The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its ...physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
•FUS phase transitions between monomer, liquid droplet, and hydrogel states•FUS mutants induce further phase transition into irreversible fibrillar hydrogels•Irreversible hydrogels sequester RNP cargo and impair RNP granule function•Formation of non-amyloid fibrillar hydrogels provides a compelling causative mechanism for neurodegeneration
Murakami et al. show that FUS transitions between monomer, liquid droplet, and hydrogel states during uptake and release of RNP granule cargo. FUS mutations accelerate transition into fibrillar hydrogels that trap RNP cargo, impair RNP granule function, and cause neurodegeneration.
Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma.
To conduct a systematic review and meta-analysis of the ...effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting β-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma.
MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017).
Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest.
Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers.
Asthma exacerbations.
Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 95% CI, 0.48 to 0.92; RD, -0.02 95% CI, -0.04 to 0.00). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 95% CI, 0.53 to 1.42; RD, 0.00 95% CI, -0.02 to 0.02), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 95% CI, 0.57 to 1.22; RD, -0.01 95% CI, -0.08 to 0.07).
In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.
To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma ...(RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes.
The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry.
Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors.
Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC.
This report describes a case study of a patient with bilateral, multifocal type 1 papillary renal cell carcinoma (RCC) and a family history of RCC that has the germline MITF p.E318K variant, known to predispose to kidney cancer. All tumors demonstrated a papillary type 1 histology and analyses of available tumors identified increased nuclear staining for the MITF transcription factor, somatic amplification of chromosomes 7 and 17, and altered expression of genes associated with tumorigenesis, including potential biomarkers, such as GPNMB. Display omitted
Abstract
Study Objectives:
To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables.
Methods:
Multisite prospective cohort ...study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16–21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant.
Results:
Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of <7 hours; 2.6% had a sleep duration of >9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset.
Conclusions:
Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy.
In the framework of quantum chromodynamics (QCD), parton distribution functions (PDFs) quantify how the momentum and spin of a hadron are divided among its quark and gluon constituents. Two main ...approaches exist to determine PDFs. The first approach, based on QCD factorization theorems, realizes a QCD analysis of a suitable set of hard-scattering measurements, often using a variety of hadronic observables. The second approach, based on first-principle operator definitions of PDFs, uses lattice QCD to compute directly some PDF-related quantities, such as their moments. Motivated by recent progress in both approaches, in this document we present an overview of lattice-QCD and global-analysis techniques used to determine unpolarized and polarized proton PDFs and their moments. We provide benchmark numbers to validate present and future lattice-QCD calculations and we illustrate how they could be used to reduce the PDF uncertainties in current unpolarized and polarized global analyses. This document represents a first step towards establishing a common language between the two communities, to foster dialogue and to further improve our knowledge of PDFs.
Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has ...been essentially limited to three histologic subtypes.
A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.
Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 BAP1, and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.
These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.
The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the “Practice ...parameter for the diagnosis and management of primary immunodeficiency.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.
The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen ...multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin.
In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well.
With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval PI, 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control.
The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).
The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation
chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib ...was assessed in a
analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation Odds Ratio (OR): 2.5, 95%CI: 0.4-15;
=0.318. Response rate to venetoclax was similar for screening SUVmax <10
≥10 (65%
62%) (n=127 enrolled), though median progression-free survival was longer at <10 months (24.7
15.4 months;
=0.0335). Six patients developed Richter's transformation on venetoclax, of whom two had screening biopsy demonstrating CLL (others did not have a biopsy) and five had screening SUVmax <10. We have defined the test characteristics for PET-CT to distinguish progression of CLL as compared to Richter's transformation when biopsied in patients treated with B-cell receptor signaling pathway inhibitors. Overall diminished sensitivity and specificity as compared to prior reports of patients treated with chemotherapy/chemoimmunotherapy suggest it has diminished ability to discriminate these two diagnoses using a SUVmax ≥10 cutoff. This cutoff did not identify venetoclax-treated patients with an inferior response but may be predictive of inferior progression-free survival. (Registered at
).
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