Doctor of Philosophy

dissertationComplex cancer phenotypes are defined by their aggressive nature and lack of known or accessible therapeutic targets. My dissertation focuses on the use of a personalized medicine approach for the identification of novel therapies against two complex cancer phenotypes: Basal-like/Claudin-low breast cancer and RAS-active nonsmall cell lung cancer. RAS-active cancer is characterized by the activation of the complex signaling network of RAS, which lacks effective therapeutics capable of inhibiting the RAS protein itself or the overall pathway. Further complicating treatment is the ability of the RAS pathway to be activated independent of the presence of an activating mutation in the RAS protein. To broadly characterize pathway activation independent of RAS protein mutation, I used a gene-expression-based biomarker for RAS network activity in nonsmall cell lung cancer (NSCLC) cell lines, and identified RAS activation in both RAS-mutant and wild-type lines. I then screened for drugs whose efficacy significantly correlated to RAS network activity and showed that EGFR and MEK co-inhibition is an effective treatment personalized against RAS-active NSCLC. Finally, I demonstrated that EGFR and MEK co-inhibition induced apoptosis and blocked both EGFR-RAS-RAF-MEK-ERK and EGFR-PI3K-AKT-RPS6 nodes simultaneously in RAS-active, but not RAS-inactive NSCLC. Secondly, I identified a novel compound effective against Basal-like and Claudin-low breast cancer (BL-CL). BL-CL is a molecular subtype of breast cancer characterized by an aggressive, recurrent and nonluminal nature, epitomized by the lack of known therapeutic targets and poor patient prognosis. Using high- iv throughput screening of a marine invertebrate compound library and sequential purification of crude fractions, I identified a previously uncharacterized sulfated sterol, Topsentinol L Trisulfate (TLT), purified from a marine sponge, and showed that it inhibits AMPK and CHK1 but activates p38. Furthermore, I indentified the potential use of known AMPK and CHK1 inhibitors, alone or in combination, as an effective therapy against BL-CL. Lastly, sensitivity to TLT was projected against various human tumors by generating a gene-expression signature that predicted breast and bladder cancer as the cancer types most receptive to TLT therapy. This work describes the identification of novel treatments personalized against BL-CL and RAS-active NSCLC, providing a framework for future pre-clinical studies

Automatic Versus Manual Solar Panel Cleaning for Remote Locations

Photovoltaic solar technology is now being widely investigated for implementation in the UAE as a possible renewable energy source. Currently the main emphasis is on the accessible areas but remote locations are now being explored for the possibility of large scale deployment. However due to the environment and location certain measures such as regular cleaning must be considered to ensure the efficient operation of the PV panels. This paper investigates the cost of current developed cleaning technologies available in the Gulf region, highlights their advantages and disadvantages and the time needed to recoup initial investment

Inactivation of Plasmodium falciparum in whole blood by riboflavin plus irradiation.

BACKGROUND: Malaria parasites are frequently transmitted by unscreened blood transfusions in Africa. Pathogen reduction methods in whole blood would thus greatly improve blood safety. We aimed to determine the efficacy of riboflavin plus irradiation for treatment of whole blood infected with Plasmodium falciparum. STUDY DESIGN AND METHODS: Blood was inoculated with 10(4) or 10(5) parasites/mL and riboflavin treated with or without ultraviolet (UV) irradiation (40-160 J/mL red blood cells [mL(RBCs)]). Parasite genome integrity was assessed by quantitative amplification inhibition assays, and P. falciparum viability was monitored in vitro. RESULTS: Riboflavin alone did not affect parasite genome integrity or parasite viability. Application of UV after riboflavin treatment disrupted parasite genome integrity, reducing polymerase-dependent amplification by up to 2 logs (99%). At 80 J/mL(RBCs), riboflavin plus irradiation prevented recovery of viable parasites in vitro for 2 weeks, whereas untreated controls typically recovered to approximately 2% parasitemia after 4 days of in vitro culture. Exposure of blood to 160 J/mL(RBCs) was not associated with significant hemolysis. CONCLUSIONS: Riboflavin plus irradiation treatment of whole blood damages parasite genomes and drastically reduces P. falciparum viability in vitro. In the absence of suitable malaria screening assays, parasite inactivation should be investigated for prevention of transfusion-transmitted malaria in highly endemic areas

Correlations between biochemical testing, pathology findings and preoperative sestamibi scans: a retrospective study of the minimally invasive radioguided parathyroidectomy (MIRP) approach

