Optimal hypofractionated radiation therapy schemes for early-stage hepatocellular carcinoma.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been emerging as an efficacious and safe treatment modality for early-stage hepatocellular carcinoma (HCC), but optimal fractionation regimens are unknown. This study aims to analyze published clinical tumor control probability (TCP) data as a function of biologically effective dose (BED) and to determine radiobiological parameters and optimal fractionation schemes for SBRT and hypofractionated radiation therapy of early-stage HCC. MATERIAL AND METHODS: Clinical 1- to 5-year TCP data of 4313 patients from 41 published papers were collected for hypofractionated radiation therapy at 2.5-4.5 Gy/fraction and SBRT of early-stage HCC. BED was calculated at isocenter using three representative radiobiological models developed per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. Radiobiological parameters were determined from a fit to the TCP data using the least χ2 method with one set of model parameters regardless of tumor stages or Child-Pugh scores A and B. RESULTS: The fits to the clinical TCP data for SBRT of early-stage HCC found consistent α/ß ratios of about 14 Gy for all three radiobiological models. TCP increases sharply with BED and reaches an asymptotic maximal plateau, which results in optimal fractionation schemes of least doses to achieve asymptotic maximal tumor control for SBRT and hypofractionated radiation therapy of early-stage HCC that are found to be model-independent. CONCLUSION: From the fits to the clinical TCP data, we presented the first determination of radiobiological parameters and model-independent optimal fractionation regimens in 1-20 fractions to achieve maximal tumor control whenever safe for SBRT and hypofractionated radiation therapy of early-stage HCC. The determined optimal fractionation schemes agree well with clinical practice for SBRT of early-stage HCC. However, most existing hypofractionated radiation therapy schemes of 3-5 Gy/fraction are not optimal, higher doses are required to maximize tumor control, further validation of these findings is essential with clinical TCP data.

Randomized Pilot Study of a Keratin-based Topical Cream for Radiation Dermatitis in Breast Cancer Patients.

Purpose: Radiotherapy (RT) is commonly used in the treatment of breast cancer and often, despite advances in fractionated dosing schedules, produces undesirable skin toxicity. The purpose of this study was to evaluate the feasibility of using a keratin-based topical cream, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA) to manage the symptoms of radiation dermatitis (RD) in breast cancer patients undergoing RT. Materials and Methods: A total of 24 subjects were enrolled on this single-center, randomized, open-label study. Participants were randomly assigned to KC or standard of care (SOC, patient's choice of a variety of readily available creams or moisturizers). Patients were asked to apply the assigned treatment to the irradiated area twice daily, beginning with day 1 of RT, through 30 days post-RT. The primary outcome was compliance of use. Secondary outcomes included safety and tolerability of KC, as well as RD severity assessed using the Radiation Therapy Oncology Group (RTOG) scale and the patient-reported Dermatology Life Quality Index (DLQI). Results: All subjects in the KC group were assessed as compliant with no adverse events. The rate of RTOG Grade 2 RD was lower in the KC group (30.8%) compared to the SOC group (54.5%, P = .408). At the final RT visit, the mean RTOG RD score was lower in the KC group (1.0) versus the SOC group (1.4). Similarly, patient-reported quality of life measured by the DLQI at the end of RT was improved in the KC group (mean 4.25, small effect) versus the SOC group (mean 6.18, moderate effect, P = .412). Conclusions: KC was safe and well tolerated with no adverse events. Though efficacy measures were not powered to draw definitive conclusions, trends and clinical assessments suggest that there is a benefit of using KC compared to SOC for breast cancer patients treated with RT, and a larger powered study for efficacy is warranted. Trial Registry: This clinical trial is registered as NCT03374995 titled KeraStat(R) Cream for Radiation Dermatitis.

Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes.

