Relational forms of aggression are known to increase during the middle school years. To date, the majority of efficacy studies of elementary school-based programs have focused on the reduction of ...physical and direct verbal aggression, to the exclusion of effects on relational aggression. Steps to Respect: A Bullying Prevention Program is one exception, which explicitly addresses relational forms of aggression such as malicious gossip and social exclusion. The current study assessed the short-term efficacy of Steps to Respect on reducing observed malicious gossip on the playground. Beliefs about aggressive norms and friends' social support were examined as moderators of program impact. Participants were 544 students from six schools in the Pacific Northwest. Mixed hierarchical modeling was used to test hypotheses. Results provide support for the effects of universal prevention programs on reducing relational aggression, and highlight the need to consider how aggression norms and supportive friends may impact victim responses and continued victimization.
Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related ...chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to
SETD5
gene mutations, falls into this group of disorders. KBG syndrome, caused by
ANKRD11
gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A
de novo
deletion of 116 kb partially involving
SETD5
and two
de novo
frameshift variants in
SETD5
were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider
SETD5
gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.
This open access book is a unique resource for health professionals who are interested in understanding the philosophical foundations of their daily practice. It provides tools for untangling the ...motivations and rationality behind the way medicine and healthcare is studied, evaluated and practiced. In particular, it illustrates the impact that thinking about causation, complexity and evidence has on the clinical encounter. The book shows how medicine is grounded in philosophical assumptions that could at least be challenged. By engaging with ideas that have shaped the medical profession, clinicians are empowered to actively take part in setting the premises for their own practice and knowledge development. Written in an engaging and accessible style, with contributions from experienced clinicians, this book presents a new philosophical framework that takes causal complexity, individual variation and medical uniqueness as default expectations for health and illness.
Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. ...The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine, and feces. Six healthy female subjects of nonchildbearing potential were enrolled; each received a single 30-ml oral suspension containing 150 mg of vismodegib with 6.5 μg of (14)Cvismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi). Plasma, urine, and feces samples were collected over 56 days to permit sample collection for up to 5 elimination half-lives. Nonradioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry, and total radioactivity in plasma, urine, and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, most of which was recovered in feces. The estimated excretion of the administered dose was 86.6% on average, with 82.2 and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing >98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans included oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that vismodegib and any associated metabolic products are mainly eliminated through feces after oral administration in healthy volunteers.
Increasing atmospheric concentrations of phytotoxic ozone (O3) can constrain growth and carbon sink strength of forest trees, potentially exacerbating global radiative forcing. Despite progress in ...the conceptual understanding of the impact of O3 on plants, it is still difficult to detect response patterns at the leaf level.
Here, we employed principal component analysis (PCA) to analyse a database containing physiological leaf-level parameters of 60-yr-old Fagus sylvatica (European beech) trees. Data were collected over two climatically contrasting years under ambient and twice-ambient O3 regimes in a free-air forest environment.
The first principal component (PC1) of the PCA was consistently responsive to O3 and crown position within the trees over both years. Only a few of the original parameters showed an O3 effect. PC1 was related to parameters indicative of oxidative stress signalling and changes in carbohydrate metabolism. PC1 correlated with cumulative O3 uptake over preceding days.
PC1 represents an O3-responsive multivariate pattern detectable in the absence of consistently measurable O3 effects on individual leaf-level parameters. An underlying effect of O3 on physiological processes is indicated, providing experimental confirmation of theoretical O3 response patterns suggested previously.
In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and ...nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.
Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA.
A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 μmol/L) and human serum albumin less strongly (K(D) = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination.
GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.
