A single bout of aerobic exercise improves executive function; however, the mechanism for the improvement remains unclear. One proposal asserts that an exercise-mediated increase in cerebral blood flow (CBF) enhances the efficiency of executive-related cortical structures. Here, participants completed separate 10-min sessions of moderate to heavy intensity aerobic exercise, a hypercapnic environment (i.e., 5% CO2), and a non-exercise and non-hypercapnic control condition. The hypercapnic condition was included because it produces an increase in CBF independent of metabolic demands. An estimate of CBF was achieved via transcranial doppler ultrasound and near-infrared spectroscopy that provided measures of middle cerebral artery blood velocity (BV) and deoxygenation (HHb), respectively. Exercise intensity was adjusted to match participant-specific change in BV and HHb associated with the hypercapnic condition. Executive function was assessed prior to and after each session via antisaccades (i.e., saccade mirror-symmetrical to a target) because the task is mediated via the same executive networks that demonstrate task-dependent modulation following single- and chronic-bouts of aerobic exercise. Results showed that hypercapnic and exercise conditions were associated with comparable BV and HHb changes, whereas the control condition did not produce a change in either metric. In terms of antisaccade performance, the exercise and hypercapnic - but not control - conditions demonstrated improved post-condition reaction times (RT), and the magnitude of the hypercapnic and exercise-based increase in estimated CBF was reliably related to the post-condition improvement in RT. Accordingly, results evince that an increase in CBF represents a reliable candidate for a post-exercise improvement in executive function.
Introduction: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. Methods: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d•wk −1 ; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. Results: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = −1) relative to CTRL/SED. Conclusion: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.
Introduction: Post-chemotherapy residual masses (PCRMs) may contain persistent cancer or teratoma in more than 50% of patients with metastatic non-seminomatous germ cell tumours (mNSGCTs). Retroperitoneal lymph node dissection (RPLND) is curative, but controversy exists about selection criteria for surgery. A validated prediction model by Vergouwe et al (2007) based on over 1000 patients was evaluated at our centre. Methods: mNSGCT patients treated with RPLND for PCRMs were identified from an electronic database. Typographical errors in the model were identified and corrected using their 2003 publication, but retaining the 2007 coefficients. Six clinical variables were included in the model and the calculated probability of benign tissue was compared with pathology. "Benign tissue only" was considered a positive test outcome in patients with a predicted probability of "benign tissue only" greater than 70%. Results: Fifty-two (52) mNSGCT patients between 1980 and 2014 were evaluable. Median age was 32 years (range 17-52) and International Germ Cell Consensus Classification (IGCCC) prognostic stages were: good 46.2%, intermediate 32.7%, and poor 21.2%. Most patients received bleomycin/etoposide/cisplatin (BEP) chemotherapy and full bilateral RPLND. Pathology showed residual cancer or teratoma in 31 patients (59.6%) and benign findings in 21 patients (40.6%). Positive and negative predictive values and accuracy were 100%, 69%, and 73%, respectively. Conclusions: "Benign tissue only" was found in 100% of patients in whom this was predicted using our pre-determined criteria. This study involved a limited number of patients, but confirms the potential value of the Vergouwe et al model. Routine use of this prediction model in clinical practice should be tested for mNSGCT patients with PCRMs.
Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofibre characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofibre cross-sectional area was not different between groups. There were more smaller-sized fibers in HFD-EX (p<0.05 vs. CON), and more fibrosis in HFD-SED (p<0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p=0.059) and more fibro-adipogenic progenitors (FAPs) in HFD-EX (p<0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB, was markedly reduced in the insterstitium of HFD-EX (p<0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise, reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty Bullets: • Exercise improves muscle architecture in mice with preneoplastic colorectal lesion • Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions
Background: Consuming adequate dietary fiber is a promising strategy for reducing systemic inflammation. Objective: To evaluate relationships between dietary fiber intake, markers of metabolic endotoxemia, and systemic inflammation in adults. Methods: This was a cross-sectional study of 129 healthy participants (age 33.6 ± 6.1 years, BMI 30.5 ± 6.9 kg/m2). Dietary fiber intake was assessed by food frequency questionnaire. Adiposity was measured using dual energy X-ray absorptiometry (DXA). Fecal short chain fatty acids (SCFA) were quantified using gas chromatography mass spectrometry. Fecal microbiota sequence data (V4 region, 16S rRNA gene) were analyzed using DADA2 and QIIME2. Inflammatory cytokines were assessed with enzyme-linked immunosorbent assays; flow cytometry was conducted for monocyte surface marker quantification. Bivariate correlations and generalized step-wise linear modeling were used for statistical analyses. Results: Plasma C-reactive protein (CRP) and interleukin (IL)-6 concentrations were positively related to whole-body (CRP r = 0.45, p = <0.0001; IL-6 r = 0.34, p = 0.0002) and visceral adiposity (CRP r = 0.33, p = 0.0003; IL-6 r = 0.38, p = 0.0002). Plasma lipopolysaccharide binding protein (LBP) concentrations were inversely related to dietary fiber intake (r = -0.22, p = 0.03) and fecal SCFA (acetate r = -0.25, p = 0.01; propionate r = -0.28, p = 0.003; butyrate r = -0.23, p = 0.02). Whole-body adiposity, dietary fiber, and fecal SCFA were the most predictive of plasma LBS-BP concentrations. Conclusions: Novel findings included associations between dietary fiber intake, the gastrointestinal microbiota, and systemic inflammation.
