Synthesis and Biological Evaluation of 4-Anilino-quinazolines and -quinolines as Inhibitors of Breast Cancer Resistance Protein (ABCG2).

Chemotherapeutic treatment of cancer often fails due to overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCG2, triggering active efflux of various structurally unrelated drugs. This so-called multidrug resistance (MDR) may be reversed by selective, potent, and nontoxic inhibitors of ABCG2. As only a few potent inhibitors are known, new compounds based on a 4-substituted-2-phenylquinazoline scaffold were investigated.

Sensitive CH detection applying quantum cascade laser based optical feedback cavity-enhanced absorption spectroscopy.

We report on sensitive detection of atmospheric methane employing quantum cascade laser based optical feedback cavity-enhanced absorption spectroscopy (OF-CEAS). An instrument has been built utilizing a continuous-wave distributed feedback quantum cascade laser (cw-QCL) with a V-shaped cavity, a common arrangement that reduces feedback to the laser from non-resonant reflections. The spectrometer has a noise equivalent absorption coefficient of 3.

No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3.

Background: Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing.

PTPN22 R620W minor allele is a genetic risk factor for giant cell arteritis.

Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an 'archetypal non-HLA autoimmunity gene'.

The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2).

During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives.

Extended boiling of peanut progressively reduces IgE allergenicity while retaining T cell reactivity.

Background: Current peanut oral immunotherapy is hampered by frequent adverse events. It has been shown that boiling can reduce peanut allergenicity. Hypoallergenic peanut products have the potential to reduce treatment-related reactions during desensitization.

An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion.

Amino acid sensing is an intracellular function that supports nutrient homeostasis, largely through controlled release of amino acids from lysosomal pools. The intracellular pathogen Leishmania resides and proliferates within human macrophage phagolysosomes. Here we describe a new pathway in Leishmania that specifically senses the extracellular levels of arginine, an amino acid that is essential for the parasite.

Drug-induced toxicity and patient reported outcomes in rheumatoid arthritis patients following intensive treated-to-target strategy: does ceasing therapy due to toxicity worsen outcomes in long term?

Aim: While the introduction of the treat-to-target (T2T) strategy has been an important advance in the management of rheumatoid arthritis (RA), the potential for increased toxicity due to use of concurrent drugs could adversely affect patient reported outcomes (PROs). The objective was to determine whether the cessation of therapy due to toxicity affects long-term improvement in PROs in patients treated according to T2T strategy.

Methods: A total of 149 patients from an inception cohort of early RA were included.

Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1).

Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay.

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport.

Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ.

Ten years of publicly funded biological disease-modifying antirheumatic drugs in Australia.

Biological disease-modifying antirheumatic drugs (bDMARDs) for rheumatoid arthritis (RA) treatment were among the first high-cost medicines to be subsidised in Australia. High-cost medicines pose several challenges to the Australian National Medicines Policy, which aims to provide timely access to effective medicines at a cost individuals and the community can afford. Thus, novel restriction criteria were developed to encourage cost-effective use of bDMARDs.

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours.

Background: Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT).

A model-based evaluation of single metrics for discriminating changes in rheumatoid arthritis disease activity.

Aims: Composite indices for quantifying rheumatoid arthritis (RA) disease activity such as the 28-joint disease activity score (DAS28) are comprised of single parameters ('metrics') in various combinations. Population modelling methods were used to evaluate single metrics for their ability to reflect changes in disease activity with a view to understanding and improving composite indices.

Methods: A total of 11 single metrics of RA disease activity (tender and swollen joint counts, acute phase reactants and global health, pain and physical function assessments) were obtained from 203 patients with recent onset RA.

Postnatal Hematopoiesis and Gut Microbiota in NOD Mice Deviate from C57BL/6 Mice.

Neonatal studies in different mouse strains reveal that early life colonization affects the development of adaptive immunity in mice. The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes, but neonatal studies of NOD mice are lacking. We hypothesized that NOD mice deviate from another much used mouse strain, C57BL/6, with respect to postnatal microbiota and/or hematopoiesis and compared this in newborn mice of dams housed under the same conditions.

Gut Microbiota in Children Hospitalized with Oedematous and Non-Oedematous Severe Acute Malnutrition in Uganda.

