Rationale for Combining Radiotherapy and Immune Checkpoint Inhibition for Patients With Hypoxic Tumors

In order to compensate for the increased oxygen consumption in growing tumors, tumors need angiogenesis and vasculogenesis to increase the supply. Insufficiency in this process or in the microcirculation leads to hypoxic tumor areas with a significantly reduced pO2, which in turn leads to alterations in the biology of cancer cells as well as in the tumor microenvironment. Cancer cells develop more aggressive phenotypes, stem cell features and are more prone to metastasis formation and migration. In addition, intratumoral hypoxia confers therapy resistance, specifically radioresistance. Reactive oxygen species are crucial in fixing DNA breaks after ionizing radiation. Thus, hypoxic tumor cells show a two- to threefold increase in radioresistance. The microenvironment is enriched with chemokines (e.g., SDF-1) and growth factors (e.g., TGFβ) additionally reducing radiosensitivity. During recent years hypoxia has also been identified as a major factor for immune suppression in the tumor microenvironment. Hypoxic tumors show increased numbers of myeloid derived suppressor cells (MDSCs) as well as regulatory T cells (Tregs) and decreased infiltration and activation of cytotoxic T cells. The combination of radiotherapy with immune checkpoint inhibition is on the rise in the treatment of metastatic cancer patients, but is also tested in multiple curative treatment settings. There is a strong rationale for synergistic effects, such as increased T cell infiltration in irradiated tumors and mitigation of radiation-induced immunosuppressive mechanisms such as PD-L1 upregulation by immune checkpoint inhibition. Given the worse prognosis of patients with hypoxic tumors due to local therapy resistance but also increased rate of distant metastases and the strong immune suppression induced by hypoxia, we hypothesize that the subgroup of patients with hypoxic tumors might be of special interest for combining immune checkpoint inhibition with radiotherapy

Ty1 insertions in intergenic regions of the genome of Saccharomyces cerevisiae transcribed by RNA polymerase III have no detectable selective effect

The retrotransposon Ty1 of Saccharomyces cerevisiae inserts preferentially into intergenic regions in the vicinity of RNA polymerase III-transcribed genes. It has been suggested that this preference has evolved to minimize the deleterious effects of element transposition on the host genome, and thus to favor their evolutionary survival. This presupposes that such insertions have no selective effect. However, there has been no direct test of this hypothesis. Here we construct a series of strains containing single Ty1 insertions in the vicinity of tRNA genes, or in the rDNA cluster on chromosome XII, which are otherwise isogenic to strain 337, containing zero Ty1 elements. Competition experiments between 337 and the strains containing single Ty1 insertions revealed that in all cases, the Ty1 insertions have no selective effect in rich medium. These results are thus consistent with the hypothesis that the insertion site preference of Ty1 elements has evolved to minimize the deleterious effects of transposition on the host genome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72266/1/S1567-1356_03_00199-5.pd

Correlations among adiposity measures in school-aged children

BACKGROUND: Given that it is not feasible to use dual x-ray absorptiometry (DXA) or other reference methods to measure adiposity in all pediatric clinical and research settings, it is important to identify reasonable alternatives. Therefore, we sought to determine the extent to which other adiposity measures were correlated with DXA fat mass in school-aged children. METHODS: In 1110 children aged 6.5-10.9 years in the pre-birth cohort Project Viva, we calculated Spearman correlation coefficients between DXA (n=875) and other adiposity measures including body mass index (BMI), skinfold thickness, circumferences, and bioimpedance. We also computed correlations between lean body mass measures. RESULTS: 50.0% of the children were female and 36.5% were non-white. Mean (SD) BMI was 17.2 (3.1) and total fat mass by DXA was 7.5 (3.9) kg. DXA total fat mass was highly correlated with BMI (r(s)=0.83), bioimpedance total fat (r(s)=0.87), and sum of skinfolds (r(s)=0.90), and DXA trunk fat was highly correlated with waist circumference (r(s)=0.79). Correlations of BMI with other adiposity indices were high, e.g., with waist circumference (r(s)=0.86) and sum of subscapular plus triceps skinfolds (r(s)=0.79). DXA fat-free mass and bioimpedance fat-free mass were highly correlated (r(s)=0.94). CONCLUSIONS: In school-aged children, BMI, sum of skinfolds, and other adiposity measures were strongly correlated with DXA fat mass. Although these measurement methods have limitations, BMI and skinfolds are adequate surrogate measures of relative adiposity in children when DXA is not practical

