Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.

PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

Decreased salivary alpha-amylase reactivity for excluded young women after a speech task.

Salivary alpha-amylase (sAA) has gained popularity as an easily collected biomarker for sympathetic nervous system activation, and research has shown increases in sAA after completing experimental stress tasks in certain groups. However, recent work suggests that salivary cortisol, another stress biomarker, is suppressed after a speech task among experimentally induced exclusion in young women. The present analysis investigated the sAA response in biologically female undergraduates (n=31) who completed a game of Cyberball and then a speech anticipation task. Results showed that women in the social exclusion experimental group had a greater decrease in sAA compared to young women in the inclusion group after the speech task. Results of this study provide support for stress response suppression in women who have experienced social exclusion. The present findings provide pilot evidence for future, larger studies to advance the tend-and-befriend theory.

Cardiorespiratory fitness and submaximal exercise dynamics in normal-weight obesity and metabolically healthy obesity.

PURPOSE: Cardiorespiratory fitness (CRF) is critical for cardiovascular health. Normal-weight obesity (NWO) and metabolically healthy obesity (MHO) may be at increased risk for cardiovascular disease, but a comparison of CRF and submaximal exercise dynamics against rigorously defined low- and high-risk groups is lacking. METHODS: Four groups (N = 40; 10/group) based on body mass index (BMI), body fat %, and metabolic syndrome (MetS) risk factors were recruited: healthy controls (CON; BMI 18.5-24.9 kg/m2, body fat < 25% [M] or < 35% [F], 0-1 risk factors), NWO (BMI 18.5-24.9 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F]), MHO (BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 0-1 risk factors), or metabolically unhealthy obesity (MUO; BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 2 + risk factors). All participants completed a V ˙ O2peak test on a cycle ergometer. RESULTS: V ˙ O2peak was similarly low in NWO (27.0 ± 4.8 mL/kg/min), MHO (25.4 ± 6.7 mL/kg/min) and MUO (24.6 ± 10.0 mL/kg/min) relative to CON (44.2 ± 11.0 mL/kg/min) when normalized to total body mass (p's < 0.01), and adjusting for fat mass or lean mass did not alter these results. This same differential V ˙ O2 pattern was apparent beginning at 25% of the exercise test (PGroup*Time < 0.01). CONCLUSIONS: NWO and MHO had similar peak and submaximal CRF to MUO, despite some favorable health traits. Our work adds clarity to the notion that excess adiposity hinders CRF across BMI categories. CLINICALTRIALS: gov registration: NCT05008952.

Postprandial triglycerides across the aging spectrum: A secondary analysis utilizing an abbreviated fat tolerance test.

BACKGROUND & AIMS: Elevated postprandial triglycerides are an independent cardiovascular disease risk factor and observed in older adults. However, differences in postprandial triglycerides across the spectrum of adulthood remain unclear. METHODS AND RESULTS: We performed a secondary analysis of six studies where adults (aged 18-84 years; N = 155) completed an abbreviated fat tolerance test (9 kcal/kg; 70% fat). Differences in postprandial triglycerides were compared in those ≥50 and <50 years and by decade of life, adjusting for sex and BMI. Compared to those <50 years, participants ≥50 years had higher fasting, 4 h, and Δ triglycerides from baseline (p's < 0.05). When examining triglyceride parameters by decade, no differences were observed for fasting triglycerides, but 50 s, 60 s, and 70s-80 s displayed greater 4 h and Δ triglycerides versus 20 s (p's ≤ 0.001). The frequency of adverse postprandial triglyceride responses (i.e., ≥220 mg/dL) was higher in participants ≥50 versus <50 years (p < 0.01), and in 60 s compared to all other decades (p = 0.01). CONCLUSION: Older age was generally associated with higher postprandial triglycerides, with no divergence across the spectrum of older adulthood. In our sample, postprandial triglyceride differences in older and younger adults were driven by those >50 years relative to young adults in their 20 s. REGISTRATION: N/A (secondary analysis).

Whole-body bone mineral density and markers of bone homeostasis in adults with normal-weight obesity.

