The Impact of Mismatch Repair Status in Colorectal Cancer on the Decision to Treat With Adjuvant Chemotherapy: An Australian Population-Based Multicenter Study.

BACKGROUND: Testing for mismatch repair (MMR) status in colorectal cancer (CRC) may provide useful prognostic and predictive information. We evaluated the impact of such testing on real-world practice regarding adjuvant chemotherapy for patients with resected CRC. PATIENTS AND METHODS: A total of 175 patients with stage II and III mismatch repair-deficient (MMRD) CRC were identified from an Australian population-based study of incident CRCs. Their treatment decisions were compared with those for a cohort of 773 stage-matched patients with mismatch repair-proficient (MMRP) CRCs. The effect of MMR status, age, and pathologic characteristics on treatment decisions was determined using multiple regression analysis. RESULTS: Overall, 32% of patients in stage II and 71% of patients in stage III received adjuvant chemotherapy. Among the stage II patients, those with MMRD cancer were less likely to receive chemotherapy than were MMRP cases (15% vs. 38%; p < .0001). In this group, the treatment decision was influenced by age, tumor location, and T stage. MMR status influenced the treatment decision such that its impact diminished with increasing patient age. Among patients with stage III tumors, no difference was found in the chemotherapy rates between the MMRD and MMRP cases. In this group, age was the only significant predictor of the treatment decision. CONCLUSION: The findings of this study suggest that knowledge of the MMR status of sporadic CRC influences treatment decisions for stage II patients, in an era when clear recommendations as to how these findings should influence practice are lacking. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair found in 15% of sporadic colorectal cancers. Until recently, expert guidelines on the role of MSI as a valid biomarker in the selection of stage II patients for adjuvant chemotherapy were lacking. Conducted at a time when the clinical utility of routine MSI testing was unclear, this study found that clinicians were influenced by MSI status in selecting stage II patients for chemotherapy. Furthermore, the impact of MSI on treatment decisions was greatest in younger patients and declined progressively until age 80 years, when no effect was found.

α,ß-Unsaturated aldehyde pollutant acrolein suppresses cardiomyocyte contractile function: Role of TRPV1 and oxidative stress.

Air pollution is associated with an increased prevalence of heart disease and is known to trigger a proinflammatory response via stimulation of transient receptor potential vanilloid cation channels (TRPV1, also known as the capsaicin receptor). This study was designed to examine the effect of acrolein, an essential α,ß-unsaturated aldehyde pollutant, on myocardial contractile function and the underlying mechanism involved with a focus on TRPV1 and oxidative stress. Cardiomyocyte mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix MyoCam® system including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90 ), fura-2 fluorescence intensity (FFI) and intracellular Ca(2+) decay. Changes in apoptosis and TRPV1 were evaluated using Western blot analysis. The degree of oxidative stress was assessed using the ratio between reduced and oxidized glutathione. Results obtained revealed that exposure of cardiomyocytes to acrolein acutely compromised contractile and intracellular Ca(2+) properties including depressed PS, ± dL/dt and ΔFFI, as well as prolonged TR90 and intracellular Ca(2+) decay. In addition, acrolein exposure upregulated TRPV1 associated with an increase in both apoptosis and oxidative stress. However, the acrolein-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, as well as apoptosis (as evidenced by Bcl-2, Bax, FasL, Caspase-3 and -8), were negated by the reactive oxygen species (ROS) scavenger glutathione or the TRPV1 antagonist capsazepine. Collectively these data suggest that the α,ß-unsaturated aldehyde pollutant acrolein may play a role in the pathogenesis and sequelae of air pollution-induced heart disease via a TRPV1- and oxidative stress-dependent mechanism.

α,ß-Unsaturated aldehyde crotonaldehyde triggers cardiomyocyte contractile dysfunction: role of TRPV1 and mitochondrial function.

Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential α,ß-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca2+ decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca2+ property including depressed PS, ±dL/dt, ΔFFI and SERCA activity, as well as prolonged TR90 and intracellular Ca2+ decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1α and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism.

Inhibition of advanced glycation endproduct (AGE) rescues against streptozotocin-induced diabetic cardiomyopathy: Role of autophagy and ER stress.

Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques. Diabetes compromised cardiac contractile function shown as reduced fractional shortening and ejection fraction, enlarged left ventricular end systolic/diastolic diameters, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged shortening and relengthening duration as well as impaired intracellular Ca2+ homeostasis, the effects of which were alleviated or reversed by aminoguanidine treatment. Diabetes also inhibited autophagy, increased ER stress and phosphorylation of pro-hypertrophic signaling molecules Akt and mTOR, the effect of which was reversed by aminoguanidine. In vitro study revealed that methylglyoxal-derived AGE (MG-AGE) incubation in isolated cardiomyocytes promoted oxidation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and production of superoxide, the effects of which were negated by the autophagy inducer rapamycin, the ER stress chaperone TUDCA or the antioxidant N-acetylcysteine. Taken together, these data revealed that inhibition of AGE formation rescues against experimental diabetes-induced cardiac remodeling and contractile dysfunction possible through regulation of autophagy and ER stress.

The molecular characteristics of colonic neoplasms in serrated polyposis: a systematic review and meta-analysis.