BACKGROUND: Sestamibi imaging is the most widely used preoperative localization study for patients with hyperparathyroidism. Previous reports examine the relationship between the weight and volume of excised parathyroid glands and preoperative serum calcium and parathyroid hormone (PTH) levels. The aim of this study was to examine whether these variables correlate with the results of preoperative Sestamibi scans. MATERIAL AND METHODS: A retrospective review of 150 consecutive patients who underwent preoperative sestamibi imaging for primary hyperparathyroidism between 1998 and 2007 was performed. Variables studied included patient demographics, diagnostic test (sestamibi) results, operative/pathology findings and surgical outcome (normocalcaemia vs. persistent hypercalcaemia). Sestamibi scans were designated as either "negative" (NSS) or "positive" (PSS), where PSS correctly localized abnormal gland(s) enabling a focused neck exploration. The results of sestamibi imaging were correlated with calcium/PTH levels, weight/volume of excised glands and patient outcomes and demographics. RESULTS: Total excised gland weight/volume and preoperative serum calcium levels were significantly higher with PSS (all, p < 0.04). Higher preoperative serum calcium levels and greater total gland weight/volume were significantly associated with successful operative outcome (presence of postoperative normocalcaemia; all, p < 0.01). Factors associated with operative failure included multi-gland disease (p < 0.01) and NSS (p < 150 pg/mL) were associated with greater excised gland mass (p < 0.05) and volume (p < 0.05). Male gender was associated with higher preoperative serum calcium levels (p < 0.02). Of interest, patients with single-gland disease had significantly higher preoperative PTH levels than patients with multi-gland disease (155 vs. 109 pg/mL, p < 0.05). CONCLUSION: Positive sestamibi scans are associated with heavier/larger parathyroid glands and higher preoperative serum calcium levels. Male gender was associated with higher preoperative serum calcium levels, while single-gland disease was associated with higher preoperative PTH levels. In addition, successful surgical outcome was associated with higher preoperative serum calcium levels and with greater excised parathyroid gland mass/volume. Surgical failure was associated with multi-gland disease and negative sestamibi

Interocular Symmetry in Macular Choroidal Thickness in Children

Objective. To report interocular differences in choroidal thickness in children using spectral domain optical coherence tomography (SD-OCT) and correlate findings with biometric data. Methods. This observational cross-sectional study included 91 (182 eyes) healthy children aged 6 to 17 years with no ocular abnormality except refractive error. After a comprehensive eye exam and axial length measurement, high definition macular scans were performed using SD-OCT. Two observers manually measured the choroidal thickness at the foveal center and at 1500 µm nasally, temporally, inferiorly, and superiorly. Interocular differences were computed; correlations with age, gender, refractive error, and axial length were performed. Results. Mean age was 10.40 ± 3.17 years; mean axial length and refractive error values were similar between fellow eyes. There was excellent correlation between the two observers’ measurements. No significant interocular differences were observed at any location. There was only a trend for right eyes to have higher values in all thicknesses, except the superior thickness. Most of the choroidal thickness measurements correlated positively with spherical equivalent but not with axial length, age, or gender. Conclusion. Choroidal thickness measurements in children as performed using SD-OCT revealed a high level of interobserver agreement and consistent interocular symmetry. Values correlated positively with spherical equivalent refraction

LYMPHOMA: EXPLORING AWARENESS IN LEBANON

In 2012, 14.1 million patients were diagnosed with cancer worldwide of which 385,700 estimated new cases of non-Hodgkin lymphoma (NHL). Also, 81,080 new cases of lymphoma were reported in the United States (US) among both genders in 2016. In Lebanon, Lymphoma represents the fifth most frequent cancer, nonetheless, little is known regarding its epidemiological attributes. This study aims to determine the current knowledge of the Lebanese people living in Lebanon about Lymphoma. About 400 participants were approached in public places, universities, hospitals or work places in different regions across Lebanon. A survey including questions about lymph nodes, cancer and lymphoma as well as demographic characteristics was given to all eligible participants. The data was collected and analyzed using SPSS and p value \u3c 0.05 was considered significant. When asked about the types of cancers they knew, the majority of participants (93.5%) were able to identify breast cancer, while less than half of (30.67%) identified lymphoma as a cancer. Enlargement of the lymph nodes (LN) was the most common recognized symptom (93.4%) whereas 76.42% thought that family history of lymphoma was the most frequent risk factor for lymphoma. Among those who claim to know about lymphoma (30%), true in-depth knowledge about lymphoma was still lacking. The results of this independently conducted survey reveal the lack of awareness about lymphomas among the Lebanese population and highlight the need for campaigns to increase the knowledge and awareness

Beyond zero deforestation in the Brazilian Amazon: Progress and remaining challenges to sustainable cattle intensification

Key Messages • A governance approach, combining public policy and private initiatives was effective in slowing down deforestation, but was unable to support a transition to more sustainable production systems. • New technical intensification models must be identified for low-productivity systems in degraded lands, adapted to the biophysical and sociotechnical conditions of the Amazonian landscapes. • Multiple constraints inhibit progress toward sustainable intensification of cattle ranching, and reversing them requires that all such constraints be addressed in a coordinated way. • Designing options that work for all stakeholders, and monitoring and verifying progress of territories toward sustainability is essential to support current public policies and private initiatives

Collaborative Coding in Multi-National Teams: Benefits, Challenges and Experiences Promoting Equitable Research

Within multi-national research collaborations, power dynamics often shape who is involved in which parts of the research process. The analysis phase of research has historically been framed as requiring expert perspective, excluding national or local researchers whose role is often limited to collecting data and transferring it to others to analyze. In this paper, we describe and reflect on the process of collaborative coding across a multi-national team based in Lebanon and the United Kingdom, as part of a broader approach to co-production. We explore the value and benefit of collaborative coding, reflecting on how coding together enabled greater inclusion, teamwork, improved analysis as well as improved future data collection. We also discuss the technical and logistical challenges we faced in coding within a team and using internet-based software, including the complications involved in navigating power dynamics between researchers and coming to final decisions about codes. Over time, we found collaborative coding became a smoother process, however working in this way is not straight-forward. Our paper contributes a reflexive analysis on the power dynamics and decision-making complexities involved in collaborative coding. It emphasizes the importance of investing in interpersonal relationships over time and prioritizing less-centralized decision-making within research collaborations