Exercise and obesity regulate hematopoiesis, in part through alterations in cellular and soluble components of the bone marrow niche. Extracellular vesicles (EVs) are components of the bone marrow niche that regulate hematopoiesis; however, the role of exercise training or obesity induced EVs in regulating hematopoiesis remains unknown. To address this gap, donor EVs were isolated from control diet-fed, sedentary mice (CON-SED), control diet-fed exercise trained mice (CON-EX), high fat diet-fed, sedentary mice (HFD-SED), and high fat diet-fed, exercise trained mice (HFD-EX) and injected into recipient mice undergoing stress hematopoiesis. Hematopoietic and niche cell populations were quantified, and EV miRNA cargo was evaluated. EV content did not differ between the four groups. Mice receiving HFD-EX EVs had fewer hematopoietic stem cells (HSCs) (p < 0.01), long-term HSC (p < 0.05), multipotent progenitors (p < 0.01), common myeloid progenitors (p<0.01), common lymphoid progenitors (p < 0.01), and granulocyte-macrophage progenitors (p < 0.05), compared to mice receiving HFD-SED EVs. Similarly, mice receiving EX EVs had fewer osteoprogenitor cells compared to SED (p < 0.05) but enhanced mesenchymal stromal cell (MSC) osteogenic differentiation in vitro (p < 0.05) compared to SED EVs. HFD EVs enhanced mesenchymal stromal cell (MSC) adipogenesis in vitro (p < 0.01) compared to CON EVs. HFD-EX EVs had lower microRNA-193 and microRNA-331-5p content, microRNAs implicated in inhibiting osteogenesis and leukemic cell expansion respectively, compared to HFD-SED EVs. The results identify alterations in EV cargo as a novel mechanism by which exercise training alters stress hematopoiesis and the bone marrow niche.
Introduction: Intensified chemotherapy improved outcomes for men with poor prognosis metastatic germ cell cancer (GCC) and unfavorable tumor marker decline (UTMD) after one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in the GETUG-13 trial. Herein, we report our experience to date using a similar approach. Methods: Patients were identified from our electronic GCC database. Men with poor prognosis GCC and UTMD were offered intensified chemotherapy consisting of T-BEP (three cycles) plus paclitaxel, ifosfamide, and cisplatin (TIP) (one cycle), along with prophylactic granulocyte-colony stimulating factor (G-CSF) and resection of residual masses. Cisplatin, etoposide and ifosfamide (PEI) replaced last cycle of T-BEP for bleomycin pulmonary concerns. Serious toxicities, progression-free survival, and overall survival were evaluated retrospectively. Results: Ten patients with poor prognosis GCC were identified May 2012 to April 2016. Eight patients had UTMD. Six were offered and received intensified chemotherapy (two T-BEPx3 + TIP and four T-BEPx2 + PEI + TIP). Serious toxicities included neutropenic sepsis, deep venous thrombosis, and C. difficile colitis, but there were no toxic deaths. One patient died of synchronous metastatic adenocarcinoma ex teratoma. The remaining five patients achieved marker negative partial response, two had residual mature teratoma excised, and four have no evidence of disease after surgery. All are alive at a median of 57.6 months (range 37.2‒65.3 months); one patient has grade 2 peripheral sensory neuropathy, and one patient has grade 2 cognitive disturbance. Of four patients treated with standard BEP, two have died of disease and two are alive at 44.9 and 47.2 months. Conclusions: Our experience with intensified chemotherapy for men with poor prognosis GCC and UTMD confirms that it is feasible, reasonably safe, and appears to provide results similar to those reported in GETUG-13.
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