Search

We compare Einstein-Boltzmann solvers that include modifications to general relativity and find that, for a wide range of models and parameters, they agree to a high level of precision. We look at three general purpose codes that primarily model general scalar-tensor theories, three codes that model Jordan-Brans-Dicke (JBD) gravity, a code that models f(R) gravity, a code that models covariant Galileons, a code that models Hořava-Lifschitz gravity, and two codes that model nonlocal models of gravity. Comparing predictions of the angular power spectrum of the cosmic microwave background and the power spectrum of dark matter for a suite of different models, we find agreement at the subpercent level. This means that this suite of Einstein-Boltzmann solvers is now sufficiently accurate for precision constraints on cosmological and gravitational parameters.

Introduction: Ewing Sarcoma (EWS) has been reported in seven children with Down syndrome (DS). To date, a detailed assessment of this solid tumour in DS patients is yet to be made., Methods: Here, we characterise a chemo-resistant mediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches., Results: The tumour showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability., Discussion: In this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peirone, Tirtei, Campello, Parlato, Guarrera, Mareschi, Marini, Asaftei, Bertero, Papotti, Priante, Perrone, Cereda and Fagioli.)

Selective KRAS G12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS G12C -mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients' biopsies identified a number of acquired KRAS mutations -both in cis and in trans- in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRAS G12C -selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRAS G12C (ON) inhibitor RMC-6291 alone or in combination with KRAS G12C (OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading., (© 2024. The Author(s).)

Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an "exon definition" mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The onset of multiple and metachronous tumors in young patients induces to suspect the presence of genetic variants in genes associated with tumorigenesis. We describe here the unusual case of a 16-year-old patient who developed a synchronous bifocal colorectal adenocarcinoma with distant metastases. We provide high throughput molecular characterization with whole-exome sequencing (WES) and DNA targeted sequencing of different tumoral lesions and normal tissue samples that led to unveil a germline POLE mutation (p.Ser297Cys) coexisting with the PMS2 c.2174 + 1 G > A splicing mutation. This clinical scenario defines a "POLE-LYNCH" collision syndrome, which explains the ultra-mutator phenotype observed in the tumor lesions, and the presence of MMR deficiency-associated unusual signatures. The patient was successfully treated with immune checkpoint inhibitors but subsequently developed a high-grade urothelial carcinoma cured by surgery. We complement this analysis with a transcriptomic characterization of tumoral lesions with a panel targeting 770 genes related to the tumor microenvironment and immune evasion thus getting insight on cancer progression and response to immunotherapy., (© 2022. The Author(s).)

Artificial intelligence, or the discipline of developing computational algorithms able to perform tasks that requires human intelligence, offers the opportunity to improve our idea and delivery of precision medicine. Here, we provide an overview of artificial intelligence approaches for the analysis of large-scale RNA-sequencing datasets in cancer. We present the major solutions to disentangle inter- and intra-tumor heterogeneity of transcriptome profiles for an effective improvement of patient management. We outline the contributions of learning algorithms to the needs of cancer genomics, from identifying rare cancer subtypes to personalizing therapeutic treatments.

Heterogeneity is a fundamental feature of complex phenotypes. So far, genomic screenings have profiled thousands of samples providing insights into the transcriptome of the cell. However, disentangling the heterogeneity of these transcriptomic Big Data to identify defective biological processes remains challenging. Here we present GSECA, a method exploiting the bimodal behavior of RNA-sequencing gene expression profiles to identify altered gene sets in heterogeneous patient cohorts. Using simulated and experimental RNA-sequencing data sets, we show that GSECA provides higher performances than other available algorithms in detecting truly altered biological processes in large cohorts. Applied to 5941 samples from 14 different cancer types, GSECA correctly identified the alteration of the PI3K/AKT signaling pathway driven by the somatic loss of PTEN and verified the emerging role of PTEN in modulating immune-related processes. In particular, we showed that, in prostate cancer, PTEN loss appears to establish an immunosuppressive tumor microenvironment through the activation of STAT3, and low PTEN expression levels have a detrimental impact on patient disease-free survival. GSECA is available at https://github.com/matteocereda/GSECA., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The kinetics of the cis-3-hexene + OH reaction were investigated by an experimental relative rate method and at the density functional theory level. The experimental set-up consisted of a 200 L Teflon bag, operated at atmospheric pressure and 298 K. OH radicals were produced by the photolysis of H2O2 at 254 nm. Relative rate coefficients were determined by comparing the decays of the cis-3-hexene and reference compounds (cyclohexene, 2-buten-1-ol and allyl ether). The mean second-order rate coefficient value found was (6.27 ± 0.66) × 10(-11) cm(3) molecule(-1) s(-1), the uncertainty being estimated by propagation of errors. Theoretical calculations for the addition reaction of OH to cis-3-hexene have also been performed, at the BHandHLYP/aug-cc-pVDZ level, in order to investigate the reaction mechanism, to clarify the experimental observations and to model the reaction kinetics. Different conformations of the reactants, pre-barrier complexes and saddle points were considered in our calculations. The individual rate coefficients, calculated for each conformer of the reactant, at 298 K, using a microcanonical variational transition state method, are 4.19 × 10(-11) and 1.23 × 10(-10) cm(3) molecule(-1) s(-1). The global rate coefficient was estimated from the Boltzmann distribution of the conformers to be 8.10 × 10(-11) cm(3) molecule(-1) s(-1), which is in agreement with the experimental value. Rate coefficients calculated over the temperature range from 200-500 K are also given. Our results suggest that the complex mechanism, explicitly considering different conformations for the stationary points, must be taken into account for a proper description of the reaction kinetics.

