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Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.

Kinases are the major anticancer drug target class of the 21st century with nearly sixty small molecule kinase inhibitors approved for clinical use in the first two decades. While there are more than 500 kinases encoded by the human genome, currently approved inhibitors act primarily through approximately twenty different targets. Key to the success of kinase inhibitor therapy has been the simultaneous development of biomarker assays to enable the selection of patients most likely to respond. Predictive drug response biomarkers can be identified with cancer cell panel profiling, which is the parallel testing of compounds on a large panel of cancer cell lines. By correlating drug sensitivity with genomic information of the cell lines, strategies for patient stratification or drug repurposing have been developed [1-3]. In two earlier studies [2,3], we compared the kinase selectivity and the cellular inhibition profiles of all kinase inhibitors approved by the FDA until May 2018. Here, we will present the cancer cell panel profiling of all twenty small molecule kinase inhibitors approved since then. Several of these inhibitors act through well-known targets, such as ALK (lorlatinib), BRAF (encorafenib), EGFR (dacomitinib) and MEK1 (binimetinib, selumetinib). Others act through kinases for which no small molecule inhibitors have been approved before, such as CSF1R (pexidartinib), FGFR (erdafitinib, pemigatinib), c-MET (capmatinib), RET (selpercatinib, pralsetinib) and TRK (larotrectinib, entrectinib). All compounds were profiled on a panel of 102 cancer cell lines, known as Oncolines, representing a wide range of solid tumors and hematological malignancies, and harboring mutant and wild-type versions of many major cancer driver genes [3]. To determine similarities in the mechanisms underlying the anti-proliferative activity of the inhibitors, their IC50 fingerprint in the cell proliferation assays were compared by hierarchical clustering [4]. Compounds that act through the same primary kinase clustered together in this analysis. Exceptions were investigated further by profiling of additional cell lines, representing cancer gene alterations that were not present in the 102 cell line panel, such as FLT3 mutation and TRK-gene fusions, which occur in relatively small cancer patient populations. To compare the genomic targeting of kinase inhibitors acting on the same biochemical target, the cancer cell lines were classified as either “mutant” or “wild-type” for specific cancer gene alterations and were grouped per cancer gene. The relationship between drug sensitivity and cancer gene mutation status was examined. Detailed genomic biomarker analyses and comparative profiling results of novel BTK, EGFR, FGFR, FLT3 and TRK kinase inhibitors will be presented.[1] Mol Cancer Ther 2017;26:2609-17; [2] PLoS ONE 2014;9:e92146; [3] Mol Cancer Ther 2019;18:470-81; [4] Mol Cancer Ther 2016;15:3097-109 Citation Format: Jeffrey J. Kooijman, Wilhelmina E. van Riel, Martine B. Prinsen, Jelle Dylus, Jeroen A. de Roos, Yvonne Grobben, Nicole Willemsen-Seegers, Michelle Muller, Jos de Man, Yugo Narumi, Yusuke Kawase, Rogier C. Buijsman, Suzanne J. van Gerwen, Guido J. Zaman. Comparative cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1480.

Background Congenital rubella syndrome (CRS) includes disorders associated with intrauterine rubella infection. Incidence of CRS is higher in countries with no rubella-containing vaccines (RCV) in their immunization schedules. In the World Health Organization African region, RCVs are being introduced as part of the 2012–2020 global measles and rubella strategic plan. This study aimed to describe the epidemiology of confirmed CRS in South Africa prior to introduction of RCVs in the immunization schedule. Methods This was a descriptive study with 28 sentinel sites reporting laboratory-confirmed CRS cases in all 9 provinces of South Africa. In the retrospective phase (2010 to 2014), CRS cases were retrieved from medical records, and in the prospective phase (2015 to 2017) clinicians at study sites reported CRS cases monthly. Results There were 42 confirmed CRS cases in the retrospective phase and 53 confirmed CRS cases in the prospective phase. Most frequently reported birth defects were congenital heart disease and cataracts. The median age of mothers of CRS cases was 21 years in the retrospective phase (range: 11 to 38 years) and 22 years in the prospective phase (range: 15 to 38 years). Conclusion Baseline data on laboratory-confirmed CRS will enable planning and monitoring of RCV implementation in the South African Expanded Programme on Immunization program. Ninety-eight percent of mothers of infants with CRS were young women 14–30 years old, indicating a potential immunity gap in this age group for consideration during introduction of RCV., Sentinel site surveillance for congenital rubella in South Africa identified 95 cases from 2010 through 2017. Mothers of infants with congenital rubella were 14–38 years old. This information will inform planning of rubella vaccine introduction in the region.

