We show that for every 1<n<∞, there exists a Banach space Xn containing proximinal subspaces of codimension n but no proximinal finite codimensional subspaces of higher codimension. Moreover, the set ...of norm-attaining functionals of Xn contains n-dimensional subspaces, but no subspace of higher dimension. This gives an n-by-n version of the solutions given by Read and Rmoutil to problems of Singer and Godefroy. We also study the existence of strongly proximinal subspaces of finite codimension, showing that for every 1<n<∞ and 1⩽k<n, there is a Banach space Xn,k containing proximinal subspaces of finite codimension up to n but not higher, and containing strongly proximinal subspaces of finite codimension up to k but not higher. Finally, we deal with possible infinite-dimensional versions of the previous results showing, among other results, that there are non-separable Banach spaces whose set of norm-attaining functionals contains infinite-dimensional separable linear subspaces but no non-separable subspaces.
nab-Paclitaxel is approved for the treatment of metastatic breast cancer on an every-3-week schedule based on positive findings from a pivotal phase III trial in which nab-paclitaxel 260 mg/m(2) ...every 3 weeks was superior to solvent-based paclitaxel 175 mg/m(2) every 3 weeks for the primary endpoint of overall response rate (33 % vs 19 %; P = 0.001). Subsequently, a number of trials have examined different schedules, doses, and combinations in efforts to optimize nab-paclitaxel-based therapy for metastatic and early-stage breast cancer. The goal of this review is to evaluate the clinical experiences to date with nab-paclitaxel as a single agent or in combination with targeted agents in different treatment settings - with a focus on the feasibility of administration, adverse event profile, and standard efficacy endpoints, such as overall survival, progression-free survival, overall response rate, and pathologic complete response rate. In general, weekly dosing during the first 3 of 4 weeks appears to achieve the best clinical benefit in both the metastatic and early-stage settings. Furthermore, the data suggest that high doses of nab-paclitaxel, such as 150 mg/m(2) during first 3 of 4 weeks or 260 mg/m(2) every 2 weeks, may be more feasible and appropriate for treatment of early-stage disease compared with metastatic disease. Intense regimens of nab-paclitaxel may not be the best treatment approach for unselected patients with metastatic breast cancer, but may suit a subset of patients for whom immediate disease control is required. The growing number of nab-paclitaxel trials in breast cancer will lead to greater refinements in tailoring therapy to patients based on their individual disease and patient characteristics.
The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a ...mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation, and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward proinflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify strategies for intervention in mitochondrial-related diseases.
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•Mitochondrial dysfunction causes lysosomal storage disorder and sphingolipidosis•Respiration-impaired cells increase lysosomal compartment through TFEB•Mitochondrial control of lysosome function restrains inflammatory T cell responses•Restoration of NAD+ levels improves lysosome function and inflammatory responses
Baixauli et al. show a critical role for mitochondria in the regulation of T cell inflammatory responses by controlling lysosome function. Abnormal endolysosomal function and sphingomyelin accumulation in respiration-impaired cells link mitochondrial dysfunction to lysosomal storage disorders and exacerbated inflammatory responses.
In this paper, we introduce and study a Lipschitz version of the Bishop–Phelps–Bollobás property (Lip-BPB property). This property deals with the possibility of making a uniformly simultaneous ...approximation of a Lipschitz map F and a pair of points at which F almost attains its norm by a Lipschitz map G and a pair of points such that G strongly attains its norm at the new pair of points. We first show that if M is a finite pointed metric space and Y is a finite-dimensional Banach space, then the pair (M,Y) has the Lip-BPB property, and that both finiteness assumptions are needed. Next, we show that if M is a uniformly Gromov concave pointed metric space (i.e. the molecules of M form a set of uniformly strongly exposed points), then (M,Y) has the Lip-BPB property for every Banach space Y. We further prove that this is the case for finite concave metric spaces, ultrametric spaces, and Hölder metric spaces. The extension of the Lip-BPB property from (M,R) to some Banach spaces Y and some results for compact Lipschitz maps are also discussed.
