast cancer patients and larger tumor sizes. Unfortunately, the glypican-1 expression demonstrated no obvious relationship with the expression of various biomarkers in breast cancer.Conclusion: This study may establish glypican-1 as a promising new therapeutic target for the development of therapy in breast cancer.Keywords: cancer, glypicans, immunohistochemistry, protoglycans, heparan sulfate proteoglycans

Yousef M Al-saraireh,1 Fatemah OFO Alshammari,2 Ahmed MM Youssef,3 Fatima Al-Tarawneh,4 Sameeh Al-Sarayreh,5 Ghadeer H Almuhaisen,6 Anas O Satari,7 Jehad Al-Shuneigat,5 Hamzeh Mohammad Alrawashdeh8 1Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 2Department of Medical Laboratory Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh, Kuwait; 3Department of Pharmacology, Faculty of Pharmacy, Mutah University, Al-Karak, Jordan; 4Department of Allied Medical Sciences, Faculty of Al-Karak, Al-Balqa Applied University, Al-Karak, Jordan; 5Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 6Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan; 7Faculty of Medicine, Mutah University, Al-Karak, Jordan; 8Department of Ophthalmology, Sharif Eye Centers, Irbid, JordanCorrespondence: Yousef M Al-sarairehDepartment of Pharmacology, Faculty of Medicine, Mutah University, P.O. Box: 7, Al-Karak, 61710, JordanTel +962 799172658Email Yousef.sar@mutah.edu.joPurpose: Triple-negative breast cancer (TNBC) is characterized by high mortality rate, and its clinical management is difficult and complex. Therefore, there is a need for extensive efforts aimed at accelerating the discovery of novel therapies for TNBC. CYP4Z1 has been implicated in the development of breast cancer. The current study aimed at characterizing the expression of CYP4Z1 on TNBC.Materials and Methods: Using immunohistochemistry, CYP4Z1 expression was evaluated on 122 TNBC samples, four samples of breast cancers expressing ER, PR, and HER-2, and four samples of normal breast tissues. The association between the enzyme and various histopathological features and survival of patients were determined.Results: CYP4Z1 was strongly expressed in 83.3% of various histopathological subtypes of TNBC, when compared to negative expression in normal breast tissues. Interestingly, there were marked variations in CYP4Z1 expression with respect to histopathology subtype, histological grade, histological stage and tumor diameter. There was a high incidence of CYP4Z1 expression in patients with advanced grades, late stages and larger tumor sizes. Importantly, CYP4Z1 expression was correlated with the survival of TNBC patients, but it was an independent determinant of the poor prognosis of TNBC (p< 0.05).Conclusion: CYP4ZI may be a potential biomarker or target for evolving new CYP4Z1-targeted treatments.Keywords: triple-negative breast cancer, cytochrome P450, immunohistochemistry

Background: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. Methods: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme’s relationship to several clinicopathological features and survival was explored. Results: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p &lt, 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p &lt, 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p &lt, 0.05). Conclusions: CYP4Z1 expression is associated with cervical cancer patients’ survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.

Bladder cancer is the tenth most common cancer worldwide, where its burden remains a challenge and needs new novel therapies. Several reports indicate expression of CYP4Z1 and CYP1B1 in many tumours. Their expressions are associated with a poor prognosis, and therefore proposed as promising biomarkers or targets for anticancer therapy. By using immunohistochemistry, expression of CYP4Z1 and CYP1B1 was evaluated in a panel of different types of bladder cancer, and the enzymes’ relation to histopathological features were assessed. Results showed an increased expression of CYP4Z1 (54.3%) and CYP1B1 (76.9%) in the majority of bladder cancers compared to weak or lack of expression of both enzymes in normal tissues. CYP4Z1expression was significantly associated with tumour grade and stage where the expression was markedly increased in a high grade and advanced stage of the disease (p p