Systemic cytokine release and on-target/off-tumor toxicity to normal tissues are the main adverse effects limiting the clinical utility of T cell-redirecting therapies. This study was designed to ...determine how binding affinity for CD3 and tumor target HER2 impact the efficacy and nonclinical safety of anti-HER2/CD3 T cell-dependent antibodies (TDBs). Affinity was found to be a major determinant for the overall tolerability. Higher affinity for CD3 associated with rapidly elevated peripheral cytokine concentrations, weight loss in mice, and poor tolerability in cynomolgus monkeys. A TDB with lower CD3 affinity was better tolerated in cynomolgus monkeys compared with a higher CD3-affinity TDB. In contrast to tolerability, T cell binding affinity had only limited impact on in vitro and in vivo antitumor activity. High affinity for HER2 was critical for the tumor-killing activity of anti-HER2/CD3 TDBs, but higher HER2 affinity also associated with a more severe toxicity profile, including cytokine release and damage to HER2-expressing tissues. The tolerability of the anti-HER2/CD3 was improved by implementing a dose-fractionation strategy. Fine-tuning the affinities for both the tumor target and CD3 is likely a valuable strategy for achieving maximal therapeutic index of CD3 bispecific antibodies.
Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was ...demonstrated by targeting the translocator protein in activated macrophages using (R)-11CPK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer 18Ffluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model.
18Ffluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo 18Ffluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-11CPK11195.
18Ffluoro-PEG-folate was synthesized with a purity >97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, 18Ffluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with 18Ffluoro-PEG-folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee-to-blood ratios of 18Ffluoro-PEG-folate were increased compared with those of (R)-11CPK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute 18Ffluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios.
The novel PET tracer 18Ffluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-11CPK11195. These results warrant further exploration of 18Ffluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients.
Studies have demonstrated that the generation of immunity to tumor antigens is associated with improved prognosis for many cancers. A candidate antigen is the folate receptor alpha (FRalpha), which ...is overexpressed in breast and ovarian cancers. Our goal in this study was to attain a better understanding of the extent of endogenous FRalpha immunity.
Using a CD4+ T cell epitope prediction algorithm, we predicted promiscuous epitopes of FRalpha, and tested for immunity in 30 breast (n = 17) or ovarian (n = 13) cancer patients and 18 healthy donors using enzyme-linked immunospot analysis.
Fourteen peptides were predicted, seven each from the carboxy- and amino-terminus halves of the protein. More than 70% of patients demonstrated immunity to at least one FRalpha peptide. Patients responded to an average of 3 +/- 0.5 peptides, whereas healthy donors responded to 1 +/- 0.4 peptides (P = .004). Five peptides were recognized by more than 25% of patients. Responses to three peptides were higher (P < .05) in patients than in healthy donors, suggesting augmented immunity. Compared with healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor (P = .03). There was no difference between each group in the responses to nonspecific (P = .2) and viral stimuli (P = .5). Lastly, patients demonstrated elevated levels of FRalpha antibodies consistent with a coordinated immune response.
These findings demonstrate that the FRalpha is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.
Preeclampsia, a complication of pregnancy characterized by hypertension and proteinuria, has been found to reduce the subsequent risk for breast cancer in female offspring. As this pro- tective ...effect could be due to exposure to preeclampsia-specific proteins during intrauterine life, the proteomic profiles of umbilical cord blood plasma between preeclamptic and normotensive pregnancies were compared. Umbilical cord plasma samples, depleted of 14 abundant proteins, were subjected to proteomic analysis using the quantitative method of nanoACQUITY ultra performance liquid chromatography-mass spectrometry with elevated energy mode of acquisitionE （NanoUPLC-MSE）. Sixty-nine differentially expressed proteins were identified, of which 15 and 6 proteins were only detected in preeclamptic and normotensive pregnancies, respectively.Additionally, expression of 8 proteins （gelsolin, complement C5, keratin type I cytoskeletal 10, pigment epithelium-derived factor, complement factor B, complement component C7, hemoglobin subunit gamma-2 and alpha-fetoprotein） were up-regulated in preeclampsia with a fold change of 1〉 2.0 when compared to normotensive pregnancies. The identification of alpha-fetoprotein in pre- eclamptic umbilical cord blood plasma supported the validity of this screen as alpha-fetoprotein has anti-estrogenic properties and has previously been linked to preeclampsia as well as a reduced breast cancer risk. The findings of this pilot study may provide new insights into the mechanistic link between preeclampsia and potentially reduced breast cancer susceptibility in adult life.
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