The compared kinetics of the reactions of unsaturated alcohols and alkenes with OH radicals is a topic of great interest from both the theoretical chemistry and the atmospheric chemistry points of view. The enhanced reactivity of an unsaturated alcohol, with respect to its alkene analogue, toward OH radicals has been previously demonstrated, at 298 K, by experimental and theoretical research. In this work, a new comparative investigation of such reactions is performed for 3-buten-1-ol and 1-butene. The model assumes that the overall kinetics is governed by the first OH addition steps of the mechanism. Calculations have been performed at the DFT level, employing the BHandHLYP functional and the cc-pVDZ and aug-cc-pVDZ basis sets, and the rate coefficients have been determined on the basis of the microcanonical variational transition state theory. The rate coefficients obtained for the OH reactions with 3-buten-1-ol (kOH(31BO)) and 1-butene (kOH(1B)) at 298.15 K are lower than the experimental rate coefficient available in the literature, showing deviations of 18% and 25%, respectively. Negative temperature dependence is verified for these rate coefficients. The kOH(31BO)/kOH(1B) ratios have also been investigated as a function of the temperature, suggesting that at room temperature the unsaturated alcohol reacts with the OH radicals faster than 1-butene, by a factor of 1.2, but at higher temperatures (400-500 K), the alkene should react faster, and that the stabilization of prebarrier complexes and saddle points due to hydrogen bonds is no longer an important factor to govern the reactivity of the unsaturated alcohol toward OH radicals, with respect to the alkene analogue.

The aim of the present study was to investigate, "in vitro", the degree of organogenetic potentiality of the cells of the cardiogenic area during the early developmental stages of the chick embryo. Embryos from between the end of the presomitic stage to the 8 somite stage were studied. The subcephalic fold was cultured in liquid medium for up to 7 days. After 24 hs of culturing, an extended migration ring was observed. In the explants, from 3 somite stage, onwards, beating masses were noted, the shape and size of which suggested a vascular-like structure. Sections of the cultures were processed for the detection of the N-Cadherin adhesion molecule. The observations stated that the diffusion and intensity of expression of this receptor is related to the stage od development of the embryo. Cultures from the presomitic stage to 3 somite stage did not express the molecule. Instead, expression took place in those cultures of embryos at the 3 somite stage, onwards. In the cultures to which the antiserum against N-Cadherin had been to the medium, the formation of vascular-like structures was affected. The changes depended on the age of the embryos. These observations suggest that the expression of the N-Cadherin is related to the potentiality of the presumptive myocardic cells to organize themselves, at least "in vitro", to form a well-defined tridimensional structure. The expression of the adhesion molecule and the potentiality of the cells to build tubular structures were transient features, "in vitro" in our cultures. This suggests that "in vivo" the expression of the N-Cadherin must be aided by factors which, at present, are unidentified.

A review of the birth locus and the first developmental stages of cardiomyocytes and Purkinje cells in the chick embryo is presented in the light of recent experimental results. Experiments done in vitro have shown that the stage of 2 somites is an important morphogenetic phase, characterized by mutual identification, selective adhesion and spatial organization of the putative cardiac cells of the splanchnopleural sheet in the cardiogenic area. Many experimental data suggest that the neural crest cells moving through the corridor of the dorsal mesocardium, as well as the cholinergic system related to them, may play a role of myogenic inductors on the mesothelial putative cardiac cells. In addition, other experimental findings suggest that the Purkinje cells of the conduction system may have a crestal origin. This hypothesis is well grounded, although the origin of Purkinje cells remains to be clarified.