The reduced prevalence of insulin resistance and type 2 diabetes in countries with endemic parasitic worm infections suggests a protective role for worms against metabolic disorders, however clinical evidence has been non-existent. This 2-year randomised, double-blinded clinical trial in Australia of hookworm infection in 40 male and female adults at risk of type 2 diabetes assessed the safety and potential metabolic benefits of treatment with either 20 (n = 14) or 40 (n = 13) Necator americanus larvae (L3) or Placebo (n = 13) (Registration ACTRN12617000818336). Primary outcome was safety defined by adverse events and completion rate. Homoeostatic model assessment of insulin resistance, fasting blood glucose and body mass were key secondary outcomes. Adverse events were more frequent in hookworm-treated participants, where 44% experienced expected gastrointestinal symptoms, but completion rates were comparable to Placebo. Fasting glucose and insulin resistance were lowered in both hookworm-treated groups at 1 year, and body mass was reduced after L3-20 treatment at 2 years. This study suggests hookworm infection is safe in people at risk of type 2 diabetes and associated with improved insulin resistance, warranting further exploration of the benefits of hookworms on metabolic health.

Quality and health dimensions of pulse-based dairy alternatives with chickpeas, lupins and mung beans.

Health and environmental issues regarding dairy consumption have been highlighted in recent years leading to tremendous consumer demand for plant-based substitutes. In this review, we focused on quality and health dimensions of pulse-based dairy alternatives (PuBDA) using chickpeas, lupins and mung beans. Appraisal of existing documents show that there is limited information on PuBDA with the said pulses compared to similar materials such as soy and pea. Most of the studies focused on milk or fermented milks, either in full or partial substitution of the dairy ingredients with the pulses. Issues on stability, sensory properties, shelf life and nutritional quality were underlined by existing literature. Although it was emphasized in some reports the health potential through the bioactive components, there is scarce data on clinical studies showing actual health benefits of the featured PuBDA in this paper. There is also a scant number of these PuBDA that are currently available in the market and in general, these products have inferior nutritional quality compared to the animal-based counterparts. Technological innovations involving physical, biological and chemical techniques can potentially address the quality problems in the use of chickpeas, lupins, and mung beans as raw materials in dairy alternatives.

RPPA SPACE: an R package for normalization and quantitation of Reverse-Phase Protein Array data.

SUMMARY: Reverse-Phase Protein Array (RPPA) is a robust high-throughput, cost-effective platform for quantitatively measuring proteins in biological specimens. However, converting raw RPPA data into normalized, analysis-ready data remains a challenging task. Here, we present the RPPA SPACE (RPPA Superposition Analysis and Concentration Evaluation) R package, a substantially improved successor to SuperCurve, to meet that challenge. SuperCurve has been used to normalize over 170 000 samples to date. RPPA SPACE allows exclusion of poor-quality samples from the normalization process to improve the quality of the remaining samples. It also features a novel quality-control metric, 'noise', that estimates the level of random errors present in each RPPA slide. The noise metric can help to determine the quality and reliability of the data. In addition, RPPA SPACE has simpler input requirements and is more flexible than SuperCurve, it is much faster with greatly improved error reporting. AVAILABILITY AND IMPLEMENTATION: The standalone RPPA SPACE R package, tutorials and sample data are available via https://rppa.space/, CRAN (https://cran.r-project.org/web/packages/RPPASPACE/index.html) and GitHub (https://github.com/MD-Anderson-Bioinformatics/RPPASPACE). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Smoking and Radiation-induced Skin Injury: Analysis of a Multiracial, Multiethnic Prospective Clinical Trial.

INTRODUCTION: Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT. PATIENTS AND METHODS: Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria. RESULTS: Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI. CONCLUSIONS: Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.

Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma.

PURPOSE: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. EXPERIMENTAL DESIGN: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1-6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297). RESULTS: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. CONCLUSIONS: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

Analysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA.

Circulating tumor DNA (ctDNA) is released from tumor cells into blood in advanced cancer patients. Although gene mutations in individual tumors can be diverse and heterogenous, ctDNA has the potential to provide comprehensive biomarker information. Here, we performed multi-region sampling (three sites) per resected specimen from 10 gastric cancer patients followed by targeted sequencing and proteomic profiling using reverse-phase protein arrays. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were present in all three regions and were designated as founder mutations. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis also demonstrated a good concordance between founder and truncal mutations, defined as mutations shared by all simulated clones at the trunk of the tumor phylogenetic tree. These findings led us to prioritize founder mutations for quantitative ctDNA monitoring by digital PCR with individually-designed primer/probe sets. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Proteomic heterogeneity was present across the tumor regions both within and between patients independent of mutational status. Our results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be immediately useful for quantitative ctDNA monitoring but do not provide sufficient information to predict the proteomic composition of tumors.