Serrated polyposis is a rare disorder characterised by the presence of multiple serrated polyps in the large intestine, and an increased personal and familial risk of colorectal cancer. Knowledge of the molecular characteristics of colonic lesions which develop in this syndrome is fragmented, making it difficult to understand the underlying genetic basis of this condition. We conducted a systematic review and meta-analysis of all studies which evaluated the molecular characteristics of colorectal neoplasms found in individuals with serrated polyposis. We identified 4561 potentially relevant studies, but due to a lack of consensus in the reporting of findings, only fourteen studies were able to be included in the meta-analysis. BRAF mutation was found in 73% (95% CI 65-80%) of serrated polyps, 0% (95% CI 0-3%) of conventional adenomas and 49% (95%CI 33-64%) of colorectal cancers. In contrast, KRAS mutation was present in 8% (95% CI 5-11%) of serrated polyps, 3% (95% CI 0-13%) of conventional adenomas and 6% (95% CI 0-13%) of colorectal cancers. Absence of MLH1 immunostaining was found in 3% (95% CI 0-10%) of serrated polyps and 53% (95% CI 36-71%) of colorectal cancers. Overall, microsatellite instability was found in 40% (95% CI 18-64%) of colorectal cancers arising in the setting of serrated polyposis. Our results indicate that diverse molecular pathways are likely to contribute to the increased predisposition for colorectal cancer in individuals with serrated polyposis. We also propose a set of minimum standards for the reporting of future research in serrated polyposis as this is a rare syndrome and collation of research findings from different centres will be essential to identify the molecular mechanisms involved in the pathogenesis of this condition.

17-ß estradiol attenuates ovariectomy-induced changes in cardiomyocyte contractile function via activation of AMP-activated protein kinase.

Menopause increases the risk of cardiometabolic diseases in women. This circumstance is usually attributed to a deficiency in circulating estrogen levels although the underlying mechanism remains elusive. Given the pivotal role of AMP-activated protein kinase (AMPK) in the regulation of energy metabolism and cardiac function, this study was designed to examine the role of AMPK in estrogen deficiency and replacement-exerted cardiomyocyte responses. Adult female WT and AMPK kinase dead (KD) mice were subjected to bilateral ovariectomy (OVX) or sham operation. A cohort of ovariectomized mice received 17ß-estradiol (E2) (40µg/kg/day, i.p.) for 6 weeks. Mechanical and intracellular Ca(2+) properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90%-relengthening (TR90), and maximal velocity of shortening/relengthening (±dL/dt). Levels of AMPK, Akt JNK, ACC, SERCA, membrane Glut4, AS160 and PGC-1α were assessed using Western blot. OVX significantly decreased PS, ±dL/dt and intracellular Ca(2+) rise in responsible to electric stimulus, prolonged TR90 and intracellular Ca(2+) decay without affecting TPS and resting intracellular Ca(2+), the effects of which were reconciled by E2 replacement. Western blot analysis depicted that OVX suppressed phosphorylation of Akt AMPK and ACC although it promoted JNK phosphorylation, the effects of which were mitigated or significantly attenuated by E2 treatment in WT but not KD mice. Moreover, OVX procedure downregulated SERCA2a and membrane Glut4 while inhibiting AS160 phosphorylation without affecting PGC-1α levels. In vitro study revealed that E2 corrected cardiomyocyte contractile dysfunction elicited by OVX in cardiomyocytes from WT but not the AMPK kinase dead mice. Taken together, these data suggest that E2 treatment ameliorates estrogen deficiency-induced changes in cardiac contractile function possibly through an AMPK-dependent mechanism.

Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: role of Ca2+/calmodulin-activated protein kinase II.

Nitric oxide synthase (NOS) may be uncoupled to produce superoxide rather than nitric oxide (NO) under pathological conditions such as diabetes mellitus and insulin resistance, leading to cardiac contractile anomalies. Nonetheless, the role of NOS uncoupling in insulin resistance-induced cardiac dysfunction remains elusive. Given that folic acid may produce beneficial effects for cardiac insufficiency partially through its NOS recoupling capacity, this study was designed to evaluate the effect of folic acid on insulin resistance-induced cardiac contractile dysfunction in a sucrose-induced insulin resistance model. Mice were fed a sucrose or starch diet for 8 weeks before administration of folic acid in drinking water for an additional 4 weeks. Cardiomyocyte contractile and Ca(2+) transient properties were evaluated and myocardial function was assessed using echocardiography. Our results revealed whole body insulin resistance after sucrose feeding associated with diminished NO production, elevated peroxynitrite (ONOO(-)) levels, and impaired echocardiographic and cardiomyocyte function along with a leaky ryanodine receptor (RYR) and intracellular Ca(2+) handling derangement. Western blot analysis showed that insulin resistance significantly promoted Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, which might be responsible for the leaky RYR and cardiac mechanical dysfunction. NOS recoupling using folic acid reversed insulin resistance-induced changes in NO and ONOO(-), CaMKII phosphorylation, and cardiac mechanical abnormalities. Taken together, these data demonstrated that treatment with folic acid may reverse cardiac contractile and intracellular Ca(2+) anomalies through ablation of CaMKII phosphorylation and RYR Ca(2+) leak.