Huntington's disease (HD) is one of many neurodegenerative diseases with reported alterations in brain iron homeostasis that may contribute to neuropathogenesis. Iron accumulation in the specific brain areas of neurodegeneration in HD has been proposed based on observations in post-mortem tissue and magnetic resonance imaging studies. Altered magnetic resonance imaging signal within specific brain regions undergoing neurodegeneration has been consistently reported and interpreted as altered levels of brain iron. Biochemical studies using various techniques to measure iron species in human samples, mouse tissue, or in vitro has generated equivocal data to support such an association. Whether elevated brain iron occurs in HD, plays a significant contributing role in HD pathogenesis, or is a secondary effect remains currently unclear.

Avec la recente adhesion de dix nouveaux pays a la communaute europeenne, notre article a pour objectif la description des professions annexes aux chirurgiens dentistes dans les vingt-cinq pays de l’union. Trois grandes categories professionnelles emergent de cette etude. Les prothesistes dentaires representent celle ayant le mode d’exercice le plus similaire d’un etat a l’autre. Allant de la reception des patients a la realisation de certains actes, l’activite des assistantes dentaires quant a elle varie entre les etats. Enfin, exercant dans les domaines de l’hygiene et de la prophylaxie, les hygienistes dentaires ne sont pas reconnus dans tous les etats. L’harmonisation des systemes de sante intra-communautaires laisse envisager la mise en place de reformes afin d’offrir aux patients la plus grande qualite de soins.

Contains fulltext : 153826.pdf (Publisher’s version ) (Closed access) BACKGROUND: Magnesium (Mg(2+)) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg(2+) levels

Description of the Mathematics Investigation Center (MIC), a tool to help elementary teachers differentiate the curriculum for their gifted mathematics students. Using the same mathematical theme that the rest of the class is studying, the activities provide depth for the gifted students by shifting from a computation level to a problem solving level.

We present a case of a 59 year old asymptomatic lady who was found to have incidental findings of pulmonary, osseous and hepatic involvement with sarcoidosis. The osseous lesions were lytic and involved unusual sites such as the vertebrae and skull base. The initial clinical concern had been of multiple myeloma or disseminated metastases. Biopsy of material obtained following mediastinoscopy revealed chronic, non-necrotising granulomatous lymphadenopathy indicative of sarcoidosis. Cases such as this could greatly benefit from multidisciplinary team discussion particularly when the clinical picture is not typical of malignancy.

A través de uma análise comparativa dos conjuntos residenciais de Pelotas, RS, este estudo visa a identificar variáveis que permitam aprimorar as práticas de gestão habitacional, buscando contribuir para a melhoria desses espaços e propor parâmetros para novos projetos. Foram realizados quatro estudos de caso em conjuntos habitacionais, públicos e privados. Com ênfase nos processos de gestão habitacional, efetuou-se uma avaliação pósocupação funcional, técnica e comportamental. Os principais resultados encontrados foram: (a) os espaços coletivos dos conjuntos públicos apresentam problemas de manutenção e conservação; (b) a maioria dos moradores não participa da organização do condomínio em ambos os tipos de conjuntos habitacionais; e (c) foram detectadas mudanças feitas pelos moradores, inserindo novos usos e ampliações, não existindo controle destes por parte do condomínio. Esses resultados mostram que a habitação de interesse social deve ser entendida como prestação de serviços habitacionais. Além disto, a avaliação da gestão condominial desses conjuntos tem mostrado a fragilidade da lei de condomínios para lidar com as complexas relações existentes nos conjuntos habitacionais populares., Based on a comparative analysis of housing estates from Pelotas, RS, this study aims to identify variables that support the improvement of housing management practices, in order to make contributions for the improvement of such spaces and propose parameters for new designs. Four case studies were carried out in housing estates, some promoted by both the state and others by private developers. A functional, technical and behavioural post occupancy evaluation was carried out, emphasising housing management processes. The main results of this research study were: (a) the housing states promoted by the state had problems related to maintenance and conservation of collective spaces; (b) most dwellers do not take part in the condominium organisation in both types of estates; and (c) several changes made by dwellers were detected, including new uses and building extensions, and the building managers do not have control on them. The results suggest that social housing must be regarded as the provision of housing services. Moreover, the assessment of condominium management in those housing estates indicates that the Brazilian condominium law is inadequate for dealing with the complex relationships that exist in housing estates for low income people.

