Gastro-esophageal adenocarcinomas (GEA) are among the fastest rising malignancies in North America. Despite advances in cancer prevention and treatment for other cancers, the number of GEA cases continues to rise and prognosis remains bleak with five-year survival rates of only 20%. Additionally, many GEA patients won’t respond to first line therapy, many may develop therapeutic resistance, or will show disease recurrence. Previous drug screen models failed clinical trials due to the failure of the model to adequately recapitulate the primary sample. A new model, the patient-derived organoid (PDO), has become the newest method of investigating and testing numerous characteristics of the in vivo tumor. Initial studies have demonstrated the organoid’s advantages: PDOs are highly heterogeneous, may be maintained in culture indefinitely, and have the capability to model carcinogenesis and therapeutic response. However, limitations exist and questions remain that have yet to be addressed. Indeed, one of the challenges of using organoids is knowing whether the organoids are recapitulating normal or tumor tissue. Additionally, there seem to be limits on immortality of the organoids and the heterogeneity. Finally, without the stroma and Tumor Microenvironment (TME) in culture, the model is limited in its ability to test the response to immunotherapy-based drugs. Current research aims to develop a clinical pipeline utilizing organoids regularly as a diagnostic tool to evaluate therapeutic response, identify emergence of chemoresistance and perform targeted drug screens. Overall, PDOs are a burgeoning method of investigating GEA and are a powerful translational tool from bench to bedside.

Background. The majority of childhood acute myeloid leukemia (AML) patients lack a matched-related bone marrow transplant (BMT) donor in first remission. Procedure. Disease-free survival (DFS), overall survival (OS), relapse-free survival (RFS), and post-relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent-to-treat, ITT) or who received (as-treated, AT) only chemotherapy intensification. Results. Outcomes at 8 years post-induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P ≤ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15-2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 >12 months portends a much better OS for patients who relapse. Post-relapse treatment included BMT in 47% of patients. Conclusions. OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post-relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race.

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A dissertation submitted in fulfillment of the requirements for the degree of Master of Science to the Faculty of Science, University of the Witwatersrand, Johannesburg, 2019 / Lung cancer is the second most common form of cancer, accounting for approximately 13% of all new cancer cases.Of these cancers about 85% are non-small cell lung car cinoma (NSCLC). The epidermal growth factor (EGF) receptor is a protein kinase, which is crucial in a cell’s life cycle, from cell growth to cell death. The over expres sion of the EGF receptor is observed in many forms of cancers including NSCLC, breast, ovarian, colorecteral and brain cancers. Although there are current kinase inhibitors on the market, they su↵er from dose limiting toxicity or drug resistance due to mutations in the kinase domain of EGFR. The focus of this body of work is on the development of more ecacious EGFR inhibitors that can overcome drug resistance issues associated with current EGFR inhibitors, as well as being less toxic to the body. This class of inhibitor should be a covalent inhibitor, requiring it to react with the solvent exposed cysteine residue that is positioned on the edge of the ATP binding pocket of EGFR. The carbonyl group of the ketoamide should undergo a 1,2 addition with this cysteine residue to form a covalent, yet reversible bond. We report herein our progress towards the synthesis and biological evaluation of a novel class of quinazoline ketoamides. The key step in this synthesis route was to form a thiol on the quinazoline core. This was to be achieved by the addition of a thiocabamoyl group to the exposed alcohol 33 to form O-4-[(3-bromophenyl)amino] 7-methoxyquinazolin-6-yldimethylcarbamothioate 49, this compound successfully un derwent the Miyazaki-Newman-Kwart rearrangement, in which the oxygen and sulfur are exchanged to form S-4-[(3-bromophenyl)amino]-7-methoxyquinazolin-6-yldimethyl carbamothioate 48 , allowing the sulfur to be on the quinazoline core. the characterisation for this compound included 1H NMR spectroscopy and 13C NMR spec troscopy to confirm it’s structure. The same rearrangement was attempted on the 3 chloro-4-fluoro analogue O-4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin 6-yldimethylcarbamothioate 66, however this rearrangement was not successfully iso lated and characterised. The next step required the carbamoyl group to be removed to expose the thiol. Although this step was attempted on both analogues, the products 4-[(3-bromo)amino]-7-methoxyquinazolin-6-thiol 47 and 4-[(3-chloro-4-fluoro)amino] 7-methoxyquinazolin-6-thiol 67 were not successfully synthesised and isolated. / TL (2020)

The effects of rat fibroblast interferon and a retinoid (Ro 10-9359) on the transformed state were investigated using normal rat kidney (NRK) fibroblasts and its derived cell lines, B77-NRK, transformed by temperature-sensitive mutants of Rous sarcoma virus.

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Yes / The integrin family of cell surface receptors integrates cell-extracellular matrix interactions with the cell cytoskeleton and signalling across the cell membrane, resulting in an important role in cell adhesion, mobility and migration, proliferation, and survival. Changes in the number and identity of integrin receptors are common in cancer cells resulting in alteration of the ability of malignant cells to interact with the extracellular matrix, and promoting migration as well as facilitating survival outside the tumour normal environment. Beta3 integrins are potentially involved in every step of the metastatic process and expression of both alphaIIbbeta3 and alphaVbeta3 is correlated with metastatic ability of tumour cells. The recognition of the RGD binding motif common to the disintegrins and natural integrin ligands such as fibrinogen allowed the development of small molecule beta3 integrin antagonists, progressing from linear peptides containing the RGD sequence to cyclic peptides with well-defined conformation, and hence to small molecule peptidomimetics with improved pharmacological properties. In this review, we summarize the role of the beta3-subfamily of integrins when expressed in normal and tumour tissue, the development of small-molecule antagonists of beta3 integrins and their potential anti-cancer applications / EPSRC, Yorkshire Cancer Research