Effect at One Year of Adjuvant Trastuzumab for HER2+ Breast Cancer Combined with Radiation or an Anthracycline on Left Ventricular Ejection Fraction.

To determine the impact of radiation therapy (XRT) in addition to trastuzumab (TZB) adjuvant chemotherapy for HER2+ breast cancer on left ventricular systolic function, we assessed demographics, oncologic treatment history including XRT exposure, and serial measurements of left ventricular ejection fraction (LVEF) in 135 consecutively identified women receiving TZB for treatment of adjuvant breast cancer. Longitudinal mixed effects models were fit to identify baseline to treatment changes in LVEF among those receiving TZB with or without concomitant anthracycline or XRT. Women averaged 53 ± 3 years in age, 77% were white, 62% patients had 1 or more cardiovascular risk factors at baseline, and mean duration of TZB was 11 ± 5 months. Seventy-seven women were treated with XRT and received between 4000 and 5500 cGy of radiation. The LVEF declined by an average of 3.4% after 1 year for those in the study. Relative to baseline upon completion of adjuvant TZB, LVEF remained reduced for those receiving anthracycline with or without XRT (p=0.002 for both), or XRT alone (p=0.002), but not in those without these therapies. Amongst patients treated only with XRT and TZB, LVEF declined 3.1% on average in those with left-sided disease and 6.9% on average in those with right-sided disease (p= 0.06, p= 0.008 respectively). Among women receiving TZB for adjuvant treatment of HER-2 positive breast cancer, the administration of XRT, anthracycline, or the combination of the 2 is associated with a persistent post-treatment as opposed to a temporary treatment related decline in LVEF.

Effectiveness of Breast-Conserving Surgery and 3-Dimensional Conformal Partial Breast Reirradiation for Recurrence of Breast Cancer in the Ipsilateral Breast: The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial.

IMPORTANCE: Mastectomy is standard for recurrence of breast cancer after breast conservation therapy with whole breast irradiation. The emergence of partial breast irradiation led to consideration of its application for reirradiation after a second lumpectomy for treatment of recurrence of breast cancer in the ipsilateral breast. OBJECTIVES: To assess the effectiveness and adverse effects of partial breast reirradiation after a second lumpectomy and whether the treatment is an acceptable alternative to mastectomy. DESIGN, SETTING, AND PARTICIPANTS: The NRG Oncology/Radiation Therapy Oncology Group 1014 trial is a phase 2, single-arm, prospective clinical trial of 3-dimensional, conformal, external beam partial breast reirradiation after a second lumpectomy for recurrence of breast cancer in the ipsilateral breast after previous whole breast irradiation. The study opened on June 4, 2010, and closed June 18, 2013. Median follow-up was 5.5 years. This analysis used all data received at NRG Oncology through November 18, 2018. Eligible patients experienced a recurrence of breast tumor that was less than 3 cm and unifocal in the ipsilateral breast more than 1 year after breast-conserving therapy with whole breast irradiation and who had undergone excision with negative margins. INTERVENTIONS: Adjuvant partial breast reirradiation, 1.5 Gy twice daily for 30 treatments during 15 days (45 Gy), using a 3-dimensional conformal technique. MAIN OUTCOMES AND MEASURES: The main outcomes of the present study were the predefined secondary study objectives of recurrence of breast cancer in the ipsilateral breast, late adverse events (>1 year after treatment), mastectomy incidence, distant metastasis-free survival, overall survival, and circulating tumor cell incidence. RESULTS: A total of 65 women were enrolled, with 58 evaluable for analysis (mean [SD] age, 65.12 [9.95] years; 48 [83%] white). Of the recurrences of breast cancer in the ipsilateral breast, 23 (40%) were noninvasive and 35 (60%) were invasive. In all 58 patients, 53 (91%) had tumors 2 cm or smaller. All tumors were clinically node negative. A total of 44 patients (76%) tested positive for estrogen receptor, 33 (57%) for progesterone receptor, and 10 (17%) for ERBB2 (formerly HER2 or HER2/neu) overexpression. Four patients had breast cancer recurrence, with a 5-year cumulative incidence of 5% (95% CI, 1%-13%). Seven patients underwent ipsilateral mastectomies for a 5-year cumulative incidence of 10% (95% CI, 4%-20%). Both distant metastasis-free survival and overall survival rates were 95% (95% CI, 85%-98%). Four patients (7%) had grade 3 and none had grade 4 or higher late treatment adverse events. CONCLUSIONS AND RELEVANCE: For patients experiencing recurrence of breast cancer in the ipsilateral breast after lumpectomy and whole breast irradiation, a second breast conservation was achievable in 90%, with a low risk of re-recurrence of cancer in the ipsilateral breast using adjuvant partial breast reirradiation. This finding suggests that this treatment approach is an effective alternative to mastectomy.