This study evaluated the surface finish of three direct resin composites polished with three different systems. Disk-shaped specimens (n=16 per material; phi=8.0 mm x h=2.0 mm) were formed in a stainless steel mold by packing uncured material, either a hybrid composite (Z250, 3M ESPE) or two micro-hybrid composites (Point 4, Kerr; Esthet-X, Dentsply), and light-cured from the top and the bottom surfaces with a light-emitting diode (LED) curing unit (NRG, Dentsply). After storing the specimens in deionized water at 37 degrees C for seven days, one side of each specimen was finished through 1200-grit SiC abrasive (Buehler). Five specimens of each resin composite were randomly assigned to one of the three polishing systems (Identoflex, Kerr; Pogo, Dentsply; Sof-Lex, 3M ESPE). Manufacturers' instructions were followed during the polishing procedures. The average surface roughness (Ra) was determined by generating tracings across the polished surface of each disk using a scanning profilometer (Surfanalyzer System 5000, Federal Products Co). The results were analyzed by Kruskal-Wallis and Mann and Whitney tests (por = 0.05). The smoothest surfaces were produced with the celluloid strip (control group) on all the resin composites tested. The aluminum oxide disks (Sof-Lex) produced a statistically equivalent surface finish (Ra) on the three resin composites. The lowest mean roughness values were recorded with diamond micropolisher disks (PoGo) on the hybrid composite (Z250). Overall, the two new polishing systems, Identoflex and PoGo, created a comparable surface finish to that produced by the Sof-Lex system on all three resin composites.

Arg249 in the large (alpha) subunit of human electron transfer flavoprotein (ETF) heterodimer is absolutely conserved throughout the ETF superfamily. The guanidinium group of alphaArg249 is within van der Waals contact distance and lies perpendicular to the xylene subnucleus of the flavin ring, near the region proposed to be involved in electron transfer with medium chain acyl-CoA dehydrogenase. The backbone amide hydrogen of alphaArg249 is within hydrogen bonding distance of the carbonyl oxygen at the flavin C(2). alphaArg249 may modulate the potentials of the two flavin redox couples by hydrogen bonding the carbonyl oxygen at C(2) and by providing delocalized positive charge to neutralize the anionic semiquinone and anionic hydroquinone of the flavin. The potentials of the oxidized/semiquinone and semiquinone/hydroquinone couples decrease in an alphaR249K mutant ETF generated by site directed mutagenesis and expression in Escherichia coli, without major alterations of the flavin environment as judged by spectral criteria. The steady state turnover of medium chain acyl-CoA dehydrogenase and glutaryl-CoA dehydrogenase decrease greater than 90% as a result of the alphaR249Ks mutation. In contrast, the steady state turnover of short chain acyl-CoA dehydrogenase was decreased about 38% when alphaR249K ETF was the electron acceptor. Stopped flow absorbance measurements of the oxidation of reduced medium chain acyl-CoA dehydrogenase/octenoyl-CoA product complex by wild type human ETF at 3 degrees C are biphasic (t(1/2)=12 ms and 122 ms). The rate of oxidation of this reduced binary complex of the dehydrogenase by the alphaR249K mutant ETF is extremely slow and could not be reasonably estimated. alphaAsp253 is proposed to function with alphaArg249 in the electron transfer pathway from medium chain acyl-CoA dehydrogenase to ETF. The steady state kinetic constants of the dehydrogenase were not altered when ETF containing an alphaD253A mutant was the substrate. However, t(1/2) of the rapid phase of oxidation of the reduced medium chain acyl-CoA dehydrogenase/octenoyl-CoA charge transfer complex almost doubled. betaTyr16 lies on a loop near the C(8) methyl group, and is also near the proposed site for interflavin electron transfer with medium chain acyl-CoA dehydrogenase. The tyrosine residue makes van der Waals contact with the C(8) methyl group of the flavin in human ETF and Paracoccus denitrificans ETF (as betaTyr13) and lies at a 30 degrees C angle with the plane of the flavin. Human betaTyr16 was substituted with leucine and alanine residues to investigate the role of this residue in the modulation of the flavin redox potentials and in electron transfer to ETF. In betaY16L ETF, the potentials of the flavin were slightly reduced, and steady state kinetic constants were modestly altered. Substitution of an alanine residue for betaTyr16 yields an ETF with potentials very similar to the wild type but with steady state kinetic properties similar to betaY16L ETF. It is unlikely that the beta methyl group of the alanine residue interacts with the flavin C(8) methyl. Neither substitution of betaTyr16 had a large effect on the fast phase of ETF reduction by medium chain acyl-CoA dehydrogenase.