EUAdb: A Resource for COVID-19 Test Development and Comparison

Due to the sheer number of COVID-19 (coronavirus disease 2019) cases there is a need for increased world-wide SARS-CoV-2 testing capability that is both efficient and effective. Having open and easy access to detailed information about these tests, their sensitivity, the types of samples they use, etc. would be highly useful to ensure their reproducibility, to help clients compare and decide which tests would be best suited for their applications, and to avoid costs of reinventing similar or identical tests. Additionally, this resource would provide a means of comparing the many innovative diagnostic tools that are currently being developed in order to provide a foundation of technologies and methods for the rapid development and deployment of tests for future emerging diseases. Such a resource might thus help to avert the delays in testing and screening that was observed in the early stages of the pandemic and plausibly led to more COVID-19-related deaths than necessary. We aim to address these needs via a relational database containing standardized ontology and curated data about COVID-19 diagnostic tests that have been granted Emergency Use Authorizations (EUAs) by the FDA (US Food and Drug Administration). Simple queries of this actively growing database demonstrate considerable variation among these tests with respect to sensitivity (limits of detection, LoD), controls and targets used, criteria used for calling results, sample types, reagents and instruments, and quality and amount of information provided

Primary care services co-located with Emergency Departments across a UK region: early views on their development

Background Co-location of primary care services with Emergency Departments (ED) is one initiative aiming to reduce the burden on EDs of patients attending with non-urgent problems. However, the extent to which these services are operating within or alongside EDs is not currently known. This study aimed to create a typology of co-located primary care services in operation across Yorkshire and Humber (Y&H) as well as identify early barriers and facilitators to their implementation and sustainability. Methods A self-report survey was sent to the lead consultant or other key contact at 17 EDs in the Y&H region to establish the extent and configuration of co-located primary care services. Semi-structured interviews were then conducted with urgent and unscheduled care stakeholders across five hospital sites to explore the barriers and facilitators to the formation and sustainability of these services. Results Thirteen EDs completed the survey and interviews were carried out with four ED consultants, one ED nurse and three general practitioners (GPs). Three distinct models were identified: ‘Primary Care Services Embedded within the ED’ (seven sites), ‘Co-located Urgent Care Centre’ (two sites) and ‘GP out-of-hours’ (nine sites). Qualitative data were analysed using framework analysis. Four interview themes emerged (justification for the service, level of integration, referral processes and sustainability) highlighting some of the challenges in implementing these co-located primary care services. Conclusion Creating a service within or alongside the ED in which GPs can use their distinct skills and therefore add value to the existing skill mix of ED staff is an important consideration when setting up these systems. Effective triage arrangements should also be established to ensure appropriate patients are referred to GPs. Further research is required to identify the full range of models nationally and to carry out a rigorous assessment of their impact

Повышение эффективности проведения геолого-технических мероприятий на нефтяных месторождениях Западной Сибири

Рассмотрены существующие методы ГТМ, проведен анализ особенностей разных ГТМ на месторождениях Западной Сибири, предложены инновационные методы по повышению их эффективности.Existing methods of geological and technical measures are considered, the analysis of the features of different geological and technical measures at fields in Western Siberia is carried out, innovative methods for increasing their efficiency are proposed

Cross-sectional associations between sleep duration, sedentary time, physical activity, and adiposity indicators among Canadian preschool-aged children using compositional analyses