Background: Normal-weight obesity (NWO) describes individuals with a normal body mass index (BMI), but high body fat percent. NWO are at-risk for cardiometabolic diseases, but little is known about their bone health. Methods: Adults (N = 24) were classified as NWO (n = 12; 5M/7F) or low body fat percent controls (Con; n = 12; 6M/6F). Body composition and whole-body bone mineral density (BMD) were assessed using DXA. A serum bioplex assay was performed to examine markers related to bone formation and resorption. Results: In addition to higher body fat percent and visceral fat, NWO had lower whole-body BMD relative to Con (p's < 0.05). Circulating leptin was higher in NWO than Con (p < 0.05). Two biomarkers generally associated with lower bone mass - sclerostin and parathyroid hormone - were higher in NWO compared to Con (p's < 0.05). Conclusion: In this preliminary study, adults with NWO displayed lower whole-body BMD alongside evidence of bone resorption. Impaired bone health may be another subclinical risk factor present in NWO.

Adverse childhood experiences and obesity linked to indicators of gut permeability and inflammation in adult women.

Gut permeability may increase cardiovascular disease risk by allowing bacterial components (e.g., lipopolysaccharide or LPS) to enter the bloodstream, leading to low-grade inflammation. People with adverse childhood experiences (ACEs) consistently display evidence of chronic inflammation, but the source of this inflammation, and whether gut permeability may contribute, is unknown. Moreover, whether ACE status may further perturb obesity-associated gut permeability and inflammation is unknown. Women (N = 79, aged 18-84y) free of cardiometabolic diseases and inflammatory conditions and not regularly taking anti-inflammatory medications were included in a 2 × 2 factorial design with low or high ACE status (either 0 ACEs or 3+ ACEs) and body mass index (BMI) (either normal-weight [18.5-24.9 kg/m2; NW] or obesity [>30 kg/m2; OB]) as factors (n = 15-27/group). Serum LPS binding protein (LBP), soluble CD14 (sCD14), fatty-acid binding protein-2 (FABP2), LPS core IgM, and the ratio of LBP:sCD14 were used as indicators of gut permeability. Inflammatory markers C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were also measured. Data were analyzed using 2-way ANCOVA (age-adjusted). LBP, LBP:sCD14 and FABP2 were higher in OB versus NW, regardless of ACE status (PBMI < 0.05). Higher ACE status was associated with increased circulating LBP:sCD14 and LPS core IgM (PACE < 0.05). sCD14 was unrelated to BMI or ACEs. CRP was elevated in OB versus NW (PBMI < 0.001) and tended to be higher with 3+ ACEs compared to 0 ACEs (PACE = 0.06). Moreover, TNF-α was greater in 3+ ACEs relative to 0 ACEs (PACE = 0.03). IL-6 was unrelated to BMI or ACE status. No interaction effects were observed for any marker of gut permeability or inflammation. In sum, ACE status and obesity were independently associated with evidence of gut permeability and systemic inflammation but did not interact in relation to indicators of gut permeability.

Hypocortisolemic reactivity to acute social stress among lonely young women.

We examined biopsychosocial stress of acute social pain in relation to chronic loneliness. Hypotheses: 1) Cyberball exclusion (vs. inclusion) would be associated with lower cortisol reactivity to a speech task, and 2) loneliness would moderate the relationship between social exclusion and cortisol reactivity to a speech task, such that higher loneliness would be linked to lower cortisol. Participants (n = 31, women, aged 18-25, 51.6% non-Hispanic white) were randomized to be excluded or included in a game of Cyberball, then completed a speech task. Salivary cortisol was measured at baseline, pre-speech, post-speech, and 15 minutes post-speech. Cortisol reactivity was calculated using area under the curve-increase (AUCi). ANOVA revealed a non-significant, meaningful effect of Cyberball exclusion on cortisol AUCi (p=.103, ηp2=.10), accounting for contraceptive use. Moderation analysis revealed among women with high loneliness, women in the exclusion condition had significantly lower cortisol reactivity than women in the inclusion condition (p=.001). For women with low and medium loneliness, there were no significant differences by Cyberball condition. In sum, lonely young women who are excluded may have hypocortisolemic responses to social stress. Results are consistent with literature suggesting that chronic stress is linked to lower cortisol responses, which is linked to negative physical health outcomes.

Postprandial triglycerides and fibroblast growth factor 19 as potential screening tools for paediatric non-alcoholic fatty liver disease.