Analytical Platforms 3: Processing Samples via the RPPA Pipeline to Generate Large-Scale Data for Clinical Studies.

Reverse phase protein array (RPPA) is a functional proteomics technology amenable to moderately high throughputs of samples and antibodies. The University of Texas MD Anderson Cancer Center RPPA Core Facility has implemented various processes and techniques to maximize RPPA throughput; key among them are maximizing array configuration and relying on database management and automation. One major tool used by the RPPA Core is a semi-automated RPPA process management system referred to as the RPPA Pipeline. The RPPA Pipeline, developed with the aid of MD Avnderson's Department of Bioinformatics and Computational Biology and InSilico Solutions, has streamlined sample and antibody tracking as well as advanced quality control measures of various RPPA processes. This chapter covers RPPA Core processes associated with the RPPA Pipeline workflow from sample receipt to sample printing to slide staining and RPPA report generation that enables the RPPA Core to process at least 13,000 samples per year with approximately 450 individual RPPA-quality antibodies. Additionally, this chapter will cover results of large-scale clinical sample processing, including The Cancer Genome Atlas Project and The Cancer Proteome Atlas.

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells.

Our clinically relevant finding is that glucocorticoids block estrogen (E2)-induced apoptosis in long-term E2-deprived (LTED) breast cancer cells. However, the mechanism remains unclear. Here, we demonstrated that E2 widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNFα in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFα expression. Furthermore, dexamethasone was synergistic or additive with E2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFα expression induced by E2 in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, dexamethasone effectively blocked activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by E2, but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1α) expression increased by E2 Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1α-mediated degradation of PI3K/Akt-associated signal pathways activated by E2 Unexpectedly, activated GR preferentially repressed nuclear factor-κB (NF-κB) DNA-binding activity and expression of NF-κB-dependent gene TNFα induced by E2, leading to the blockade of E2-induced apoptosis. Together, these data suggest that trans-suppression of NF-κB by GR in the nucleus is a fundamental mechanism thereby blocking E2-induced apoptosis in LTED breast cancer cells. This study provided an important rationale for restricting the clinical use of glucocorticoids, which will undermine the beneficial effects of E2-induced apoptosis in patients with aromatase inhibitor-resistant breast cancer.

GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and ß-catenin activity.

Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased ß-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased ß-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of ß-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.

Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

INTRODUCTION: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered "possible." In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

Potential prognostic markers for survival and neurologic death in patients with breast cancer brain metastases who receive upfront SRS alone.

PURPOSE/OBJECTIVES: Stereotactic radiosurgery (SRS) is used as a treatment option for breast cancer brain metastases. It is unclear what factors predict neurologic death for these patients. MATERIALS/METHODS: A total of 128 patients with breast cancer brain metastases were treated with upfront SRS alone in this study. Survival was estimated using the Kaplan-Meier method. Clinicopathologic factors evaluated included age, ER/PR status, Her2 status, numbers of brain metastases treated, minimum SRS dose, disease-specific GPA, extracranial disease status and systemic disease burden. RESULTS: ER or PR positivity was associated with a trend towards decreased neurologic death (subdistribution hazard ratio (sHR) = 0.54, p=0.06). Factors associated with non-neurologic death include extracranial disease status (sHR = 2.02, p=0.02) and dose (sHR = 1.11, p=0.02); Her2-positivity was associated with reduced hazard of non-neurologic death (sHR 0.52, p=0.05). CONCLUSIONS: ER/PR positivity was associated with a trend towards less neurologic death. HER2 positivity was associated with a trend towards less non-neurologic death.

