The desymmetrization of p-peroxyquinols using a Brønsted acid-catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. ...Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cancer cell-growth inhibition.
While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both ...canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in three canine HSA cell lines (DEN-, CIN-, and SB-HSA). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, and vascular endothelial growth factor production in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin. These results suggest that inhibitors of the PI3K/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, migration, and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and potentially human, HSA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Canine cancer cell lines have progressively been developed, but are still underused resources for radiation biology research. Measurement of the cellular intrinsic radiosensitivity is important ...because understanding the difference may provide a framework for further elucidating profiles for prediction of radiation therapy response. Our studies have focused on characterizing diverse canine cancer cell lines in vitro and understanding parameters that might contribute to intrinsic radiosensitivity. First, intrinsic radiosensitivity of 27 canine cancer cell lines derived from ten tumor types was determined using a clonogenic assay. The 27 cell lines had varying radiosensitivities regardless tumor type (survival fraction at 2 Gy, SF2 = 0.19-0.93). In order to understand parameters that might contribute to intrinsic radiosensitivity, we evaluated the relationships of cellular radiosensitivity with basic cellular characteristics of the cell lines. There was no significant correlation of SF2 with S-phase fraction, doubling time, chromosome number, ploidy, or number of metacentric chromosomes, while there was a statistically significant correlation between SF2 and plating efficiency. Next, we selected the five most radiosensitive cell lines as the radiosensitive group and the five most radioresistant cell lines as the radioresistant group. Then, we evaluated known parameters for cell killing by ionizing radiation, including radiation-induced DNA double strand break (DSB) repair and apoptosis, in the radiosensitive group as compared to the radioresistant group. High levels of residual γ-H2AX foci at the sites of DSBs were present in the four out of the five radiosensitive canine cancer cell lines. Our studies suggested that substantial differences in intrinsic radiosensitivity exist in canine cancer cell lines, and radiation-induced DSB repair was related to radiosensitivity, which is consistent with previous human studies. These data may assist further investigations focusing on the detection of DSB for predicting individual response to radiation therapy for dogs, regardless of tumor type.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The neural mechanisms underlying susceptibility to eating more in response to large portions (i.e., the portion size effect) remain unclear. Thus, the present study examined how neural responses to ...portion size relate to changes in weight and energy consumed as portions increase. Associations were examined across brain regions traditionally implicated in appetite control (i.e., an appetitive network) as well as the cerebellum, which has recently been implicated in appetite-related processes. Children without obesity (i.e., BMI-for-age-and-sex percentile < 90; N = 63; 55% female) viewed images of larger and smaller portions of food during fMRI and, in separate sessions, ate four meals that varied in portion size. Individual-level linear and quadratic associations between intake (kcal, grams) and portion size (i.e., portion size slopes) were estimated. The response to portion size in cerebellar lobules IV-VI was associated with the quadratic portion size slope estimated from gram intake; a greater response to images depicting smaller compared to larger portions was associated with steeper increases in intake with increasing portion sizes. Within the appetitive network, neural responses were not associated with portion size slopes. A decreased cerebellar response to larger amounts of food may increase children's susceptibility to overeating when excessively large portions are served.
Background
Quality improvement (QI) initiatives often reflect approaches based on anecdotal evidence, but it is unclear how initiatives can best incorporate scientific literature and methods into the ...QI process. Review of studies of QI initiatives that aim to systematically incorporate evidence review (termed evidence-based quality improvement (EBQI)) may provide a basis for further methodological development.
Methods
In this scoping review (registration:
https://osf.io/hr5bj
) of EBQI, we searched the databases PubMed, CINAHL, and SCOPUS. The review addressed three central questions: How is EBQI defined? How is evidence used to inform evidence-informed QI initiatives? What is the effectiveness of EBQI?
Results
We identified 211 publications meeting inclusion criteria. In total, 170 publications explicitly used the term “EBQI.” Published definitions emphasized relying on evidence throughout the QI process. We reviewed a subset of 67 evaluations of QI initiatives in primary care, including both studies that used the term “EBQI” with those that described an evidence-based initiative without using EBQI terminology. The most frequently reported EBQI components included use of evidence to identify previously tested effective QI interventions; engaging stakeholders; iterative intervention development; partnering with frontline clinicians; and data-driven evaluation of the QI intervention. Effectiveness estimates were positive but varied in size in ten studies that provided data on patient health outcomes.
Conclusions
EBQI is a promising strategy for integrating relevant prior scientific findings and methods systematically in the QI process, from the initial developmental phase of the IQ initiative through to its evaluation. Future QI researchers and practitioners can use these findings as the basis for further development of QI initiatives.
