Investigations into Photosensitized Racemization of Atropisomers Guided by Density Functional Theory and Machine Learning

While much work has been devoted to the enantioselective synthesis of atropisomers, methods for facilitating their enantiomerization remain underexplored. This thesis focuses on the use of computational chemistry and representation learning to elucidate the mechanism of photosensitized racemization of structurally diverse, sterically hindered biaryls and better understand their singlet and triplet properties. A survey of molecular representations and associated representation learning models is presented. Molecular representations are important for understanding and predicting properties of and relationships between chemicals. The advantages and disadvantages of common representations including strings, vectors, graphs, and coordinates are discussed. Simple linear and models are introduced in the context of molecular modeling along with nonlinear and representation learning techniques such as graph neural networks, recurrent neural networks, and transformers. The importance of selecting appropriate representations that capture relevant molecular information is emphasized, as it directly impacts the accuracy and interpretability of modeling efforts. The second chapter delves into the specific topic of photosensitized racemization of sterically hindered biaryls. Density functional theory (DFT) calculations are employed to study the singlet and triplet states of these biaryls, providing insights into their electronic structures and energy landscapes. Experimental results using iridium photosensitizers demonstrate the feasibility of photoracemization of clinically relevant heterobiaryls and lend legitimacy to computed rotational barriers. Systematic DFT investigations were conducted to examine steric and electronic trends. A simple parametric model was developed and found to accurately predict rotational barriers of biphenyls by evaluating steric contributions of each substituent. Additionally, calculations for a series of isosteric arenes with varying triplet energies revealed that rotational barriers decrease upon excitation in a manner proportional to the triplet energy and ground state barrier. A high throughput virtual screening approach was taken to develop a general model for predicting ground and excited state rotational barriers of biaryls. A representative dataset was generated using virtual cross coupling of commercially available fragments. A multi-tiered computational workflow was used to collect training data for a neural network model. Using a novel fingerprint representation that encodes localization information, transition state energies were estimated with high accuracy

Clinical benefit of surveillance after resection of pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.

BACKGROUND The value of routine surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear, and expert guidelines offer conflicting recommendations. This study is a systematic review of evidence for surveillance programs. METHODS A systematic review of studies evaluating different surveillance methods was undertaken. A meta-analysis was performed for those studies reporting rates of asymptomatic recurrence, treatment of recurrence and overall survival, according to different surveillance methods. RESULTS Ten studies were included in the literature review, with five studies appropriate for meta-analysis (1596 patients). Patients within active surveillance programs were more likely to have recurrence detected at an asymptomatic stage (Pooled Rate: 49.3% vs. 19.1%, p = 0.043). Within studies reporting these outcomes, patients with asymptomatic recurrence were more likely to receive treatment for recurrence (Odds Ratio 3.49; 95% CI: 1.73-7.07; p < 0.001) and had longer overall survival (Mean Difference: 9.5 months; 95% CI: 4.1-14.8; p < 0.001) than those with symptoms at time of recurrence. DISCUSSION Routine surveillance after surgery for PDAC appears to detect more patients at an asymptomatic stage. Data from these non-randomised trials also suggest that treatment rates and survival may be superior in patients were recurrence is detected when asymptomatic. As such, these data suggest that routine surveillance may improve patient outcomes, although an appropriately conducted trial would be required to address concerns that various sources of bias may be affecting these results

Report from the 19th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Winnipeg, Manitoba; 29–30 September 2017

The 19th annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Winnipeg, Manitoba, 29–30 September 2017. The WCGCCC is an interactive multidisciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer