Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs

Marine-originated spirocyclic bromotyrosines are considered as promising scaffolds for new anticancer drugs. In a continuation of our research to develop potent and more selective anticancer compounds, we synthesized a library of 32 spirocyclic clavatadine analogs by replacing the agmatine, i.e., 4-(aminobutyl)guanidine, side chain with different substituents. These compounds were tested for cytotoxicity against skin cancer using the human melanoma cell line (A-375) and normal human skin fibroblast cell line (Hs27). The highest cytotoxicity against the A-375 cell line was observed for dichloro compound 18 (CC50 0.4 ± 0.3 µM, selectivity index (SI) 2). The variation of selectivity ranged from SI 0.4 to reach 2.4 for the pyridin-2-yl derivative 29 and hydrazide analog of 2-picoline 37. The structure–activity relationships of the compounds in respect to cytotoxicity and selectivity toward cancer cell lines are discussed

Umbilically and Peripherally Inserted Thin Central Venous Catheters Have Similar Risks of Complications in Very Low-Birth-Weight Infants

Catheter complications can be life-threatening in very low-birth-weight (VLBW) infants. We retrospectively evaluated non-elective removals of the first thin (1-2F) umbilical vein catheters (tUVCs (n = 92)) and peripherally inserted central venous catheters (PICCs (n = 103)) among 195 VLBW infants. Catheters were removed non-electively in 78 infants (40%), typically due to suspected infection (n = 42) or catheter dislocation (n = 30). Infants with complications had lower birth weights and gestational ages than others. The frequencies and causes of catheter removal were similar in the tUVC and PICC groups. Thirty-one infants had true catheter infections. The number of infections/1000 catheter days was higher in the tUVC group than in the PICC group. In a multivariable analysis, gestational age was associated with catheter infection, but catheter type was not. The odds of catheter complications decreased with increasing gestational age, but no clear association with thin catheter type was found.publishedVersionPeer reviewe

Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6

The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.This work was supported by (J.-H.L. and J.C.) Wellcome Trust and the Royal Society (107633/Z/15/Z), European Research Council Starting Grant (679411), and the Cambridge Stem Cell Institute Core grant (07922/Z/11/Z) from Wellcome Trust and Medical Research Council; (J.-H.L.) the Hope Funds for Cancer Research; (M.P.) American Lung Association (400553); (A.R.) Howard Hughes Medical Institute, the Klarman Cell Observatory, and NCI grant 1U24CA180922; (A.R., T.T., and T.J.) the Koch Institute Core grant P30-CA14051 from the NCI; (T.T.) the National Cancer InstituteK99 CA187317, the Sigrid Juselius Foundation, the Hope Funds for Cancer Research; (T.J.) a Howard Hughes Medical Institute Investigator, a David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar; and (C.F.K.) R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402, Harvard Stem Cell Institute, Alfred and Gilda Slifka, Gail and Adam Slifka, and the CFMS Fund

Upconversion assisted self-pulsing in a high-concentration erbium doped fiber laser

We report results on experimental and theoretical characterisation of self-pulsing in high concentration erbium doped fibre laser which is free from erbium clusters. Unlike previous models of self-pulsing accounting for pair-induced quenching (PIQ) on the clustered erbium ions, new model has been developed with accounting for statistical nature of the excitation migration and upconversion and resonance-like pumpto-signal intensity noise transfer. The obtained results are in a good agreement with the experimental data

Extended life span of human endometrial stromal cells transfected with cloned origin-defective, temperature-sensitive simian virus 40.

Human endometrial stromal cells transfected with an origin-defective, temperature-sensitive simian virus 40 recombinant plasmid are dependent on T-antigen function for proliferation and at the permissive temperature have an extended life span in culture. Southern blot analysis indicates that the transfected gene is present in low copy number, possibly at a single integration site. Normal stromal cells are capable of 10 to 20 population doublings in culture. Transfected cultures have been carried at the permissive temperature to 80 population doublings before crisis. In the multistep model of malignant transformation of human cells, these cells represent one of the earliest stages: extended but finite life span. We have used these cells to investigate alterations in signal transduction that may be responsible for this early stage of transformation caused by the large T antigen. Temperature shift experiments indicate that the expression of ornithine decarboxylase (ODC) but not of c-fos is altered by the large T antigen. Induction of c-fos by serum or 12-O-tetradecanoylphorbol-13-acetate is independent of temperature. However, in the transfected cells, the induction of ODC by asparagine or serum is greatly enhanced at the permissive temperature. This result indicates that the large T antigen acts downstream of c-fos but upstream of ODC expression in the signal-transducing cascade