Chick embryos between final presomitic and 4 somites stage were studied. The subcephalic fold was handly severed from the embryos and cultivated in liquid medium for 7 days. Because of the embryo age, no heart anlage was observed at the moment of dissection. After 4 hours of culture the cells began to migrate from the explants. After 20 hours a very extended migration ring was observed in all of the cultures; in the explants, one or more newformed tubular or spherical masses of cells throbbed rhythmically. Their size and shape were related to the embryos age: from presomitic embryos, irregular clusters appeared, while starting from two somites embryos tubular, vascular-like structures were formed. The cells of the throbbing areas at submicroscopic observation showed organizing myofibrillar apparatus into the cytoplasm; junctional complexes between the cells and gap junctions in course of organization were present in the vascular-like structures. This suggests that very early, in the lateral mesoderm are the presumptive cardiac cells which can develop "in vitro" as myocardic elements even in absence of the interactions that occur during the development "in vitro"; the observed vascular-like structures may be considered as an attempt to form a sort of cardiac primordium "in vitro", and a further step in the expression of the cardiogenic potentiality, involving cell-cell communications. The serial sections of the embryos enhanced that into the cultivated areas, vessels from yolk sac are always present; this suggests that the vascular structures, i.e. the endothelium may be involved in the determination of the myocardic elements.

The distribution of calcitonin gene-related peptide (CGRP), enkephalin, galanin, neuropeptide Y (NPY), somatostatin, tachykinins and vasoactive intestinal polypeptide (VIP) was compared in cervical, thoracic, lumbar and sacral segmental levels of spinal cord and dorsal root ganglia of horse and pig. In both species, immunoreactivity for the peptides under study was observed at all segmental levels of the spinal cord. Peptide-immunoreactive fibres were generally concentrated in laminae I-III, the region around the central canal, and in the autonomic nuclei. A general increase in the number of immunoreactive nerve fibres was noted in the lumbosacral segments of the spinal cord, which was particularly exaggerated in the case of VIP immunoreactivity. In the horse, some CGRP-, somatostatin- or tachykinin-immunoreactive cell bodies were present in the dorsal horn. In the pig, cells immunoreactive for somatostatin, enkephalin or NPY were noted in a similar location. In the ventral horn most motoneurones were CGRP-immunoreactive in both species. However, in pig many other cell types were CGRP-immunoreactive not only in the ventral horn, but also in laminae V-VI of the dorsal horn. With the exception of enkephalin and NPY immunoreactivity, which was not seen in pig dorsal root ganglia, all peptides studied were localised to neuronal cell bodies and/or fibres in the dorsal root ganglia. In both species, immunolabeled cell bodies were observed in ganglia from cervical, thoracic, lumbar and sacral levels, with the exception of VIP-immunoreactive cells that were detected only in the lumbosacral ganglia. Numerous CGRP- and tachykinin-immunoreactive cell bodies were visualised in both species, while the cells immunolabeled with other peptide antisera were much lower in number. In both species, immunostaining of serial sections revealed that a subset of CGRP-immunoreactive cells co-expressed tachykinin, galanin or somatostatin immunoreactivity. In the horse some enkephalin-immunoreactive cells were also CGRP positive and occasionally combinations of three peptides, e.g. CGRP, tachykinin and galanin or CGRP, tachykinin and enkephalin were identified. The results obtained suggest that the overall pattern of distribution of peptide immunoreactivities is in general agreement with that so far described in other mammals, although some species variations have been observed, particularly regarding the presence of immunoreactive cell bodies in the dorsal horn of the spinal cord.

The histogenesis of iris sphincter muscle was studied in birds. Chick embryo iris "anlagen", ages from 3 days (st. 18 H.H.) to hatching, were examined. At the 4th day (st. 24 H.H.), nerve fibers were observed in the mesenchyme of the inferotemporal quadrant of the optic cup near the colobomic fissue. Among the mesenchymal cells, there were cells characterized by AChE activity, presence of desmin filaments, exhibiting ACh receptors, and ultrastructurally similar to the presumptive skeletal myoblasts. One day later (st. 27 H.H.), these myoblasts could be cultivated. The formation of myotubes began between 10 and 12 days. From 9 to 14 days, cells left the anterior epithelium of the iris to give rise to the smooth iris muscle; during this evolution some epithelial cells fused with the myotubes taking part in the histogenesis of striated muscle. The possibility of a neurogenic determination for the iris skeletal muscle is discussed.