BACKGROUND: Better screening tools for paediatric NAFLD are needed. We tested the hypothesis that the postprandial triglyceride (TG) and fibroblast growth factor 19 (FGF19) response to an abbreviated fat tolerance test (AFTT) could differentiate adolescents with NAFLD from peers with obesity and normal weight. METHODS: Fifteen controls with normal weight (NW), 13 controls with obesity (OB) and 9 patients with NAFLD completed an AFTT. Following an overnight fast, participants consumed a high-fat meal. TG and FGF19 were measured at baseline and 4 h post-meal. Liver steatosis and fibrosis were measured via Fibroscan. RESULTS: Fasting TG and FGF19 did not differ among groups; 4 h TG in the NAFLD and OB groups were greater (197 ± 69 mg/dL; 157 ± 72 mg/dL, respectively) than NW (105 ± 45 mg/dL; p < 0.05) and did not differ from one another. Within the entire cohort, 4 h TG were stratified by high and low steatosis. Adolescents with high steatosis had 98% greater 4 h TG than adolescents with low steatosis. 4 h FGF19, but not fasting FGF19, was higher in children with low steatosis compared with high steatosis (p < 0.05). Using area under the receiver operating curve (AUROC), the only biochemical outcome with diagnostic accuracy for NAFLD was 4 h TG (0.77 [95% CI: 0.60-0.94; p = 0.02]). CONCLUSIONS: The postprandial TG response is increased in adolescents with obesity with hepatic steatosis, with or without NAFLD. Our preliminary analysis demonstrates 4 h TG differentiate patients with NAFLD from those without, supporting a role for the AFTT as a screening tool for paediatric NAFLD.

A survey of aquatic macroinvertebrates in a river from the dry corridor of Nicaragua using biological indices and DNA barcoding.

Aquatic macroinvertebrates are widely used as indicators for water quality assessment around the world. Modern strategies for environmental assessment implement molecular analysis to delimitate species of aquatic macroinvertebrates. Delimitation methods have been established to determine boundaries between species units using sequencing data from DNA barcodes and serve as first exploratory tools for taxonomic revisions. This is useful in regions such as the neotropics where aquatic macroinvertebrate habitats are threatened by human interference and DNA databases remain understudied. We asked whether the biodiversity of aquatic macroinvertebrates in a stream in Nicaragua, within the Central American Dry Corridor, could be characterized with biological indices and DNA barcoding. In this study, we combined regional biological indices (BMWP-CR, IBF-SV-2010) along with distance-based (ASAP, BIN) and tree-based (GMYC, bPTP) delimitation methods, as well as nucleotide BLAST in public barcode databases. We collected samples from the upper, middle, and low reaches of the Petaquilla river. The three sites presented excellent water quality with the BMWP-CR index, but evidence of high organic pollution was found in the middle reach with the IBF-SV-2010 index. We report a total of 219 COI sequences successfully generated from 18 families and 8 orders. Operational taxonomic units (OTUs) designation ranged from 69 to 73 using the four methods, with a congruency of 92% for barcode assignation. Nucleotide BLAST identified 14 species (27.4% of barcodes) and 33 genera (39.3% of barcodes) from query sequences in GenBank and BOLD system databases. This small number of identified OTUs may be explained by the paucity of molecular data from the Neotropical region. Our study provides valuable information about the characterization of macroinvertebrate families that are important biological indicators for the assessment of water quality in Nicaragua. The application of molecular approaches will allow the study of local diversity and further improve the application of molecular techniques for biomonitoring.

Postprandial triglycerides, endothelial function, and inflammatory cytokines as potential candidates for early risk detection in normal-weight obesity.

PROBLEM: Normal-weight obesity (NWO) is associated with increased cardiovascular disease (CVD) risk. However, NWO's clinical presentation is often unremarkable based on common risk factors. We examined whether CVD risk factors not routinely measured clinically including postprandial triglycerides, flow-mediated dilation (FMD), and inflammatory cytokines would be abnormal in NWO, consistent with their future risk. METHODS: Individuals were recruited into 3 groups (n = 10/ group): controls (Con), NWO, and metabolic syndrome (MetS). Con was defined as a normal body mass index (BMI), < 25% (M) or < 35% (F) body fat, and < 1 International Diabetes Federation (IDF) criteria. NWO were above this body fat cutoff while maintaining a normal BMI and MetS was defined per the IDF. Participants underwent an abbreviated fat tolerance test (i.e., difference in fasting and 4 h triglycerides following a high-fat meal [9 kcal/kg; 73% fat)] and fasting and postprandial lipid and glucose metrics, as well as FMD were measured. A T cell cytokine bioplex was also performed using fasting serum. RESULTS: NWO and MetS had similar body fat% and both were higher than Con (p < 0.0001). Despite having similar fasting triglycerides to Con, NWO had 4-hour triglycerides 66% greater than Con, but 46% lower than MetS (p < 0.01). FMD decreased in all groups after the high-fat meal (p < 0.0001). MetS displayed lower fasting FMD than Con, and NWO was similar to both groups (p < 0.05). No group differences were observed with postprandial FMD and the majority of fasting cytokines assessed. However, MetS exhibited higher fasting TNF-α than Con (p < 0.05), and NWO was similar to both groups. CONCLUSIONS: Overall, NWO was associated with higher postprandial triglycerides than Con, but displayed little evidence of impaired vascular health or inflammation.