Influence of Exercise Mode on Post-exercise Arterial Stiffness and Pressure Wave Measures in Healthy Adult Males.

Background: Exercise mode has been reported to be an important determinant of arterial stiffness and wave reflection changes following a brief bout of exercise with inconsistent results to date. This study examined the impact of exercise mode on arterial stiffness and pressure wave measures following acute aerobic exercise (AER), resistance exercise (RES), and a control (CON) condition with no exercise. Methods: In a randomized, cross-over, repeated measures design, 21 healthy adult males (26.7 ± 7.2 years) undertook three experimental intervention sessions: AER (30-min cycle ergometry at 70-75% maximum heart rate), RES (3 × 10 repetitions of six upper and lower body exercises at 80-90% of 10-repetition maximum) and CON (30-min seated rest). Measures of arterial stiffness and pressure waves, such as carotid-femoral pulse wave velocity (cf-PWV), augmentation index (AIx), AIx corrected for heart rate of 75 (AIx75), and forward wave (Pf), backward wave (Pb) and reflection magnitude, were assessed at Rest and at 10-min intervals for 60 min after the intervention sessions. Comparisons between interventions and over time were assessed via repeated measures ANOVA and post-hoc Tukey's tests. Results: No significant differences in cf-PWV were noted between the three interventions at rest or post-intervention. However, RES led to significantly greater post-intervention AIx, AIx75, Pf, and Pb compared to AER and CON with AIx75 also remaining significantly elevated throughout the post-intervention period. In contrast, AER resulted in a brief, significant elevation of AIx75 and no change in cf-PWV, Pf, Pb, and reflection magnitude. Conclusions: Exercise mode, specifically RES and AER, significantly influenced the time course of pressure wave reflection responses following a brief bout of exercise in healthy adult males. Distinct adjustments during exercise including changes in blood pressure and vasomotor tone may be key modulators of post-exercise arterial function. Identification of modal differences may assist in understanding the impact of exercise on cardiovascular function and the mechanisms by which exercise benefits vascular health.

Association Between Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in a Multiracial/Ethnic Breast Cancer Population.

Purpose This study examined an inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), in radiotherapy (RT)-induced early adverse skin reactions or toxicities in breast cancer. Patients and Methods Between 2011 and 2013, 1,000 patients with breast cancer who underwent RT were evaluated prospectively for skin toxicities through the National Cancer Institute-funded Wake Forest University Community Clinical Oncology Program Research Base. Pre- and post-RT plasma hsCRP levels and Oncology Nursing Society skin toxicity criteria (0 to 6) were used to assess RT-induced skin toxicities. Multivariable logistic regression analyses were applied to ascertain the associations between hsCRP and RT-induced skin toxicities after adjusting for potential confounders. Results The study comprised 623 white, 280 African American, 64 Asian/Pacific Islander, and 33 other race patients; 24% of the patients were Hispanic, and 47% were obese. Approximately 42% and 15% of patients developed RT-induced grade 3+ and 4+ skin toxicities, respectively. The hsCRP levels differed significantly by race and body mass index but not by ethnicity. In multivariable analysis, grade 4+ skin toxicity was significantly associated with obesity (odds ratio [OR], 2.17; 95% CI, 1.41 to 3.34], post-RT hsCRP ≥ 4.11 mg/L (OR, 1.61; 95% CI, 1.07 to 2.44), and both factors combined (OR, 3.65; 95% CI, 2.18 to 6.14). Above-median post-RT hsCRP (OR, 1.93; 95% CI, 1.03 to 3.63), and change in hsCRP (OR, 2.80; 95% CI, 1.42 to 5.54) were significantly associated with grade 4+ skin toxicity in nonobese patients. Conclusion This large prospective study is the first to our knowledge of hsCRP as an inflammatory biomarker in RT-induced skin toxicities in breast cancer. We demonstrate that nonobese patients with elevated RT-related change in hsCRP levels have a significantly increased risk of grade 4+ skin toxicity. The outcomes may help to predict RT responses and guide decision making.

Zooplankton From a Reef System Under the Influence of the Amazon River Plume.

