Evolution in the treatment of gastroesophageal reflux disease over the last century: from a crural-centered to a lower esophageal sphincter-centered approach and back.

The surgical management of gastroesophageal reflux disease (GERD) has evolved significantly over the past century, driven by increased understanding of the physiology of the reflux barrier, its anatomic components, and surgical innovation. Initially, emphasis was on reduction of hiatal hernias and crural closure as the etiology behind GERD was felt to be solely related to the anatomic alterations caused by hiatal hernias. With persistence of reflux-related changes in some patients despite crural closure, along with the development of what is now modern manometry and the discovery of a high-pressure zone at the distal esophagus, focus evolved to surgical augmentation of the lower esophageal sphincter (LES). With this transition to an LES-centric approach, attention shifted to reconstruction of the angle of His, ensuring sufficient intra-abdominal esophageal length, development of the now commonly employed Nissen fundoplication, and creation of devices that directly augment the LES such as magnetic sphincter augmentation. More recently, the role of crural closure in antireflux and hiatal hernia surgery has again received renewed attention due to the persistence of postoperative complications including wrap herniation and high rates of recurrences. Rather than simply preventing transthoracic herniation of the fundoplication as was originally thought, diaphragmatic crural closure has been documented to have a key role in re-establishing intra-abdominal esophageal length and contributing to the restoration of normal LES pressures. This progression from a crural-centric to a LES-centric approach and back has evolved along with our understanding of the reflux barrier and will continue to do so as more advances are made in the field. In this review, we will discuss the evolution of surgical techniques over the past century, highlighting key historical contributions that have shaped our management of GERD today.

Surgical training in the midst of a pandemic: a distributed general surgery residency program's response to COVID-19.

Summary: The coronavirus disease 2019 (COVID-19) pandemic has had a substantial impact on surgical training. We describe some of the challenges brought on by the pandemic and our program's province-wide response to them. We focus specifically on residents' provision of service, education and wellness.

Identifying Clinically Relevant Proteins for Targeted Analysis in the Development of a Multiplexed Proteomic Biomarker Assay.

In recent years, hundreds of candidate protein biomarkers have been identified using discovery-based proteomics. Despite the large number of candidate biomarkers, few proteins advance to clinical validation. Here, we describe a hypothesis driven approach to identify candidate biomarkers, previously characterized in the literature, with the highest probability of clinical applicability. A ranking method, the hypothesis directed biomarker ranking (HDBR) system, was developed to score candidate biomarkers based on seven criteria deemed important in the selection of clinically useful biomarkers. The HDBR system was initially applied to identify candidate biomarkers for the development of a diagnostic test for the early detection of colorectal cancer, but this system can be widely applied to identify biomarkers of relevance in different disease states, for diagnosis, prognostication, or any other specific purpose.

A hypothesis-directed approach to the targeted development of a multiplexed proteomic biomarker assay for cancer.

In recent years, hundreds of candidate protein biomarkers have been identified using discovery-based proteomics. Despite the large number of candidate biomarkers, few proteins advance to clinical validation. We propose a hypothesis-driven approach to identify candidate biomarkers, previously characterized in the literature, with the highest probability of clinical applicability. A ranking method, called the "hypothesis-directed biomarker ranking" (HDBR) system, was developed to score candidate biomarkers based on seven criteria deemed important in the selection of clinically useful biomarkers. To demonstrate its application, we applied the HDBR system to identify candidate biomarkers for the development of a diagnostic test for the early detection of colorectal cancer. One-hundred and fifty-one candidate biomarkers were identified from the literature and ranked based on the specified criteria. The top-ranked candidates represent a group of biomarkers whose further study and validation would be justified in order to expedite the development of biomarkers that could be used in a clinical setting.

Targeted cancer therapeutics: biosynthetic and energetic pathways characterized by metabolomics and the interplay with key cancer regulatory factors.

Reprogramming of energy metabolism has recently been added to the list of hallmarks that define cancer. Cellular metabolism plays a central role in cancer initiation and progression to metastatic disease. Genotypic and phenotypic metabolic alterations are seen throughout tumourigenesis, allowing cancer cells to sustain increased rates of proliferation. Furthermore, this shift fuels necessary substrates for nucleotide, protein, and lipid synthesis to support cell growth. Beyond the 'Warburg effect', the widely observed increase in the glycolytic processing of glucose in cancer cells, numerous other metabolic changes have been characterized in cancer. Metabolomics provides a valuable platform for the investigation of the metabolic perturbations that occur in different disease states using a systems biology approach to determine metabolic profiles of biological samples. As cell metabolism is a complex network of interdependent pathways, local alterations will have an impact on overall tumor metabolism. In this review, we will highlight particular pathways, including glycolysis, nucleotide biosynthesis, lipid metabolism, and bioenergetics with an eye towards selected metabolic targets that may provide a novel approach to therapeutic development. Specific regulatory factors, including Myc, p53, HIF-1 and mTOR are briefly highlighted, as well as the key signaling pathways that can affect cellular metabolism. To demonstrate the powerful utility of high-throughput metabolite profiling techniques, we present a practical example of the metabolomic profiling of metastatic cells derived from a lung cancer metastasis model.