Associations between Internalized Weight Stigma and Visceral Adipose Tissue Status are Observed in Women but not Men.

Purpose: This study investigated the relationship between internalized weight stigma (IWS) and visceral adipose tissue (VAT), an independent predictor of cardiometabolic disease risk, and how this relationship is moderated by gender. Methods: Participants (N=70, 81% white, 51% women, M age=30.4±7.8 years, M BMI=28.7±5.5 kg/m2, M BF%=32.4±8.9%) completed in-lab measures of demographic factors (age, gender, race/ethnicity), IWS (Weight Bias Internalization Scale-Modified; WBIS-M) and visceral adiposity. VAT mass was measured via DXA. Primary moderation analysis investigated the effect of gender on associations between IWS and VAT mass. Covariates were age, race/ethnicity, and total body fat percent. Results: After adjusting for covariates in the primary moderation analysis, WBIS-M scores displayed a positive association with VAT mass (b=32.58, p=0.033). The relationship between WBIS-M scores and VAT mass was moderated by gender (b=68.63, p=0.020); no relationship between WBIS-M scores and VAT mass was observed in men (b=-2.71, p=0.894), whereas a positive association between WBIS-M scores and VAT mass was observed in women (b=65.92, p=0.003). Conclusions: Internalization of weight stigma was associated with greater visceral adiposity in women across the BMI spectrum, suggesting it as a chronic stressor. Future studies should investigate directionality and causality of this relationship to elucidate mechanisms of stigma-associated CVD risk.

Comparison of a Standardized High-Fat Meal versus a High-Fat Meal Scaled to Body Mass for Measuring Postprandial Triglycerides: A Randomized Crossover Study.

Post-meal triglycerides are an independent cardiovascular disease (CVD) risk factor, but the ideal high-fat meal formulation has yet to be standardized and is one challenge prohibiting widespread clinical adoption of postprandial triglyceride assessment. Two general approaches often used are giving individuals a high-fat meal scaled to body weight or a standardized high-fat meal containing a set fat bolus. A recent expert panel statement has endorsed the latter, specifying 75 g of fat as an appropriate fat dosage. Despite this recommendation, no study to date has tested whether there is a difference in postprandial triglycerides or if risk classification is affected based on these different approaches. We recruited 16 generally healthy individuals with roughly equal distribution among body mass index (BMI)class (n = 5-6/per BMI category) and sex (n = 2-3 M/F) within each BMI class. Each participant underwent two abbreviated fat tolerance tests separated by ~1 week: one with a scaled to body weight high-fat meal (9 kcal/kg; 70% fat) and a standardized meal containing 75 g of fat (70% fat). Fasting, 4 h, and absolute change in triglycerides across the entire sample and within each BMI category were similar regardless of high-fat meal. Only one participant with obesity had discordant postprandial responses between the fat tolerance tests (i.e., different CVD risk classification). These findings suggest that, within a certain range of fat intake, generally healthy individuals will have a similar postprandial triglyceride response. Considering the greater convenience of utilizing standardized high-fat meals, our data suggest that a standardized high-fat meal may be acceptable for large-scale studies and clinical implementation.

Who would benefit most from postprandial lipid screening?