Deficits in executive functions (EFs), a set of cognitive processes related to self-regulation, are associated with the development of obesity. Prior studies from our group showed that lower food-cue ...related activation in brain regions implicated in self-regulation was related to a larger portion size effect. We tested the hypothesis that lower EFs in children would be positively related to the portion size effect. Healthy weight children aged 7–8 y (n = 88), who varied by maternal obesity status, participated in a prospective study. At baseline, the parent primarily in charge of feeding completed the Behavior Rating Inventory of Executive Function (BRIEF2) to assess child EFs, including Behavioral (BRI), Emotional (ERI), and Cognitive (CRI) indices. At 4 baseline sessions, children consumed meals in which the portion sizes of foods (pasta, chicken nuggets, broccoli, and grapes) varied by visit (total meal weight of 769, 1011, 1256, or 1492g). Intake increased with increasing portions in a linear trajectory (p < 0.001). EFs moderated the portion size effect such that lower BRI (p = 0.003) and ERI (p = 0.006) were associated with steeper increases in intake as portions increased. As amount of food increased, children in the lowest functioning tertiles for BRI and ERI increased intake by 35% and 36%, respectively, compared to children in the higher tertiles. Increases in intake among children with lower EFs were for higher- but not lower-energy-dense foods. Thus, in healthy weight children who varied by obesity risk, lower parentally reported EFs were associated with a larger portion size effect, and these results were independent of child and parent weight status. Therefore, EFs may be target behaviors that could be strengthened to help children moderate excess intake in response to large portions of energy-dense foods.
Meiotic crossovers (COs) are tightly regulated to ensure that COs on the same chromosome are distributed far apart (crossover interference, COI) and that at least one CO is formed per homolog pair ...(CO homeostasis). CO formation is controlled in part during meiotic double-strand break (DSB) creation in Caenorhabditis elegans, but a second level of control must also exist because meiotic DSBs outnumber COs. We show that the anti-recombinase RTEL-1 is required to prevent excess meiotic COs, probably by promoting meiotic synthesis-dependent strand annealing. Two distinct classes of meiotic COs are increased in rtel-1 mutants, and COI and homeostasis are compromised. We propose that RTEL-1 implements the second level of CO control by promoting noncrossovers.
ACC/AHA Task Force Members Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Jeffrey L. Anderson, MD, FACC, FAHA, Immediate Past Chair¶ Nancy M. Albert, PhD, ...RN, FAHA¶ Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA Lee A. Fleisher, MD, FACC, FAHA Federico Gentile, MD, FACC Samuel Gidding, MD, FAHA Mark A. Hlatky, MD, FACC John Ikonomidis, MD, PhD, FAHA Jose Joglar, MD, FACC, FAHA Richard J. Kovacs, MD, FACC, FAHA¶ E. Magnus Ohman, MD, FACC¶ Susan J. Pressler, PhD, RN, FAHA Frank W. Sellke, MD, FACC, FAHA¶ Win-Kuang Shen, MD, FACC, FAHA¶ Duminda N. Wijeysundera, MD, PhD Table of Contents Preamblee29 Introductione31 Methodology and Evidence Reviewe31 Organization of the GWCe31 Document Review and Approvale31 Scope of the Guidelinee31 General Principlese32 Mechanisms and Definitionse32 Epidemiology, Demographics, and Public Health Impacte32 Evaluation of the Patient With Suspected or Documented SVTe34 Clinical Presentation and Differential Diagnosis on the Basis of Symptomse34 Evaluation of the ECGe36 Principles of Medical Therapye40 Acute Treatment: Recommendationse41 Ongoing Management: Recommendationse43 Basic Principles of Electrophysiological Study, Mapping, and Ablatione45 Mapping With Multiple and Roving Electrodese45 Tools to Facilitate Ablation, Including 3-Dimensional Electroanatomic Mappinge45 Mapping and Ablation With No or Minimal Radiatione45 Ablation Energy Sourcese46 Sinus Tachyarrhythmiase46 Physiological Sinus Tachycardiae46 Inappropriate Sinus Tachycardiae46 Acute Treatmente46 Ongoing Management: Recommendationse53 Nonsinus Focal Atrial Tachycardia and MATe54 Focal Atrial Tachycardiae54 Acute Treatment: Recommendationse56 Ongoing Management: Recommendationse58 Multifocal Atrial Tachycardiae58 Acute Treatment: Recommendatione59 Ongoing Management: Recommendationse59 Atrioventricular Nodal Reentrant Tachycardiae60 Acute Treatment: Recommendationse61 Ongoing Management: Recommendationse63 Manifest and Concealed Accessory Pathwayse64 Management of Patients With Symptomatic Manifest or Concealed Accessory Pathwayse66 Acute Treatment: Recommendationse66 Ongoing Management: Recommendationse68 Management of Asymptomatic Pre-Excitatione69 PICOTS Critical Questionse69 Asymptomatic Patients With Pre-Excitation: Recommendationse71 Risk Stratification of Symptomatic Patients With Manifest Accessory Pathways: Recommendationse72 Atrial Fluttere72 Cavotricuspid Isthmus-Dependent Atrial Fluttere72 Non-Isthmus-Dependent Atrial Flutterse74 Acute Treatment: Recommendationse76 Ongoing Management: Recommendationse78 Junctional Tachycardiae80 Acute Treatment: Recommendationse81 Ongoing Management: Recommendationse81 Special Populationse82 Pediatricse82 Patients With Adult Congenital Heart Diseasee83 Clinical Featurese83 Acute Treatment: Recommendationse85 Ongoing Management: Recommendationse87 Pregnancye90 Acute Treatment: Recommendationse90 Ongoing Management: Recommendationse91 SVT in Older Populationse92 Acute Treatment and Ongoing Management: Recommendatione92 Quality-of-Life Considerationse93 Cost-Effectivenesse93 Shared Decision Makinge93 Evidence Gaps and Future Research Needse94 Referencese95 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)e108 Appendix 2 Reviewer Relationships With Industry and Other Entities (Relevant)e110 Appendix 3 Abbreviationse115 Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health.