Background Cytochromes P450 (CYPs) constitute an enzyme family involved in the oxidative metabolism of a wide variety of endogenous and exogenous compounds, including anti-cancer drugs and carcinogens. Unlike other human CYPs, CYP4Z1 is highly expressed in human breast carcinoma and is associated with poor prognosis. As a result, CYP4Z1 was hypothesised to be a potential biomarker or drug target for the discovery and development of promising anti-cancer therapies. Materials and methods CYP4Z1 expression was immunohistochemically studied in a set of 100 different human tissues, including normal, benign, malignant and metastatic tissues, which originated from 27 anatomical sites. As a tumour model for CYP4Z1 expression, a panel of different breast cancers was evaluated for CYP4Z1 expression and its relation to histopathological features and prognostic immunohistochemical markers. Results The immunohistochemical results revealed that CYP4Z1 was expressed in only one (4.3%) of the normal tissues from the mammary glands, while the expression of the enzyme was positive in 1 (11%), 12 (19%) and 2 (40%) of the benign, malignant and metastatic tissues, respectively. Interestingly, several tumour entities showed prominent expressions of CYP4Z1, including carcinomas of adrenal cortex, squamous cells of oesophagus, lung and cervix, as well as seminoma, astrocytoma, melanoma and lastly endometrial adenocarcinoma. In breast cancers, CYP4Z1 was expressed in 82% of the cases. Its expression was significantly associated with the pathology of tumour, histological grade and status of lymph node metastasis. Importantly, it was also significantly associated with the expressions of Her2, P53 and Ki-67. Conclusion These findings greatly support future plans for the use of CYP4Z1 as a biomarker or target for anti-cancer drugs. However, large-scale validation studies are needed to better delineate the potential use of CYP4Z1 for therapeutic purposes.

Background Current standard treatments for patients with recurrent cervical cancer are not very effective and are associated with severe toxicity. Recently, the rational approach for the discovery of new therapies for cervical cancer is based on the alterations in the molecular biology of cancer cells. One of the emerging molecular changes in cancer cells is the aberrant expression of cytochrome P450 1B1 (CYP1B1). This unique enzyme has been reported to be selectively overexpressed in several cancers. Objective The aim of this study was to examine CYP1B1 expression in cervical cancers and to assess the enzyme’s relationship with several clinicopathological features. Methods Immunohistochemistry was performed to examine CYP1B1 expression in 100 patient samples with cervical cancer and 10 patient samples with normal healthy cervical tissues. Results CYP1B1 was expressed in the majority of the cervical cancer samples (91/100, 91.0%) but not in normal healthy cervical samples. The difference in the expression of CYP1B1 between healthy and tumorous cervical tissues was significant (P=.01). Moreover, the frequency of CYP1B1 expression was found to be significantly higher in patients with advanced grades of the disease (P=.03) and in patients having metastasis to the lymph nodes (P=.01). Surprisingly, there was a significantly higher expression of CYP1B1 in patients with a high prevalence of human papilloma virus 16/18 (P=.04). Conclusions The differential profile of CYP1B1 expression between cervical cancer tissues and normal cervical tissues suggests that CYP1B1 may be used as a target for future therapeutic exploitations.

Background Adverse drug reactions (ADRs) represent a major health care problem. Objective To identify the most common ADRs, drugs implicated in ADRs, and to assess their causality, severity, preventability and risk factors predisposing to reported ADRs in Jordan. Setting Al-Karak teaching hospital, southern of Jordan. Method A cross sectional observational study was carried out for 11 months from January to November 2013. Suspected ADRs were recorded in ADRs report forms and analyzed for causality, severity, and preventability. Main outcome measure: Most common ADRs, drugs involved in these ADRs, causality, severity, and preventability of suspected ADRs. Results A total of 64 reports were received. Some patients suffered more than one ADR. The total number of ADRs identified was 108. Forty one drugs were involved in causing these ADRs. About 2/3 of adverse reactions (73.4 %) did not cause admission to the hospital, whereas 26.6 % of the ADRs resulted in admission. Majority of the ADRs were type A (62.5 %). Most of ADRs (92.2 %) were assessed as probable. Nearly, 65.6 % of ADRs were categorized as mild. Majority of ADRs were assessed as “not preventable” (75 %). The most common classes of drugs involved in ADRs were antibiotics, analgesics, vaccines and antiepileptics. The most commonly identified ADRs were abdominal pain, skin rash, shortness of breath, fever, upper gastrointestinal bleeding and vomiting. Risk factors contributed to ADRs were age and polypharmacy. Conclusion Jordanian healthcare providers should be aware of the importance of detecting and reporting ADRs, in order to prevent and reduce the incidence of ADRs. Awareness of risk factors predisposing to ADRs may help in identifying patients with higher risk and therefore reducing the risk of these ADRs and improving patient outcome.