BACKGROUND & AIMS: Individuals with fasting triglycerides (TG) <150 mg/dL can experience a deleterious postprandial TG response ≥220 mg/dL to a high-fat meal (HFM). The purpose of this study was to identify individuals based on fasting TG that would benefit most from additional postprandial screening. METHODS: We conducted a secondary analysis of 7 studies from our laboratories featuring 156 disease-free participants (64 M, 92 F; age 18-70 years; BMI 18.5-30 kg/m2). Participants observed a 10-12 h overnight fast, after which they consumed an HFM (10-13 kcal/kg body mass; 61-64% kcal from fat). Two methods were used to identify lower and upper fasting TG cut points. Method 1 identified the lower limit as the TG concentration at which ≥90% of individuals presented peak postprandial TG (PPTG) <220 mg/dL and the upper limit as the concentration which ≥90% of individuals presented PPTG ≥220 mg/dL. Method 2 utilized receiver operating characteristic (ROC) curves and identified the lower limit as the fasting TG concentration where sensitivity was ≈95% and the upper limit as the concentration at which specificity was ≈95%. RESULTS: In Method 1, 90% of individuals with fasting TG >130 mg/dL (>1.50 mmol/L) exhibited PPTG ≥220 mg/dL (≥2.50 mmol/L), while 100% of individuals with fasting TG <66 mg/dL (0.75 mmol/L) had PPTG that did not exceed 220 mg/dL (2.50 mmol/L). In Method 2, when sensitivity was ≈95%, the corresponding fasting TG concentration was 70 mg/dL (0.79 mmol/L). When specificity was ≈95%, the corresponding fasting TG concentration was 114 mg/dL (1.29 mmol/L). Based on methods 1 and 2, there was a moderate positive association (r = 0.37, p < 0.004) between fasting and PPTG for individuals with fasting TG between 70 and 130 mg/dL (0.79-1.50 mmol/L), in which 24% exhibited PPTG ≥220 mg/dL (≥2.50 mmol/L) while 76% did not. CONCLUSIONS: Postprandial TG testing is likely most useful for individuals with fasting TG concentrations between 70 and 130 mg/dL (0.79-1.50 mmol/L). Outside of this range, postprandial TG responses are largely predictable. Establishing a specific patient group for which postprandial TG testing is most useful may lead to earlier risk detection in these individuals.

The effect of black coffee on fasting metabolic markers and an abbreviated fat tolerance test.

BACKGROUND & AIMS: Coffee is typically prohibited prior to metabolic assessment in clinical and research settings. However, whether coffee meaningfully alters fasted metabolic testing or the results of a fat tolerance test is unclear. We investigated whether allowing black coffee intake within a fast prior to blood work affected fasting triglycerides (TG) and glucose, as well as the postprandial lipemic and glycemic response following an abbreviated fat tolerance test (AFTT). METHODS: Participants completed two randomized AFTTs separated by at least 1 week. For each AFTT, participants arrived into the laboratory following a 10 h overnight fast and consumed either 8 oz of water or black coffee. Thirty minutes later, a baseline blood draw was collected. Immediately following, participants consumed a standardized high-fat shake (70% fat; 9 kcal/kg body mass), vacated the laboratory, and returned 4 h later for a follow-up blood draw. RESULTS: Ten healthy individuals (5M, 5F; age: 22.9 ± 3.8 years; BMI: 24.3 ± 2.6 kg/m2) completed the study. There was no difference between trials with regard to baseline TG (MD = 1.7 mg/dL; p = 0.74), 4 h TG (MD = 2.7 mg/dL; p = 0.75), Δ TG (MD = 4.4 mg/dL; p = 0.52), or % change TG (MD = 7.7%; p = 0.99). Similarly, following coffee consumption, baseline glucose was unchanged relative to water (MD = 0.4 mg/dL; p = 0.84) and there were no differences in postprandial glucose measures, including 4 h (MD = 0.9 mg/dL; p = 0.58), Δ (MD = 1.3 mg/dL; p = 0.31), and % change in glucose (MD = 1.6%; p = 0.29). CONCLUSION: In our small study sample, coffee intake prior to an AFTT did not affect baseline or postprandial TG and glucose. Therefore, coffee intake prior to an AFTT may not affect its validity.

Fibroblast Growth Factor 19: Potential modulation of hepatic metabolism for the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease that is becoming more prevalent in concert with obesity and poor lifestyle habits. Although NAFLD is treatable via lifestyle modification in early stages, more advanced liver pathologies (eg non-alcoholic steatohepatitis [NASH]) are harder to reverse. There is no Food and Drug Administration approved pharmacological treatment for NAFLD, and little research has been done to identify compounds that target key NAFLD mechanisms. Bile acids and bile acid receptors have been implicated in NAFLD pathogenesis and modulating bile acids and bile acid receptors has recently been targeted as a therapeutic treatment option for NAFLD. Fibroblast growth factor 19 (FGF19), a nutritionally regulated post-prandial hormone, is a chief regulator of bile acid metabolism and an important player in lipid and carbohydrate metabolism, including key mechanisms of NAFLD pathogenesis. In this review, we discuss recent findings related to FGF19-regulated processes involved in the pathogenesis of NAFLD. We summarize known and conjectural frameworks and limitations for the clinical application of FGF19-targeted therapies as they relate to NAFLD.