Background: Severe acute malnutrition (SAM) among children remains a major health problem in many developing countries. SAM manifests in both an oedematous and a non-oedematous form, with oedematous malnutrition in its most severe form also known as kwashiorkor. The pathogenesis of both types of malnutrition in children remains largely unknown, but gut microbiota (GM) dysbiosis has recently been linked to oedematous malnutrition.

Phenotype of NK Cells Determined on the Basis of Selected Immunological Parameters in Children Treated due to Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. The chemotherapy for ALL is associated with a profound secondary immune deficiency.We evaluated the number and phenotype of natural killer (NK) cells at diagnosis, after the intensive chemotherapy and following the completion of the entire treatment for patients with ALL.

Obesity Suppresses Estrogen Receptor Beta Expression in Breast Cancer Cells via a HER2-Mediated Pathway.

Obesity is associated with a worse breast cancer prognosis, while greater breast tumor estrogen receptor beta (ERβ) expression is correlated with improved therapy response and survival. The objective of this study was to determine the impact of obesity on breast cancer cell ERβ expression, which is currently unknown. We utilized an in vitro model of obesity in which breast cancer cells were exposed to patient serum pooled by body mass index category (obese (OB): ≥30 kg/m2; normal weight (N): 18.

Medication Regimen Complexity and Number of Medications as Factors Associated With Unplanned Hospitalizations in Older People: A Population-based Cohort Study.

Background: Adverse drug events are a leading cause of hospitalization among older people. Up to half of all medication-related hospitalizations are potentially preventable. The objective of this study was to investigate and compare the association between medication regimen complexity and number of medications with unplanned hospitalizations over a 3-year period.

Determining the acceptable level of physician compliance with a treat-to-target strategy in early rheumatoid arthritis.

Objective: To determine the minimum cut-points for rate of physician compliance with a treat-to-target (T2T) strategy needed to achieve optimal rates of remission or low disease activity (LDA).

Method: In this analysis of longitudinal observational data from patients with early RA, physician compliance with a T2T treatment protocol was determined for each clinic visit over 3 years. Remission and LDA were measured by Disease Activity Score in 28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI).

Medication Regimen Complexity and Polypharmacy as Factors Associated With All-Cause Mortality in Older People: A Population-Based Cohort Study.

Objectives: To investigate whether medication regimen complexity and/or polypharmacy are associated with all-cause mortality in older people.

Methods: This was a population-based cohort study among community-dwelling and institutionalized people ≥60 years old (n = 3348). Medication regimen complexity was assessed using the 65-item Medication Regimen Complexity Index (MRCI) in 10-unit steps.

Knowing, planning for and fearing death: Do adults with intellectual disability and disability staff differ?

Background: Adults with intellectual disability (ID) are thought to understand less about death than the general population but there is no available research demonstrating this. Further, the detail of any possible differences in understanding is unknown.

Methods: We compared the responses of 39 adults with mild or moderate ID and 40 disability staff (representing the general population) on (a) understanding the concept of death, (b) knowledge of and self-determination about end-of-life planning, and (c) fear-of-death.

An unexpected cause for cavitary pneumonia and empyema.

Tularemia is an emerging zoonotic disease mainly of the Northern Hemisphere caused by the Gram-negative coccobacillus Francisella tularensis. It is affecting a wide range of animals and causes human disease after insect and tick bites, skin contact, ingestion and inhalation. A 66-year-old man presented to our clinic with cavitary pneumonia and distinct pleural effusion.

Effectiveness and Safety of Tenofovir Disoproxil Fumarate in Chronic Hepatitis B: A 3-Year Prospective Field Practice Study in Germany.

Background And Aims: Multiple clinical trials have demonstrated the efficacy and safety of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB). However, long-term efficacy and safety data for TDF in real-life clinical practice are limited.

Methods: Prospective German field practice study in CHB-mono-infected patients.

Sorption Behavior of Compressed CO2 and CH4 on Ultrathin Hybrid Poly(POSS-imide) Layers.

Sorption of compressed gases into thin polymeric films is essential for applications including gas sensors and membrane based gas separation. For glassy polymers, the sorption behavior is dependent on the nonequilibrium status of the polymer. The uptake of molecules by a polymer is generally accompanied by dilation, or swelling, of the polymer material.