Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies

Therapeutic monoclonal antibodies (mAbs), including immune checkpoint inhibitors (ICIs), are an important breakthrough for the treatment of cancer and have dramatically changed clinical outcomes in a wide variety of tumours. However, clinical response varies among patients receiving mAb-based treatment, so it is necessary to search for predictive biomarkers of response to identify the patients who will derive the greatest therapeutic benefit. The interaction of mAbs with Fc gamma receptors (Fc gamma R) expressed by innate immune cells is essential for antibody-dependent cellular cytotoxicity (ADCC) and this binding is often critical for their in vivo efficacy. Fc gamma RIIa (H131R) and Fc gamma RIIIa (V158F) polymorphisms have been reported to correlate with response to therapeutic mAbs. These polymorphisms play a major role in the affinity of mAb receptors and, therefore, can exert a profound impact on antitumor response in these therapies. Furthermore, recent reports have revealed potential mechanisms of ICIs to modulate myeloid subset composition within the tumour microenvironment through Fc gamma R-binding, optimizing their anti-tumour activity. The purpose of this review is to highlight the clinical contribution of Fc gamma R polymorphisms to predict response to mAbs in cancer patients

Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Associations between Screen Time and Physical Activity among Spanish Adolescents

Excessive time in front of a single or several screens could explain a displacement of physical activity. The present study aimed at determining whether screen-time is associated with a reduced level of moderate to vigorous physical activity (MVPA) in Spanish adolescents living in favorable environmental conditions. or more to total screen-time showed a 64% (OR = 0.61, 95% CI, 0.44–0.86) increased risk of failing to achieve the recommended adolescent MVPA level. Participation in organized physical activities and sports competitions were more strongly associated with MVPA than screen-related behaviors.No single screen-related behavior explained the reduction of MVPA in adolescents. However, the total time accumulated through several screen-related behaviors was negatively associated with MVPA level in boys. This association could be due to lower availability of time for exercise as the time devoted to sedentary screen-time activities increases. Participation in organized physical activities seems to counteract the negative impact of excessive time in front of screens on physical activity

Trends in eczema prevalence in children and adolescents: A Global Asthma Network Phase I Study

Background: Eczema (atopic dermatitis) is a major global public health issue with high prevalence and morbidity. Our goal was to evaluate eczema prevalence over time, using standardized methodology. Methods: The Global Asthma Network (GAN) Phase I study is an international collaborative study arising from the International Study of Asthma and Allergies in Children (ISAAC). Using surveys, we assessed eczema prevalence, severity, and lifetime prevalence, in global centres participating in GAN Phase I (2015–2020) and one/ both of ISAAC Phase I (1993–1995) and Phase III (2001–2003). We fitted linear mixed models to estimate 10-yearly prevalence trends, by age group, income, and region. Results: We analysed GAN Phase I data from 27 centres in 14 countries involving 74,361 adolescents aged 13–14 and 47,907 children aged 6–7 (response rate 90%, 79%). A median of 6% of children and adolescents had symptoms of current eczema, with 1.1% and 0.6% in adolescents and children, respectively, reporting symptoms of severe eczema. Over 27 years, after adjusting for world region and income, we estimated small overall 10-year increases in current eczema prevalence (adolescents: 0.98%, 95% CI 0.04%–1.92%; children: 1.21%, 95% CI 0.18%–2.24%), and severe eczema (adolescents: 0.26%, 95% CI 0.06%–0.46%; children: 0.23%, 95% CI 0.02%–0.45%) with larger increases in lifetime prevalence (adolescents: 2.71%, 95% CI 1.10%–4.32%; children: 3.91%, 95% CI 2.07%–5.75%). There was substantial heterogeneity in 10-year change between centres (standard deviations 2.40%, 0.58%, and 3.04%), and strong evidence that some of this heterogeneity was explained by region and income level, with increases in some outcomes in high-income children and middle-income adolescents. Conclusions: There is substantial variation in changes in eczema prevalence over time by income and region. Understanding reasons for increases in some regions and decreases in others will help inform prevention strategies

Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study

Background: Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing. Methods: This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993–95), ISAAC Phase III (2001–03), or both. We included individuals from two age groups (children aged 6–7 years and adolescents aged 13–14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders. Findings: Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993–2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0·37, 95% CI –0·69 to –0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (–1·37, –2·47 to –0·27], in children and –1·67, –2·70 to –0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries. Interpretation: Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma. Funding: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III