At the mouth of the Amazon River, a widespread carbonate ecosystem exists below the river plume, generating a hard-bottom reef (∼9500 km2) that includes mainly large sponges but also rhodolith beds. The mesozooplankton associated with the pelagic realm over the reef formation was characterized, considering the estuarine plume and oceanic influence. Vertical hauls were carried out using a standard plankton net with 200 µm mesh size during September 2014. An indicator index was applied to express species importance as ecological indicators in community. Information on functional traits was gathered for the most abundant copepod species. Overall, 179 zooplankton taxa were recorded. Copepods were the richest (92 species), most diverse and most abundant group, whereas meroplankton were rare and less abundant. Species diversity (>3.0 bits.ind-1) and evenness (>0.6) were high, indicating a complex community. Small holoplanktonic species dominated the zooplankton, and the total density varied from 107.98 ind. m-3 over the reef area to 2,609.24 ind. m-3 in the estuarine plume, with a significant difference between coastal and oceanic areas. The most abundant copepods were the coastal species ithona plumifera and Clausocalanus furcatus and early stages copepodites of Paracalanidae. The holoplanktonic Oikopleura, an important producer of mucous houses, was very abundant on the reefs. The indicator species index revealed three groups: (1) indicative of coastal waters under the influence of the estuarine plume [Euterpina acutifrons, Parvocalanus crassirostris, Oikopleura (Vexillaria) dioica and Hydromedusae]; (2) characterized coastal and oceanic conditions (Clausocalanus); (3) characterized the reef system (O. plumifera). Two major copepods functional groups were identified and sorted according to their trophic strategy and coastal-oceanic distribution. The species that dominated the coastal area and the area over the rhodolith beds are indicators of the estuarine plume and are mixed with species of the North Brazil Current. These species practically disappear offshore, where occur oceanic species commonly found in other oligotrophic tropical areas. This ecosystem shows a mixture of estuarine, coastal and oceanic communities coexisting in the waters over the Amazon reefs, with no significant differences among these areas. However, the MDS clearly separated the communities along the salinity gradient in the plume.

Acute Effects of Exercise Mode on Arterial Stiffness and Wave Reflection in Healthy Young Adults: A Systematic Review and Meta-Analysis.

Background: This systematic review and meta-analysis quantified the effect of acute exercise mode on arterial stiffness and wave reflection measures including carotid-femoral pulse wave velocity (cf-PWV), augmentation index (AIx), and heart rate corrected AIx (AIx75). Methods: Using standardized terms, database searches from inception until 2017 identified 45 studies. Eligible studies included acute aerobic and/or resistance exercise in healthy adults, pre- and post-intervention measurements or change values, and described their study design. Data from included studies were analyzed and reported in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA guidelines. Meta-analytical data were reported via forest plots using absolute differences with 95% confidence intervals with the random effects model accounting for between-study heterogeneity. Reporting bias was assessed via funnel plots and, individual studies were evaluated for bias using the Cochrane Collaboration's tool for assessing risk of bias. A modified PEDro Scale was applied to appraise methodological concerns inherent to included studies. Results: Acute aerobic exercise failed to change cf-PWV (mean difference: 0.00 ms-1 [95% confidence interval: -0.11, 0.11], p = 0.96), significantly reduced AIx (-4.54% [-7.05, -2.04], p = 0.0004) and significantly increased AIx75 (3.58% [0.56, 6.61], p = 0.02). Contrastingly, acute resistance exercise significantly increased cf-PWV (0.42 ms-1 [0.17, 0.66], p = 0.0008), did not change AIx (1.63% [-3.83, 7.09], p = 0.56), and significantly increased AIx75 (15.02% [8.71, 21.33], p < 0.00001). Significant heterogeneity was evident within all comparisons except cf-PWV following resistance exercise, and several methodological concerns including low applicability of exercise protocols and lack of control intervention were identified. Conclusions: Distinct arterial stiffness and wave reflection responses were identified following acute exercise with overall increases in both cf-PWV and AIx75 following resistance exercise potentially arising fromcardiovascular and non-cardiovascular factors that likely differ from those following aerobic exercise. Future studies should address identified methodological limitations to enhance interpretation and applicability of arterial stiffness and wave reflection indices to exercise and health.