The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 ...EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. ...However, a test that indicates there is peanut sensitization present (eg, a “positive” test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut.
These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & ...Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing “The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update.” 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, or the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.
Background Public health policies reflect concerns that certain fruit sources may not have the intended benefits and that vegetables should be preferred to fruit. We assessed the relation of fruit ...and vegetable sources with cardiovascular outcomes using a systematic review and meta-analysis of prospective cohort studies. Methods and Results MEDLINE, EMBASE, and Cochrane were searched through June 3, 2019. Two independent reviewers extracted data and assessed study quality (Newcastle-Ottawa Scale). Data were pooled (fixed effects), and heterogeneity (Cochrane-Q and I
) and certainty of the evidence (Grading of Recommendations Assessment, Development, and Evaluation) were assessed. Eighty-one cohorts involving 4 031 896 individuals and 125 112 cardiovascular events were included. Total fruit and vegetables, fruit, and vegetables were associated with decreased cardiovascular disease (risk ratio, 0.93 95% CI, 0.89-0.96; 0.91 0.88-0.95; and 0.94 0.90-0.97, respectively), coronary heart disease (0.88 0.83-0.92; 0.88 0.84-0.92; and 0.92 0.87-0.96, respectively), and stroke (0.82 0.77-0.88, 0.82 0.79-0.85; and 0.88 0.83-0.93, respectively) incidence. Total fruit and vegetables, fruit, and vegetables were associated with decreased cardiovascular disease (0.89 0.85-0.93; 0.88 0.86-0.91; and 0.87 0.85-0.90, respectively), coronary heart disease (0.81 0.72-0.92; 0.86 0.82-0.90; and 0.86 0.83-0.89, respectively), and stroke (0.73 0.65-0.81; 0.87 0.84-0.91; and 0.94 0.90-0.99, respectively) mortality. There were greater benefits for citrus, 100% fruit juice, and pommes among fruit sources and allium, carrots, cruciferous, and green leafy among vegetable sources. No sources showed an adverse association. The certainty of the evidence was "very low" to "moderate," with the highest for total fruit and/or vegetables, pommes fruit, and green leafy vegetables. Conclusions Fruits and vegetables are associated with cardiovascular benefit, with some sources associated with greater benefit and none showing an adverse association. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03394339.
Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and ...progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.
Sulfonamide Hypersensitivity Chow, Timothy G; Khan, David A
Clinical reviews in allergy & immunology
62, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Sulfonamides, particularly antimicrobial sulfonamides, have been implicated as a common cause of a spectrum of hypersensitivity reactions. Immediate IgE-mediated reactions have been reported but are ...much less common than delayed cutaneous reactions. Delayed cutaneous reactions range from benign exanthems to severe cutaneous reactions such as Stevens Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms. Sulfonamides can be subclassified as antimicrobial sulfonamides and non-antimicrobial sulfonamides, which are also distinguished by key structural differences, resulting in very low risk of cross-reactivity between these two subclasses. Immediate and delayed skin testing and in vitro testing remain limited as options in evaluating antimicrobial sulfonamide hypersensitivity. Drug challenges continue to play an important role in the evaluation of both immediate and delayed reactions, with a growing body of evidence for the safety of direct challenges regardless of human immunodeficiency virus infection status. While numerous “desensitization” protocols have been described for the management of antimicrobial sulfonamide hypersensitivity, there is limited evidence that such procedures are successful because of an induction of tolerance.
Adverse Reactions to Biologic Therapy Patel, Sheenal V; Khan, David A
Immunology and allergy clinics of North America,
05/2017, Letnik:
37, Številka:
2
Journal Article
Recenzirano
Biologic therapies are emerging as a significant therapeutic option for many with debilitating inflammatory and autoimmune conditions. As expansion in the number of FDA-approved agents continue to be ...seen, more unanticipated adverse reactions are likely to occur. Currently, the diagnostic tools, including skin testing and in vitro testing, to evaluate for immediate hypersensitivity reactions are insufficient. In this review, management strategies for common acute infusion reactions, injection site reactions, and immediate reactions suggestive of IgE-mediated mechanisms are discussed. Desensitization can be considered for reactions suggestive of IgE-mediated mechanisms, but allergists/immunologists should be involved in managing these patients.
CRISPR-Cas are prokaryotic adaptive immune systems. Cas nucleases generally use CRISPR-derived RNA guides to specifically bind and cleave DNA or RNA targets. Here, we describe the experimental ...characterization of a bacterial CRISPR effector protein Cas12m representing subtype V-M. Despite being less than half the size of Cas12a, Cas12m catalyzes auto-processing of a crRNA guide, recognizes a 5′-TTN′ protospacer-adjacent motif (PAM), and stably binds a guide-complementary double-stranded DNA (dsDNA). Cas12m has a RuvC domain with a non-canonical catalytic site and accordingly is incapable of guide-dependent cleavage of target nucleic acids. Despite lacking target cleavage activity, the high binding affinity of Cas12m to dsDNA targets allows for interference as demonstrated by its ability to protect bacteria against invading plasmids through silencing invader transcription and/or replication. Based on these molecular features, we repurposed Cas12m by fusing it to a cytidine deaminase that resulted in base editing within a distinct window.
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•Type V-M is an additional subtype of type V CRISPR-Cas system (Cas12-U1)•The miniature Cas12m lacks target-specific as well as collateral nuclease activity•Guide-specific silencing by Cas12m occurs through dsDNA binding•A synthetic Cas12m-cytidine deaminase has a distinct C-to-T base editing window
In this work, Wu et al. describe the characterization of a small CRISPR effector protein Cas12m representing subtype V-M. Cas12m is guided by a single crRNA to stably bind but not cleave complementary double-stranded DNA, potentially contributing to host defense by silencing the expression of invader DNA.
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