Abstract Background Sleep duration, sedentary behaviour, and physical activity are three co-dependent behaviours that fall on the movement/non-movement intensity continuum. Compositional data analyses provide an appropriate method for analyzing the association between co-dependent movement behaviour data and health indicators. The objectives of this study were to examine: (1) the combined associations of the composition of time spent in sleep, sedentary behaviour, light-intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) with adiposity indicators; and (2) the association of the time spent in sleep, sedentary behaviour, LPA, or MVPA with adiposity indicators relative to the time spent in the other behaviours in a representative sample of Canadian preschool-aged children. Methods Participants were 552 children aged 3 to 4 years from cycles 2 and 3 of the Canadian Health Measures Survey. Sedentary time, LPA, and MVPA were measured with Actical accelerometers (Philips Respironics, Bend, OR USA), and sleep duration was parental reported. Adiposity indicators included waist circumference (WC) and body mass index (BMI) z-scores based on World Health Organization growth standards. Compositional data analyses were used to examine the cross-sectional associations. Results The composition of movement behaviours was significantly associated with BMI z-scores (p = 0.006) but not with WC (p = 0.718). Further, the time spent in sleep (BMI z-score: γ sleep  = −0.72; p = 0.138; WC: γ sleep  = −1.95; p = 0.285), sedentary behaviour (BMI z-score: γ SB  = 0.19; p = 0.624; WC: γ SB  = 0.87; p = 0.614), LPA (BMI z-score: γ LPA  = 0.62; p = 0.213, WC: γ LPA  = 0.23; p = 0.902), or MVPA (BMI z-score: γ MVPA  = −0.09; p = 0.733, WC: γ MVPA  = 0.08; p = 0.288) relative to the other behaviours was not significantly associated with the adiposity indicators. Conclusions This study is the first to use compositional analyses when examining associations of co-dependent sleep duration, sedentary time, and physical activity behaviours with adiposity indicators in preschool-aged children. The overall composition of movement behaviours appears important for healthy BMI z-scores in preschool-aged children. Future research is needed to determine the optimal movement behaviour composition that should be promoted in this age group

Characterizing emergency admissions of patients with sickle cell crisis in NHS brent: observational study

OBJECTIVES: To characterize emergency admissions for patients with sickle cell crisis in NHS Brent and to determine which patients and practices may benefit most from primary care intervention. DESIGN: Observational study SETTING: Emergency departments attended by residents of the London borough of Brent PARTICIPANTS: Patients with sickle cell disease registered with a general practitioner (GP) in the borough of Brent MAIN OUTCOME MEASURES: Analysis of admissions between January 2008 and July 2010 that included length of stay (average and <2 days versus ≥2 days) by age group and registered GP practice. RESULTS: Thirty six percent of sickle cell disease admission spells resulted in a length of stay of less than two days. Seventy four percent of total bed days are associated with patients with more than one admission during the period of analysis, i.e. multiple admissions. Two general practices in Brent were identified as having the highest number of patients admitted to the emergency department for sickle cell crisis and may benefit most from primary care intervention. DISCUSSION: Patients with short length of stay and multiple admissions may be potentially amenable to primary care intervention. The practices which have the highest numbers of sickle cell disease patients who frequently seek emergency care will be earmarked for an education intervention designed to help further engage general practitioners in the care and management of their sickle cell patients

The disruption of JEN1 from Candida albicans impairs the transport of lactate

A lactate permease was biochemically identified in Candida albicans RM1000 presenting the following kinetic parameters at pH 5.0: Km 0.33 ± 0.09 mM and Vmax 0.85± 0.06 nmol s-1 mg dry wt-1. Lactate uptake was competitively inhibited by pyruvic and propionic acids; acetic acid behaved as a non-competitive substrate. An ORF homologous to Saccharomyces cerevisiae gene JEN1 was identified (CaJEN1). Deletions of both CaJEN1 alleles of C. albicans (resulting strain CPK2) resulted in the loss of all measurable lactate permease activity. No CaJEN1 mRNA was detectable in glucose-grown cells neither activity for the lactate transporter. In a medium containing lactic acid, CaJEN1 mRNA was detected in the RM1000 strain, and no expression was found in cells of CPK2 strain. In a strain deleted in the CaCAT8 genes the expression of CaJEN1 was significantly reduced, suggesting the role of this gene as an activator for CaJEN1 expression. Both in C. albicans and in S. cerevisiae cells CaJEN1-GFP fusion was expressed and targeted to the plasma membrane. The native CaJEN1 was not functional in a S. cerevisiae jen1Δ strain. Changing ser217-CTG codon (encoding leucine in S. cerevisiae) to a TCC codon restored the permease activity in S. cerevisiae, proving that the CaJEN1 gene codes for a monocarboxylate transporter.Deutsche Forschungsgemeinschaft (SFB 579).Fundação para a Ciência e a Tecnologia (FCT) - Programa Operacional “Ciência, Tecnologia, Inovação” (POCTI) - POCTI/1999/BME/36625 (Eixo 2, Medida 2.3, QCAIII-FEDER) , SFRH/BD/4699/2001 , PRAXIS XXI/BD/18198/98