We aimed to evaluate neurodevelopmental and growth outcomes among extremely low birth weight infants who had severe intraventricular hemorrhage that required shunt insertion compared with infants ...without shunt insertion.
Infants who were born in 1993-2002 with birth weights of 401 to 1000 g were enrolled in a very low birth weight registry at medical centers that participate in the National Institute of Child Health and Human Development Neonatal Research Network, and returned for follow-up at 18 to 22 months' corrected age were studied. Eighty-two percent of survivors completed follow-up, and 6161 children were classified into 5 groups: group 1, no intraventricular hemorrhage/no shunt (n = 5163); group 2, intraventricular hemorrhage grade 3/no shunt (n = 459); group 3, intraventricular hemorrhage grade 3/shunt (n = 103); group 4, intraventricular hemorrhage grade 4/no shunt (n = 311); and group 5, intraventricular hemorrhage grade 4/shunt (n = 125). Group comparisons were evaluated with chi(2) and Wilcoxon tests, and regression models were used to compare outcomes after adjustment for covariates.
Children with severe intraventricular hemorrhage and shunts had significantly lower scores on the Bayley Scales of Infant Development IIR compared with children with no intraventricular hemorrhage and with children with intraventricular hemorrhage of the same grade and no shunt. Infants with shunts were at increased risk for cerebral palsy and head circumference at the <10th percentile at 18 months' adjusted age. Greatest differences were observed between children with shunts and those with no intraventricular hemorrhage on these outcomes.
This large cohort study suggests that extremely low birth weight children with severe intraventricular hemorrhage that requires shunt insertion are at greatest risk for adverse neurodevelopmental and growth outcomes at 18 to 22 months compared with children with and without severe intraventricular hemorrhage and with no shunt. Long-term follow-up is needed to determine whether adverse outcomes persist or improve over time.
Behavioral phenotypes that predict future weight gain are needed to identify children susceptible to obesity.
This prospective study developed an eating behavior risk score to predict change in ...adiposity over 1 y in children.
Data from 6 baseline visits (Time 1, T1) and a 1-y follow-up visit (Time 2, T2) were collected from 76, 7- to 8-y-old healthy children recruited from Central Pennsylvania. At T1, children had body mass index (BMI) percentiles <90 and were classified with either high (n = 33; maternal BMI ≥30 kg/m2) or low (n = 43; maternal BMI ≤25 kg/m2) familial risk for obesity. Appetitive traits and eating behaviors were assessed at T1. Adiposity was measured at T1 and T2 using dual-energy x-ray absorptiometry, with a main outcome of fat mass index (FMI; total body fat mass divided by height in meters squared). Hierarchical linear regressions determined which eating measures improved prediction of T2 FMI after adjustment for covariates in the baseline model (T1 FMI, sex, income, familial risk, and Tanner stage).
Four eating measures—Portion susceptibility, Appetitive traits, loss of control eating, and eating rate—were combined into a standardized summary score called PACE. PACE improved the baseline model to predict 80% variance in T2 FMI. PACE was positively associated with the increase in FMI in children from T1 to T2, independent of familial risk (r = 0.58, P < 0.001). Although PACE was higher in girls than boys (P < 0.05), it did not differ by familial risk, income, or education.
PACE represents a cumulative eating behavior risk score that predicts adiposity gain over 1 y in middle childhood. If PACE similarly predicts adiposity gain in a cohort with greater racial and socioeconomic diversity, it will inform the development of interventions to prevent obesity.
This trial was registered at clinicaltrials.gov as NCT03341247.
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