Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.National Institutes of Health (U.S.) (U54 CA210180)MIT/Mayo Physical Sciences Center for Drug Distribution and Drug Efficacy in Brain TumorsDana-Farber Cancer Institute (PLGA Fund)Lundbeck FoundationNovo Nordisk Foundatio

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation

Pequi leaves incorporated into the soil reduce the initial growth of cultivated, invasive and native species

Estudos têm identificado potencial fitotóxico de tecidos vegetais de diversas espécies do Cerrado. Entretanto, a maior parte destes estudos foi conduzida em substrato inerte, ou fazendo uso de quantidades exageradas de material vegetal. Neste estudo investigamos o potencial fitotóxico de folhas de pequi adicionadas a substrato solo em quantidades compatíveis ao volume de liteira produzida por esta espécie no campo. Folhas de pequi foram trituradas e incorporadas a latossolo vermelho em proporções entre 0,75 e 3% (p/p), sendo o controle constituído por solo sem folhas. Estas misturas foram adicionadas a vasos plásticos irrigados diariamente. Sementes germinadas das espécies cultivadas sorgo e gergelim, da invasora braquiária, e da nativa ipê-roxo foram dispostas nos vasos e crescidas por cinco a sete dias a 30°C, com fotoperíodo de 12 h. Plântulas de todas as espécies apresentaram redução dose-dependente no crescimento, sendo o crescimento radicular mais afetado que o aéreo. Sinais de necrose foram observados nas raízes de sorgo, gergelim e braquária. Os efeitos fitotóxicos gerados por uma quantidade relativamente baixa de tecido vegetal, em substrato solo, e em razoável número de espécies de diferentes grupos funcionais sugerem que a liteira desta espécie possa exercer real potencial alelopático em condições de campo.Studies have identified the phytotoxicity of many native species of the Cerrado; however, most of them were conducted either in inert substrates, or using exaggerate proportions of plant material. We investigated the phytotoxicity of pequi leaves added to substrate soil in quantities compatible with the litter produced by this species. Pequi leaves were triturated and added to red latosol in concentrations of 0.75%, 1.5% and 3%; the control was constituted of leafless soil. These mixtures were added to pots and irrigated daily to keep them moist. Germinated seeds of the cultivated sorghum and sesame, of the invasive brachiaria and of the native purple ipê, were disposed in the pots to grow for five to seven days at 30°C within a photoperiod of 12 h. Seedlings of all the species presented a reduction in their initial growth in a dose-dependent way. In general, the root growth was more affected by the treatments than the shoot growth; moreover, signs of necrosis were observed in the roots of the sorghum, sesame and brachiaria. The phytotoxic effects generated by relatively small quantities of leaves, in a reasonable range of species within a soil substrate, suggest potential allelopathy of pequi leaves under natural conditions

Precision measurement of CP\it{CP} violation in the penguin-mediated decay Bs0→ϕϕB_s^{0}\rightarrow\phi\phi

A flavor-tagged time-dependent angular analysis of the decay $B_s^{0}\rightarrow\phi\phi$ is performed using $pp$ collision data collected by the LHCb experiment at % at $\sqrt{s}=13$ TeV, the center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6 fb^{-1}. The $\it{CP}$-violating phase and direct $\it{CP}$-violation parameter are measured to be $\phi_{s\bar{s}s} = -0.042 \pm 0.075 \pm 0.009$ rad and $|\lambda|=1.004\pm 0.030 \pm 0.009$, respectively, assuming the same values for all polarization states of the $\phi\phi$ system. In these results, the first uncertainties are statistical and the second systematic. These parameters are also determined separately for each polarization state, showing no evidence for polarization dependence. The results are combined with previous LHCb measurements using $pp$ collisions at center-of-mass energies of 7 and 8 TeV, yielding $\phi_{s\bar{s}s} = -0.074 \pm 0.069$ rad and $|lambda|=1.009 \pm 0.030$. This is the most precise study of time-dependent $\it{CP}$ violation in a penguin-dominated $B$ meson decay. The results are consistent with $\it{CP}$ symmetry and with the Standard Model predictions.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-001.html (LHCb public pages

Measurement of the Λb0→Λ(1520)μ+μ−\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-} differential branching fraction

The branching fraction of the rare decay $\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-}$ is measured for the first time, in the squared dimuon mass intervals, $q^2$, excluding the $J/\psi$ and $\psi(2S)$ regions. The data sample analyzed was collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of $9\ \mathrm{fb}^{-1}$. The result in the highest$q^{2}$interval,$q^{2} >15.0\ \mathrm{GeV}^2/c^4$, where theoretical predictions have the smallest model dependence, agrees with the predictions.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-050.html (LHCb public pages

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data