Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the ...thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free–Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
Using an adaptive trial design to minimize the exposure of patients to inactive agents and to detect more active regimens sooner, investigators found that adding veliparib and carboplatin to standard ...therapy improved outcome in triple-negative breast cancer.
Breast cancer is genetically and clinically heterogeneous, which makes it challenging to identify effective patient-specific therapies. Although mortality due to breast cancer in the United States has decreased, more than 40,000 women in the United States still die from this disease each year.
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Further decreases in mortality will require therapeutic options that target biologic properties of tumors and can be delivered early enough in the disease course to make a clinical difference.
The neoadjuvant approach facilitates the evaluation of an individual patient's response to treatment and holds promise for the development of experimental therapies for disease while it is still . . .
Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion of glutamine repeats in ubiquitously distributed huntingtin protein. Recent studies have shown that mutant ...huntingtin interferes with the function of widely expressed transcription factors, suggesting that gene expression may be altered in a variety of tissues in HD, including peripheral blood. Affymetrix and Amersham Biosciences oligonucleotide microarrays were used to analyze global gene expression in blood samples of HD patients and matched controls. We identified 322 mRNAs that showed significantly altered expression in HD blood samples, compared with controls (P < 0.0005), on two different microarray platforms. A subset of up-regulated mRNAs selected from this group was able to distinguish controls, presymptomatic individuals carrying the HD mutation, and symptomatic HD patients. In addition, early presymptomatic subjects showed gene expression profiles similar to those of controls, whereas late presymptomatic subjects showed altered expression that resembled that of symptomatic HD patients. These elevated mRNAs were significantly reduced in HD patients involved in a dose-finding study of the histone deacetylase inhibitor sodium phenylbutyrate. Furthermore, expression of the marker genes was significantly up-regulated in postmortem HD caudate, suggesting that alterations in blood mRNAs may reflect disease mechanisms observed in HD brain. In conclusion, we identified changes in blood mRNAs that clearly distinguish HD patients from controls. These alterations in mRNA expression correlate with disease progression and response to experimental treatment. Such markers may provide clues to the state of HD and may be of predictive value in clinical trials.
Although both raindrop driven processes and diffusion play important roles in the transfer of chemicals from soil to surface runoff, current transport models either do not consider the two processes ...together, or use ‘effective’ parameters with uncertain physical definitions. We developed a physically based, solute transport model that couples both mechanisms and tested it with laboratory experiments. One unique aspect of this study is that all the parameters were either directly measured or previously published, that is, there was no model ‘calibration’ or ‘fitting.’ Our model assumes that chemicals near the surface of the soil are ejected into runoff by raindrop impact and chemicals deeper in the soil diffuse into a surface layer, or ‘exchange layer,’ via diffusion. The exchange layer depth and transfer processes are derived from the ‘shield’ concept in the Rose soil erosion model (e.g.
Rose, 1985). The model's governing equations were solved numerically and the results agreed well with experimental data (
R
2>0.90). The model's sensitivity to various physical and chemical parameters illuminated the importance of both raindrop controlled processes and diffusion on chemical transport from soil to surface runoff.
Pantothenate kinase‐associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded ...studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease‐vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4′‐phosphopantetheine, normalized levels of the CoA‐, iron‐, and dopamine‐related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4′‐phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron–sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4′‐phosphopantetheine as a candidate therapeutic for PKAN.
Synopsis
Mutations in PANK2 cause pantothenate kinase‐associated neurodegeneration (PKAN), a neurodegeneration with brain iron accumulation (NBIA) disorder. This study presents a mouse model that recapitulates key features of the human disease and shows rescue by a coenzyme A pathway intermediate.
Germline deletion of Pank2, encoding pantothenate kinase 2, causes defects in CoA, iron, and dopamine metabolism and diminished activities of mitochondrial aconitase, complex I, and pyruvate dehydrogenase (PDH) in globus pallidus.
Regional biomarker abnormalities, which are revealed by isolating disease‐vulnerable brain regions, are specifically attributable to a defect in Pank2 alone, without the need to superimpose further genetic or metabolic defects.
Correction of the CoA metabolic defect by oral administration of 4′‐phosphopantetheine recovers iron and dopamine homeostasis in brain and normalizes mitochondrial complex I and PDH activities.
Mutations in PANK2 cause pantothenate kinase‐associated neurodegeneration (PKAN), a neurodegeneration with brain iron accumulation (NBIA) disorder. This study presents a mouse model that recapitulates key features of the human disease and shows rescue by a coenzyme A pathway intermediate.
Among patients with HER2-positive, hormone-receptor–negative locally advanced breast cancer, the addition of neratinib to standard therapy resulted in higher rates of pathological complete response, ...with some higher rates of toxic effects.
The treatment of aggressive, locally advanced breast cancers increasingly includes neoadjuvant therapy before surgical resection, thus providing a window of opportunity to tailor treatments on the basis of early assessments of the molecular characteristics of the cancer and their response to therapy. The existence of a well-characterized, surrogate end point — pathological complete response as assessed at the time of surgery — that is strongly correlated with both event-free survival and overall survival makes neoadjuvant therapy a particularly useful context for the rapid clinical development of targeted therapies. The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic . . .
Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell ...transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin (
). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3
macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3
phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3
macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal
as a major regulator of macrophage and stromal progenitor interactions.
Targeting antigen to dendritic cells (DC) in vivo might be an effective method of modulating immune responses. Given the functional specializations among DC subsets, we investigated how targeting ...different receptors on different DC subsets may influence antibody (Ab) production. We show here that targeting FIRE (F4/80‐like receptor) or CIRE (C‐type lectin receptor), two molecules expressed on the surface of immature CD8– DC in the mouse, increases Ab production 100–1000‐fold over a non‐targeted control. This response was equivalent to that achieved with CpG adjuvant. In contrast, targeting CD205, which is primarily expressed on CD8+ DC, did not elicit an Ab response unless an adjuvant was added. Strong Ab responses in FcRγ–/– mice, and with the use of F(ab')2 fragments, confirmed that FIRE and CIRE targeting was due to specific rather than FcR or complement binding. Our findings may reflect differences in the ability of CD8+ and CD8– DC subsets to stimulate immune responses in vivo. Although the consensus view is that Ag presentation on DC in their steady state leads to tolerance, the Ab enhancement from FIRE and CIRE targeting in the apparent absence of any “danger” or inflammatory signal would suggest that targeting certain DC molecules can supplant the need for external adjuvants for eliciting immune responses.
Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA ...Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure.
What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty?
This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 μg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 μg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment.
A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups.
Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes.
ClinicalTrials.gov; No.: NCT01350336; URL: www.
gov.
Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of ...Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.
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