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA ...hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.
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•Tet2 restoration reverses aberrant self-renewal of Tet2-deficient cells•Tet2 restoration promotes DNA demethylation, differentiation, and cell death•Vitamin C treatment mimics Tet2 restoration to block leukemia progression•Vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition
Vitamin C treatment mimics the effect of TET2 restoration on leukemic stem cells and enhances the efficacy of PARP inhibition in suppressing leukemia progression.
We study the relation between the intrinsic and the spatial numerical ranges with the recently introduced “approximated” spatial numerical range. As the main result, we show that the intrinsic ...numerical range always coincides with the convex hull of the approximated spatial numerical range. Besides, we show sufficient conditions and necessary conditions to assure that the approximated spatial numerical range coincides with the closure of the spatial numerical range.
Using the Shannon Information Entropy (IE) as a soil structure metric is proposed to analyze the effect of the particle size distribution (PSD) heterogeneity on soil bulk density values. A data base ...including 6239 soil samples from Florida is used. For each soil the IE is computed using mass proportions of the seven texture fractions that the data base provides. The range of IE values is divided into subintervals of equal length to study how differences in the soil texture metric are reflected in differences in soil bulk density values. The total range of IE values divided into equal subintervals, each subinterval corresponds to the group of soils with IE in this subinterval, average bulk density for soils in each subinterval is found, and the average information entropy value in any of the subintervals is plotted versus the average soil bulk density values. Coefficients of determination of the linear regressions ‘average IE vs. average bulk density’ were 0.99 and 0.98 for 10 and 15 subintervals respectively. Predictions based in that linear relationship give the mean predicted error (MPE) equal to 0.0015g/cm3 over the total number of soils, and the normal distribution of prediction errors with the standard deviation of to 0.16g/cm3. These results strongly support the hypothesis that Information Entropy can serve as an indicator of the typical bulk density for a soil with a given PSD. Values of IE were also computed for all samples in the database using only three texture fractions: clay, silt and sand content. Simple linear regression using the IE value as the input variable was implemented to predict bulk density value. Additionally, several published bulk density pedotransfer functions (PTFs), including organic carbon (OC) content and texture inputs, were applied to the same data base. Results show the root-mean-squared error of predictions close to 0.16g/cm3 when the IE is used as the sole input. Estimation of bulk density using Information Entropy as predictor became worse for soils in horizon A than in the horizon E, respectively, possibly due to the influence of the different organic carbon content in those horizons.
Overall, the Information Entropy metric of soil texture provides a useful input for estimating bulk density, which also might be used together with other inputs as depth or OC content.
•An information theory-based metric of the soil texture is proposed.•Bulk density mean values have linear dependence on Information Entropy mean values.•Information Entropy serves as an indicator of the typical bulk density.
TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 ...activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized.
We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status.
Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.
For decades mitochondria have been considered static round-shaped organelles in charge of energy production. In contrast, they are highly dynamic cellular components that undergo continuous cycles of ...fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival, because of their role in the modulation of apoptosis, autophagy, and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions and the implication of mitochondrial dysfunction in multifactorial human pathologies such as cancer, Alzheimer and Parkinson diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields for exploring the roles of these mitochondrial pathways in human pathologies. This review dissects the relationships between activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus on their implications for neurodegeneration.
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► Disturbance of respiratory chain complex assembly induces respirasome disassembly. ► Respiratory chain disassembly can result in increased reactive oxygen species production. ► Respiratory chain dysfunction and oxidative stress are key players in neurodegeneration. ► The reactive oxygen species–mitochondrial dynamics loop is altered in neurodegeneration.
We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic ...classification of HCC to incorporate features that explain responses/resistance to immunotherapy.
We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.
Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in
mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in
mutations (93% vs 27%, p<0.001) and
overexpression due to gene amplification and promoter hypomethylation.
mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.
We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct
patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.
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