Calcitonin gene-related peptide (CGRP)-, tachykinins- and somatostatin-immunoreactive neurones in rat dorsal root ganglia have been studied by means of single and double immunogold labelling techniques. Peptide-immunoreactive neurones are generally B- or C-type cells of small size, with well developed rough endoplasmic reticulum and scanty neurofilaments. In neurones classifiable as A2-type cells, i.e. larger neurones with a lighter cytoplasm due to the presence of poorly developed Nissl bodies and numerous neurofilaments, only CGRP immunoreactivity was detected. Immunolabelled structures were identified as large (60-100 nm diameter), electron-dense, membrane-bounded p-type granules. They were observed only in neuronal cell bodies or in the intraganglionic portions of the axons. No granules immunoreactive to the antisera applied in this study were observed in non-neuronal cells. Immuno-staining experiments with different combinations of the antisera revealed, in some cells, the presence of double immunolabelled granules; in particular localization of CGRP and tachykinins, CGRP and somatostatin, and tachykinins and somatostatin to single secretory granules was demonstrated. The finding that more than one peptide is localized to the same secretory granule supports the postulate that peptides are co-released upon nerve stimulation providing morphological support for physiological and pharmacological data demonstrating an interaction between different peptides in the modulation of synaptic activity.

Pigment granules without the properties of melanin are present in neurons of several districts (Nucleus ruber, Locus coeruleus, Ala cinerea) in the C.N.S. in Bos Taurus. The distinctive features of this pigment are autofluorescence, specifity of staining with Oil red O, Sudan Black and a strong P.A.S. positivity. The early pigment granules appear about at the end of the first year of life, their amount increases with age. The most rich pigment neurons are in the Nucleus ruber; in the neurons of the Substantia nigra, the pigment is very scanty also in the very old animals.

The technique of chicken-quail hybridization in "in vitro" cultures was used. Muscle differentiation of 9 H.H. chick embryo somites without the participation of nerve fibres was noted when they were cultured in the presence of quail pectoral muscle cells. It is suggested that this non-neural model may also be valid "in vivo", and that it probably interacts with the neurodependent mechanism demonstrated in a previous paper.

Neuronal pigment in red nucleus, locus coeruleus and substantia nigra from cattle, sheep and goat was examined with the aid of light and electron microscopy. In the red nucleus and locus coeruleus neurons of all the species examined the pigment shows the histochemical and ultrastructural features typical of lipofuscins. The ultrastructural observations indicated that the morphology of pigment granules is related to age and permitted identification of various stages of pigment evolution, which suggested a lysosomal origin of the pigment bodies. In bovine and sheep the substantia nigra is very reduced and contains no detectable pigment; while in goat, some neurons appear to contain discrete amounts of neuromelanin. Ultrastructurally this kind of pigment appears characterized by the features of a lipofuscin-like granule which stores highly electron dense material identifiable as melanin.

Somites from 9H. H. chick embryos and PC12 cells were co-cultivated in synthetic medium containing N.G.F., which induces the transformation of PC12 cells into neuron-like cells. During the first two days of culture, PC12 cells retained the spherical shape and tended to cluster. Somitic mesoderm cells exhibited a fibroblastic aspect. By the third day, PC12 cells extended long processes resembling nerve fibres which surrounded and penetrated the mesodermic explants. On the 10th day of culture, contractions, limited at first to a few cells were perceptible. Later, the contractions involved large cellular masses. Microscopic observations at 10 days revealed the presence of an increasing number of fusiform mononucleated cells. Later, long and narrow multinucleated elements appeared. Such elements never developed from cultures of only somites. Immunohistochemical observations revealed a desmin positivity in both mononucleated and multinucleated elements characterizing them as myogenic cells that are formed in and because of the presence of PC12 cells which were transformed by N.G.F. into nerve cells. After 10 days of culture, PC12 cells positive to antiserum antidesmin were noted. Desmin positivity of PC12 cells leads to the conclusion that newly-formed muscle cells exert an induction on Pheocromocytoma cells which, as derivatives of the neural crest, have a greater multipotentiality.