Pharmacological targets for gene therapy in lung inflammation

Interleukin-13 (IL-13) has been implicated as a critical inducer of a number of features of allergy and asthma including the induction of nonspecific airway hyperresponsiveness (AHR), eosinophilic inflammatory response, eotaxin production, excess mucus formation, and fibrosis. Determining the mechanism(s) of AHR, a hallmark of asthma, is crucial to our understanding of both the pathogenesis and successful treatment of asthma. After carrying out initial experiments to determine the effect of IL-13-induced AHR on murine and rat tracheal rings, mice tissues were chosen for subsequent experiments due to their consistent results and the fact that the mouse genetic map was completed in 1996, which will enable subsequent gene therapy work. Human and mouse share a high percentage of their genes with an average of 85% homology. Numerous IL-13 signalling studies have concentrated on the JAK/STAT6 pathway. IL-13 also activates phosphoinositide 3-kinase (PI3K) and downstream effector molecules. In experiments presented in this thesis pharmacological and genetic approaches implicate the involvement of PI3K and its individual isoform PI3Kδ in IL-13 induced AHR in vitro and this involvement was confirmed using a small interference RNA (siRNA) technology approach. However, IL-13 induced an early activation of PI3K, whereas increased responsiveness was not observed until overnight incubation. Arginase I induction was demonstrated to be another PI3K-dependent potential mechanism of IL-13-induced hyperresponsiveness. The epithelium is also implicated in IL-13-induced hyperresponsiveness, however, the induction of arginase I was demonstrated in both intact and denuded epithelium tracheal rings. The siRNA approach was also employed in 9HTEo-, A549 and BEAS-2B cell lines using different transfecting agents. From these findings, it is concluded that class IA p110δ could be a useful target for the treatment of asthma by preventing IL-13-induced airway smooth muscle hyperresponsiveness and also that arginase I may be involved in IL-13-induced hyperresponsiveness through PI3K- and epithelial-dependent pathways.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

ASSESSMENT OF SAPONIN RICH FRACTION FROM BALANITES AEGYPTIACA (L.) FRUITS AS ANTI SCHISTOMIASIS, ANTI-OXIDANT, ANTIMUTAGENIC AGENTS AND IN VITRO PRODUCTION OF SAPONINS FOR DRUG MANUFACTURE

Saponin rich fraction of Balanites fruits (SRF) was administered orally at a dose of 250 mg/kg to schistosoma infected mice. Treatment with SRF showed amelioration signs in all biomarkers that confirmed by significant reduction in oogram, ova count and worm burden. Histopathological examination showed extensive reduction in granuloma sizes after 6 weeks treatment. Our results showed time dependant inhibition in the DNA damage induced in infected mice after treatment. Saponins were also successfully synthesized by callus cultures using Murashige and Skoog media. NMR analysis illustrated the presence of 4 major saponins of furostanol type from both fruits of natural plant and calli. Thus, SRF of B.aegyptiaca fruits possesses antischistomiasis activity. Antioxidant and antimutagenic activities could be considered as possible mechanisms of action. Additionally, Balanites aegyptiaca saponins could be produced in continuous manner using in vitro cultures as future vision for drug production to overcome scarce of active metabolites and endangered plant

ASSESSMENT OF WATER QUALITY IN CHLORINATED DRINKING WATER DISTRIBUTION NETWORKS REGARDING TO TRIHALOMETHANES FORMATION

Chlorine disinfection in conventional water treatment plants in Egypt is a popular and inexpensive technique for disinfecting raw surface water before distribution to consumers. Nevertheless, the chlorination process in the presence of natural organic matter and decreased water quality due to uncontrollable population results in formation of high concentrations of carcinogenic disinfection by-products, from which trihalomethanes (THMs). In this paper, the water quality of Assiut drinking water network (ADWN) was assessed in terms of THMs studying different water quality parameters. An extended period simulation based on a modelling software WaterGEMS was employed to obtain the critical locations to be examined according to key parameters namely: water age, residual chlorine concentration, water velocity, and type of storage. The study concluded that THMs concentrations from all critical locations in Assiut drinking water network would not exceed the Egyptian regulatory threshold and US Environmental Protection Agency (EPA) guidelines. Even more, an investigated domestic roof tank should be critically operated under a planned scheme of monitoring and maintenance due to its deteriorated water quality

The co-presence of high-risk human papillomaviruses and Epstein-Barr virus is linked with tumor grade and stage in Qatari women with breast cancer.

High-risk human papillomaviruses (HPV) can be present and cooperate with Epstein-Barr virus (EBV) to promote the onset and/or progression of various cancers including cervical, breast, head and neck as well as colorectal. In this investigation, we explored the co-prevalence of high-risk HPV and EBV in 74 breast cancer tissues from Qatari women using polymerase chain reaction. We found that high-risk HPV and EBV are present in 48/74 (65%) and 36/74 (49%) of the cases, respectively. While we noted that the presence of HPV presence is associated with triple-negative breast cancer (TNBC) ( = .008), however, the presence of EBV did not correlate with any breast cancer subgroup. Moreover, our data revealed that high-risk HPV and EBV are co-present in 35/74 (47%) of the samples and their co-presence is significantly associated with tumor grade ( = .04) and tumor stage ( = .04). These data indicate that HPV and EBV are commonly co-present in breast cancer and their association could be linked with a more aggressive tumor phenotype. Thus, further investigations are essential to understand the underlying mechanisms of HPV and EBV cooperation in breast carcinogenesis.grants from Qatar University [QUCG-CMED-2018/2019-3, QUHI-CMED-19/20-1 and QUCG-CMED-20/21-

