Social jetlag and prostate cancer incidence in Alberta\u27s Tomorrow Project: A prospective cohort study

We investigated the association of social jetlag (misalignment between the internal clock and socially required timing of activities) and prostate cancer incidence in a prospective cohort in Alberta, Canada. Data were collected from 7455 cancer-free men aged 35-69 years enrolled in Alberta\u27s Tomorrow Project (ATP) from 2001-2007. In the 2008 survey, participants reported usual bed- and wake-times on weekdays and weekend days. Social jetlag was defined as the absolute difference in waking time between weekday and weekend days, and was categorized into three groups: 0-\u3c1 h (from 0 to anything smaller than 1), 1-\u3c2 h (from 1 to anything smaller than 2), and 2+ h. ATP facilitated data linkage with the Alberta Cancer Registry in June 2018 to determine incident prostate cancer cases

Towards refining WCRF/AICR cancer prevention recommendations for red and processed meat intake: Insights from Alberta\u27s Tomorrow Project cohort

Current cancer prevention recommendations advise limiting red meat intake to \u3c500g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined the associations of processed meat derived from red vs. non-red meats with cancer risk in a prospective cohort of 26,218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median (IQR) follow-up of 13.3 (5.1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and gender. The median (IQR) consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat were 267.9 (269.9), 53.6 (83.3), and 11.9 (31.8), respectively. High intakes (4th Quartile) of processed meat from red meat was associated with increased risk of gastro-intestinal cancer Adjusted Hazard Ratio (AHR) (95% CI): 1.68 (1.09-2.57) and colorectal cancers AHR (95% CI): 1.90 (1.12-3.22), respectively in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggests that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence toward refining cancer prevention recommendations for red and processed meat intake

Harnessing the power of data linkage to enrich the cancer research ecosystem in Canada.

Objectives We will enrich the cancer research ecosystem in Canada through linking cancer registry and administrative health data to the Canadian Partnership for Tomorrow’s Health (CanPath) cohort and biobank. CanPath is Canada’s largest population health study, including 1% of the Canadian population, which seeks to investigate cancer development. Approach We are achieving record-level linkage of the CanPath harmonized dataset to provincial cancer registry data, and hospitalization and ambulatory care data from the Canadian Institutes of Health Information (CIHI). The CanPATH harmonized dataset includes comprehensive genetics, environment, lifestyle, and behaviour data. Our linkage activities will result in interprovincial data sharing, with centrally-held linked data, a first in Canadian history. We will demonstrate the CanPath-cancer registry-CIHI linkage potential by investigating the impact of the COVID-19 pandemic on healthcare utilization and outcomes among those with cancer. Results The linkage is ongoing and anticipated to be completed by September 2022. Linked data will be made available through the CanPath Data Safe Haven, a cloud-based solution that meets the legal requirements of the data sharing agreements and provincial privacy policies, and is accessible to researchers through secure access. The CanPath Data Safe Haven will be a federated data platform for Canadian researchers to access, analyze, and contribute research in a collaborative environment. By linking these datasets, this project will: address concerns related to accessibility of cancer data in Canada; bring more value to existing data; support an enhanced understanding of the impacts of cancer on marginalized populations; and create a more integrated approach to cancer data access and management. Conclusion CanPath will be the first program in Canadian history to combine the wealth of cohort resources with cancer registry and administrative health data in a central location at a national scale. We will provide a single point of access for researchers to conduct novel investigations into cancer development and outcomes

Single Nucleotide Polymorphisms That Increase Expression of the Guanosine Triphosphatase RAC1 Are Associated With Ulcerative Colitis

BACKGROUND & AIMS: RAC1 is a GTPase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases (IBD) are associated with dysregulation of immune defenses. We studied the role of RAC1 in IBD using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms (SNPs) in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 mRNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulphate sodium (DSS). RESULTS: We observed a genetic association between RAC1 with ulcerative colitis (UC) in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the SNPs rs10951982 (Pcombined UC = 3.3 × 10–8, odds ratio [OR]=1.43 [1.26–1.63]) and rs4720672 (Pcombined UC=4.7 × 10–6, OR=1.36 [1.19–1.58]). Patients with IBD who had the rs10951982 risk allele had increased expression of RAC1, compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected them against DSS-induced colitis. CONCLUSION: Studies of human tissue samples and knockout mice demonstrated a role for the GTPase RAC1 in the development of UC; increased expression of RAC1 was associated with susceptibility to colitis

Claudin 1 Mediates TNFα-Induced Gene Expression and Cell Migration in Human Lung Carcinoma Cells

Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT, it is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFβ1 and TNFα were used to induce EMT in human lung carcinoma A549 cells, we found an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFα and not the TGFβ1 that induced the fibroblast-like morphology changes. TNFα also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFα-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFα-induced molecular functional networks related to inflammation and cell movement. Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration and fibroblast-like morphology. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFα-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.published_or_final_versio

Role of Lipid Rafts in Enterohemorragic Escherichia coli 0157:H7 Mediated Hijacking of Host Cell Signalling Pathways to Induce Intestinal Injury

Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is a human intestinal pathogen, which can cause severe disease. EHEC O157:H7 is responsible for outbreaks of diarrhea and hemorrhagic colitis. EHEC produces a potent cytotoxin known as Vero (Shiga-like) cytotoxin, which causes diarrhea-associated hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in children. Current treatment remains predominantly supportive in nature because antibiotics and non-steroidal anti-inflammatory drugs exacerbate the condition. Therefore, alternative therapeutic approaches that will prevent the EHEC colonization without the release of toxins need to be delineated. Understanding the pathobiology of disease is likely to yield novel approaches to interrupt the infectious process. My hypothesis was that pathogen-derived effectors associate with lipid rafts and, thereby, promote the recruitment of host signal transduction proteins to lipid rafts in response to EHEC O157:H7 infection. In this thesis, specific host signalling pathways hijacked by EHEC O157:H7, through lipid raft signalling platforms, to elicit pathogenic effects are studied using complementary approaches, including epithelial model cell lines and an animal model of infection (Citrobacter rodentium challenge of mice). A lack of osteopontin resulted in decreased attaching effacing lesions and reduced colonic epithelial cell hyperplasia in response to C. rodentium infection. These findings suggest that C. rodentium, mimicking EHEC O157:H7 infection, is capable of utilizing host cell components to elicit its pathogenic effects. In vitro data showed that EHEC O157:H7 effector proteins manipulate cell signalling through lipid rafts employed as platforms to recruit and activate host second messengers. PKC and PI3K activation led to attaching and effacing lesions, disruption of tight junctions, and the initiation of both innate and adaptive host immune responses. The results pointed towards a role for atypical PKC in EHEC-induced attaching and effacing lesion formation. The role of lipid rafts in EHEC O157:H7 pathogenesis was also studied using Citrobacter rodentium-infected Niemann-pick type C (NPC) mice. Infection of NPC mice, which lack lipid rafts, with C. rodentium resulted in delayed colonization and delayed onset of attaching-effacing lesion formation, compared with infected wild type mice. C. rodentium-infected NPC mice also demonstrated reduced colonic epithelial hyperplasia and decreased secretion of the pro-inflammatory cytokine, interferon-γ. Taken together, the findings presented in this thesis highlight the importance of host cell signal transduction cascades in EHEC O157:H7 disease pathogenesis, and demonstrate a role for lipid rafts and OPN in mediating host cell signaling responses to non-invasive enteric microbial pathogens.Ph