The cost of failed first-line cancer treatment related to continued smoking in Canada.

Background: Smoking by cancer patients and survivors causes adverse cancer treatment outcomes, but little information is available about how smoking can affect cancer treatment costs. Methods: We developed a model to estimate attributable cancer treatment failure because of continued smoking after a cancer diagnosis (afs). Canadian health system data were used to determine the additional treatment cost for afs for the most common cancers in Canada. Results: Of 206,000 patients diagnosed with cancer annually, an estimated 4789 experienced afs. The annual incremental cost associated with treating patients experiencing afs was estimated at between $198 million and $295 million (2017 Canadian dollars), reflecting an added incremental cost of $4,810-$7,162 per patient who continued to smoke. Analyses according to disease site demonstrated higher incremental costs where the smoking prevalence and the cost of individual second-line cancer treatment were highest. Of breast, prostate, colorectal, and lung cancers, lung cancer was associated with the highest incremental cost for treatment after afs. Conclusions: The costs associated with afs in Canada after a cancer diagnosis are considerable. Populations in which the smoking prevalence and treatment costs are high are expected to benefit the most from efforts aimed at increasing smoking cessation capacity for patients newly diagnosed with cancer.

Phytochemicals affect T helper 17 and T regulatory cells and gut integrity: implications on the gut-bone axis.

The pathology of osteoporosis is multifactorial, but a growing body of evidence supports an important role of the gut-bone axis, especially in bone loss associated with menopause, rheumatoid arthritis, and periodontal disease. Aberrant T cell responses favoring an increase in the ratio of T helper 17 cells to T regulatory cells play a critical role in the underlying etiology of this bone loss. Many of the dietary phytochemicals known to have osteoprotective activity such as flavonoids, organosulfur compounds, phenolic acids, as well as the oligosaccharides also improve gut barrier function and affect T cell differentiation and activation within gut-associated lymphoid tissues and at distal sites. Here, we examine the potential of these phytochemicals to act as prebiotics and immunomodulating agents, in part targeting the gut to mediate their effects on bone.

Exercise and intestinal permeability: another form of exercise-induced hormesis?

Regular aerobic exercise has numerous benefits on human physiology, arguably by serving as a hormetic stressor resulting in positive adaptations over time. It has long been known that aerobic exercise at a variety of intensities and durations induces intestinal permeability, which is a feature of many pathologies of the gastrointestinal tract and metabolic diseases. Given the health benefits of exercise, it seems unlikely that intestinal permeability induced by exercise outweighs the positive adaptations. In fact, a growing body of evidence suggests adoption of exercise regimens lasting weeks to months improves indicators of intestinal permeability. In this brief review, we summarize factors contributing to acute exercise-induced intestinal permeability and what is known about chronic exercise and the gut barrier. Additionally, we outline known and theoretical adaptations of the gut to chronic exercise that may explain emerging reports that exercise improves markers of gut integrity.

Half-life extension of peptidic APJ agonists by N-terminal lipid conjugation.

Agonism of the endothelial receptor APJ (putative receptor protein related to AT1; AT1: angiotensin II receptor type 1) has the potential to ameliorate congestive heart failure by increasing cardiac output without inducing hypertrophy. Although the endogenous agonist, pyr-apelin-13 (1), has shown beneficial APJ-mediated inotropic effects in rats and humans, such effects are short-lived given its extremely short half-life. Here, we report the conjugation of 1 to a fatty acid, providing a lipidated peptide (2) with increased stability that retains inotropic activity in an anesthetized rat myocardial infarction (MI) model. We also report the preparation of a library of 15-mer APJ agonist peptide-lipid conjugates, including adipoyl-γGlu-OEG-OEG-hArg-r-Q-hArg-P-r-NMeLeuSHK-G-Oic-pIPhe-P-DBip-OH (17), a potent APJ agonist with high plasma protein binding and a half-life suitable for once-daily subcutaneous dosing in rats. A correlation between subcutaneous absorption rate and lipid length/type of these conjugates is also reported.