Novel anticancer drug delivery system based on zeolite encapsulating Hamelia patens leaf and flower extracts

Nanotechnology had placed an impact in improving the antiproliferative activity of crude leaf (CL) and flower (CF) extracts of Hamelia patens on the liver (HEPG2) and breast (MCF7) carcinoma cell lines, after their encapsulation onto zeolite (ZSM-5) nanopores, which acts as a drug delivery system (DDS). The cytotoxicity of the new formulas showed remarkable improvement in the activities on HEPG2. CL had low activity on HEPG2, at the tested concentrations, but the ZSM-5 loaded one (CLZ) showed enhanced action with IC50=42 μg/mL. Also, the cytotoxicity of CF improved after Zeolite incorporation, where the IC50 has been changed from 48 μg/mL for CF to 25 μg/mL for CFZ. Moreover, the polar fraction of leaves extracted by methanol (Me.L) showed improvement on the cytotoxicity on MCF7 for zeolite loaded formula (Me.Z) (IC50 had changed from 65 to 44.4 μg/mL). Quantitative estimations for polyphenolic contents as well as the phenolic profiles for CF and CL extracts were inspected using HPLC-DAD to explore the bioactive phytochemical compounds. Acute toxicity test showed that LD50 was 1500 and 2333 mg/kg b.wt. for CL and CF, respectively. The cytogenetic study was also done to detect the chromosome aberrations in somatic and germ cells after CL and CF administration to mice. DPPH antioxidant capacity assay revealed that CL has high redox-active effect than CF. This study is a contribution to the development of a creative new DDS that help in cancer treatment

Tumorigenic potential of pituitary tumor transforming gene (PTTG) <it>in vivo</it> investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/−) transgenic mice

<p>Abstract</p> <p>Background</p> <p>Pituitary tumor-transforming gene (PTTG) is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG <it>in vivo</it> remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis.</p> <p>Methods</p> <p>Transgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53^+/- animals.</p> <p>Results</p> <p>PTTG transgenic offspring (TgPTTG) were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells. Tumorigenesis is a multi-step process, often requiring multiple oncogenes and/or inactivation of tumor suppressor genes. Therefore, to understand the contribution of p53 to PTTG induced tumorigenesis, we crossbred TgPTTG to p53^+/− mice and maintained those 8 to 10 months. TgPTTG/p53^+/− animals developed sarcomas faster than p53^+/− alone as well as different tumor types in addition to cervical carcinomas <it>in situ</it> in 10 out of 17 females.</p> <p>Conclusions</p> <p>We conclude that while PTTG is a functional transforming oncogene, it requires an additional partner to effectively promote tumorigenesis through the loss of p53 include or between function or modulation.</p

Role of frozen section in the intraoperative management of ovarian masses

Objective: To evaluate the performance and limitations of FS in the intraoperative evaluation of ovarian masses. Design: Retrospective descriptive study. Methods: The case records of patients presenting with ovarian masses who underwent surgery and intraoperative FS assessment between January 2009 and December 2012 were analyzed. Demographic and clinical data were reviewed. Data on FS analysis were compared with the final diagnosis on paraffin section. Results: Sixty patients with ovarian masses undergoing surgery and FS were included. Four cases had the diagnosis at the time of FS deferred (6.6%). In the remaining 56 patients, the FS diagnoses were benign in 24 (40%), borderline in 9 (15%), and malignant in 23 (38.4%), whereas the final diagnosis was benign in 23 (38.4%), borderline in 11 (18.3%), and malignant in 26 (43.3%). The overall accuracy of intra-operative FS diagnosis was 95.5%. The sensitivity for FS diagnosis was 100% for benign, 72.7% for borderline and 88.4% for malignant category, whereas the specificity was 97.3%, 97.9%, and 100.0%, respectively. There were 4 cases with discordance between the FS diagnoses and the final diagnoses, all of which were under-diagnosed by FS. Conclusion: Frozen section is a good tool for decision making at the time of ovarian surgery but does not always provide an immediate solution. However a large prospective study is recommended

Simultaneous occurrence of follicular and papillary thyroid carcinomas in same thyroid lobe : A case series of six patients from Qatar

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are the first and second most common thyroid cancers comprising about 85% and 10% of all thyroid cancers. Simultaneous occurrence of medullary and papillary thyroid cancer has been reported with various presentations, but simultaneous occurrence of FTC in addition to PTC as differentiated cancers, is an unusual event that is rarely reported. Presentation of cases: We report our experience of six rare cases of synchronous coexistence of FTC and PTC with unique features. Case 1 is 31 old Egyptian female. Case 2 is a 61 year old Sudanese male. Case 3 is a 59 year old Sudanese male. Case 4 is a 56 years old Indian female. Case 5 is a 35 years old Filipina female. Case 6 is a 52 years old Qatari female. The six cases are special in their co-occurrence of two thyroid carcinoma, consisting of histologic features of follicular thyroid carcinomas, and classical papillary thyroid carcinoma, possibly the first case series of simultaneous occurrence of these two types of thyroid cancer in the Middle East and North Africa Region. Conclusions: We present rare cases of concurrent FTC and PTC. These six cases add more data highlighting the coincidental simultaneous coexistence of FTC and PTC. Endocrinologists and pathologists should be aware of and vigilant to this variety. © 2020 The Author(s)Correspondence Address: El Ansari, W.; Department of Surgery, Hamad General Hospital, Hamad Medical Corporation, Qatar; email: [email protected]</p