Contribution of flow conditions and sand addition on hyporheic zone exchange in gravel beds

We conducted a series of tracer test experiments in 12 outdoor semi-natural flumes to assess the effects of variable flow conditions and sand addition on hyporheic zone conditions in gravel beds, mimicking conditions in headwater streams under sediment pressure. Two tracer methods were applied in each experiment: 2–5 tracer-pulse tests were conducted in all flumes and pulses were monitored at three distances downstream of the flume inlet (0 m, 5 m and 10 m, at bed surface), and in pipes installed into the gravel bed at 5 m and 10 m distances. The tracer breakthrough curves (total of 120 tracer injections) were then analysed with a one-dimensional solute transport model (OTIS) and compared with data from the gravel pipes in point-dilution pulse tests. Sand addition had a strong negative effect on horizontal fluxes (qh), whereas the fraction of the median travel time due to transient storage (F200) was determined more by flow conditions. These results suggest that even small additions of sand can modify the hyporheic zone exchange in gravel beds, thus making headwater streams with low sediment transport capacity particularly vulnerable to sediments transported into the stream from catchment land use activities

Aplicação da simulação discreta na gestão de estoques de sobressalentes para turbomáquinas numa empresa brasileira do setor de óleo e gás

No Brasil, as indústrias do setor de petróleo têm recentemente se deparado com o grande desafio de viabilizar a produção em um ambiente de maior complexidade de acesso e restrições operacionais, dentro de um cenário de cortes de orçamento e controle de custos. Sendo assim, a cadeia de suprimentos tem importante papel para a otimização de processos, na redução de custos de aquisição e estocagem. Neste contexto, o presente artigo trata da gestão de estoques de peças sobressalentes de uma oficina de manutenção de turbomáquinas de uma empresa petrolífera. A gestão de estoques de manutenção possui grande complexidade, devido as características intermitente e errática da demanda. Os sobressalentes das turbomáquinas também são de difícil gestão, são em sua maioria importados, de alto valor e com poucos fornecedores no mercado. Propõe-se então, neste trabalho, a utilização de técnicas de simulação discreta para comparação de diferentes políticas de gestão de estoques. Espera-se conhecer melhor os impactos das alterações nos níveis e políticas de estoques em toda a cadeia de suprimentos e estoques, visando adequar os níveis de estoque de sobressalentes aos níveis de serviço requeridos e otimizar os recursos imobilizados em estoque.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Aplicação da simulação discreta na gestão de estoques de sobressalentes para turbomáquinas numa empresa brasileira do setor de óleo e gás

No Brasil, as indústrias do setor de petróleo têm recentemente se deparado com o grande desafio de viabilizar a produção em um ambiente de maior complexidade de acesso e restrições operacionais, dentro de um cenário de cortes de orçamento e controle de custos. Sendo assim, a cadeia de suprimentos tem importante papel para a otimização de processos, na redução de custos de aquisição e estocagem. Neste contexto, o presente artigo trata da gestão de estoques de peças sobressalentes de uma oficina de manutenção de turbomáquinas de uma empresa petrolífera. A gestão de estoques de manutenção possui grande complexidade, devido as características intermitente e errática da demanda. Os sobressalentes das turbomáquinas também são de difícil gestão, são em sua maioria importados, de alto valor e com poucos fornecedores no mercado. Propõe-se então, neste trabalho, a utilização de técnicas de simulação discreta para comparação de diferentes políticas de gestão de estoques. Espera-se conhecer melhor os impactos das alterações nos níveis e políticas de estoques em toda a cadeia de suprimentos e estoques, visando adequar os níveis de estoque de sobressalentes aos níveis de serviço requeridos e otimizar os recursos imobilizados em estoque.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Small RNA combination therapy for lung cancer

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)National Institutes of Health (U.S.) (Grant 2-PO1-CA42063)National Institutes of Health (U.S.) (Grant RO1-EB000244)National Institutes of Health (U.S.) (Grant RO1-CA115527)National Institutes of Health (U.S.) (Grant RO1-CA132091)National Cancer Institute (U.S.) (1K99CA169512)American Association for Cancer Research (Fellowship)Leukemia & Lymphoma Society of America (Fellowship)National Science Foundation (U.S.). Graduate Research Fellowship ProgramMassachusetts Institute of Technology. Presidential FellowshipUnited States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship