Filamentous bodies in human glomerulonephritis

Filamentous bodies have been identified in the glomerular cells of human kidney biopsies. These structures have a close morphological resemblance to ciliary rootlets, although the cells of the glomerular tuft only occasionally bear cilia. Their significance could be, as for cilia, of a cellular disdifferentiation of a pathological cellular proliferation.     

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.     

Reactive oxygen species produced by NADPH oxidase regulate plant cell growth

Cell expansion is a central process in plant morphogenesis, and the elongation of roots and root hairs is essential for uptake of minerals and water from the soil. Ca2+ influx from the extracellular store is required for (and sets the rates of) cell elongation in roots. Arabidopsis thaliana rhd2 mutants are defective in Ca2+ uptake and consequently cell expansion is compromised--rhd2 mutants have short root hairs and stunted roots. To determine the regulation of Ca2+ acquisition in growing root cells we show here that RHD2 is an NADPH oxidase, a protein that transfers electrons from NADPH to an electron acceptor leading to the formation of reactive oxygen species (ROS). We show that ROS accumulate in growing wild-type (WT) root hairs but their levels are markedly decreased in rhd2 mutants. Blocking the activity of the NADPH oxidase with diphenylene iodonium (DPI) inhibits ROS formation and phenocopies Rhd2-. Treatment of rhd2 roots with ROS partly suppresses the mutant phenotype and stimulates the activity of plasma membrane hyperpolarization-activated Ca2+ channels, the predominant root Ca2+ acquisition system. This indicates that NADPH oxidases control development by making ROS that regulate plant cell expansion through the activation of Ca2+ channels.     

Melanogenesis from tryptophan. Biogenetic experiments with harding-passey mouse melanoma

Riassunto Il triptofano¹⁴C-uniformemente marcato nell'anello benzenico e il triptofano marcato¹⁴C nel metilene sono incorporati in modo significativo nella melanina del melanoma di Harding-Passey del topo.5-ossitriptofano e 5-ossitriptamina non mostrano invece una significativa incorporazione nella stessa melanina. L'incorporazione ottenuta con il triptofano marcato sia nel nucleo che nel metilene è all'incirca uguale a quella ottenuta per somministrazione di tirosina-2-C¹⁴, per cui anche il triptofano deve essere considerato un precursore delle melanine.     

An alternative decomplementation method for the measurement of the survival of human erythrocytes transfused into rats

Summary An alternative technique for measuring the survival of⁵¹Cr-labelled human erythrocytes transfused into rats is described, in which aggregated human gamma-globulin is substituted for cobra venom factor as a decomplementing agent.Acknowledgments. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico.     

Filamentous bodies in human glomerulonephritis

Summary Filamentous bodies have been identified in the glomerular cells of human kidney biopsies. These structures have a close morphological resemblance to ciliary rootlets, although the cells of the glomerular tuft only occasionally bear cilia. Their significance could be, as for cilia, of a cellular disdifferentiation of a pathological cellular proliferation.