Background and Aim: Thrombocytopenia is a frequent problem in patients with post- hepatitis C (HCV) liver cirrhosis and also occurs in chronic HCV-infected patients without liver cirrhosis. The aim of this study was to evaluate the role of plasma thrombopoietin (TPO) in the occurrence of thrombocytopenia in both conditions. Method: Platelet count and plasma thrombopoietin level and liver function tests were measured in four groups of patients: twenty chronic patients with post-hepatitis C liver cirrhosis and thrombocytopenia (group I), ten chronic HCV-positive patients with liver cirrhosis without

Alkaptonuria is a very rare genetic disorder, characterized by a lack of homogentisate dioxygenase and causes accumulation of homogentisic acid. Clinical manifestations include dark urine, dark-black pigmentation of connective tissues (ochronosis), and arthritis of large joints and spine. The disease is usually diagnosed in adulthood by assessment of signs and symptoms of ochronosis. Confirmation of suspected diagnosis can be achieved by quantitative measurements of homogentisic acid levels. In this study, homogentisic acid was analyzed in 17 alkaptonuria patients. After liquid-liquid extraction, the analyte was determined by Gas Chromatography/ Mass Spectrometry (GC-MS) method. For quantitation purposes, external calibration was applied first, regression coefficient of ≥ 0.995 indicated the linearity in the concentration range of 1-100 ng/µl. The instrumental detection limit (IDL) and lower limit of quantitation were 3.82 and 12.7 µg/L, respectively. Recovery rate was ≥ 89%. Precision given as relative standard deviation (RSD) ranged from 3 – 10 %. The results showed that the concentration of homogentisic acid ranged from 0.46 to 1.5 g/24 hours.

Polysialic acid (polySia) is a carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in many cancer cells where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis. PolySia-NCAM expression is strongly associated with poor clinical prognosis and correlates with aggressive/invasive disease in small cell lung cancer, pancreatic cancer, neuroblastoma and many other tumors principally of neuroendocrine origin [1]. SiRNA knockdown of polysialyltransferase ST8SiaII (STX), the enzyme primarily responsible for polySia synthesis in tumors, has been shown to abolish tumor cell migration [2]. Besides brain regions with persistent neuronal plasticity, polySia is essentially absent from the adult body. STX inhibition thus presents a novel, selective, highly attractive and largely unexplored therapeutic opportunity to reduce dissemination of polySia-expressing tumors [1]. Using cytidine monophosphate (CMP) as a tool compound, we have validated a highly sensitive HPLC-based inhibition assay, and demonstrated competitive inhibition of STX, leading to a reduction in polySia expression [3]. Having demonstrated for the first time that inhibition of STX by a small molecule leads to a reduction in tumor cell migration and invasion, we have designed and synthesised inhibitors of STX and the polysialylation process. The potency of these compounds has been increased by chemical modification, resulting in greater lipophilicity. Using an isogenic cell line system (rat glioma cells C6-STX: polySia+/STX+ and C6-WT: polySia-/STX- [4]) and naturally polySia expressing human neuroblastoma cells (SH-SY5Y, IMR-32) these compounds were evaluated for their ability to reduce polySia expression and to modulate cell migration in vitro. We have identified CMP-sialic acid precursors, including compounds ICT-3172 and ICT-3176, which reduced polySia expression and tumor cell migration by up to 70%. These effects were only found in cell lines expressing STX and polySia. In summary, we have identified a number of key modifications to polySia biosynthetic precursors which dramatically decrease cell migration in cells over-expressing STX through modulation of polySia assembly. The potential of the polySia biosynthesis pathway, and in particular STX, as attractive therapeutic targets in metastatic tumors is discussed. [1] Falconer, R.A. et al., Curr. Cancer Drug Targets, 2012, 12, 925-939 [2] Schreiber et al.,Gastroenterology, 2008, 134, 1555-1566 [3] Al-Saraireh YMJ et al., PLoS ONE, 2013, 8:e7336 [4] Suzuki, M. et al., Glycobiology, 2005, 15, 887-894. Citation Format: Virginie Viprey, Bradley R. Springett, Yousef Al-Saraireh, Matthew Northrop, Mark Sutherland, Rida Saeed, Paul M. Loadman, Laurence H. Patterson, Steven D. Shnyder, Robert A. Falconer. Polysialyltransferase ST8SiaII: a new target for the treatment of metastatic tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2014-1774