The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, ...direct patient care, and enable genetic counseling of patients and families.
In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).
Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.
Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).
Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation ...(S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.
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•Janus kinase (JAK1) mutation underlies monogenic autoinflammatory disease•S703I mutation enhances downstream signaling by transactivation of partnering JAKs•Mosaicism and monoallelic expression shape JAK1 transcription patterns•JAK inhibitor therapy resolves clinical disease
Monogenic errors of the Janus kinase (JAK) family, essential signal transduction hubs of the immune system, have dire consequences in immune function. Gruber et al. describe a JAK1 gain-of-function mutation with mosaicism and monoallelic expression that underlies a multi-system autoinflammatory disease, which is rescued by JAK inhibitor therapy.
Understanding the genetic causes of evolutionary diversification is challenging because differences across species are complex, often involving many genes. However, cases where single or few genetic ...loci affect a trait that varies dramatically across a radiation of species provide tractable opportunities to understand the genetics of diversification. Here, we begin to explore how diversification of bioluminescent signals across species of cypridinid ostracods (“sea fireflies”) was influenced by evolution of a single gene, cypridinid‐luciferase. In addition to emission spectra (“colour”) of bioluminescence from 21 cypridinid species, we report 13 new c‐luciferase genes from de novo transcriptomes, including in vitro assays to confirm function of four of those genes. Our comparative analyses suggest some amino acid sites in c‐luciferase evolved under episodic diversifying selection and may be associated with changes in both enzyme kinetics and colour, two enzymatic functions that directly impact the phenotype of bioluminescent signals. The analyses also suggest multiple other amino acid positions in c‐luciferase evolved neutrally or under purifying selection, and may have impacted the variation of colour of bioluminescent signals across genera. Previous mutagenesis studies at candidate sites show epistatic interactions, which could constrain the evolution of c‐luciferase function. This work provides important steps toward understanding the genetic basis of diversification of behavioural signals across multiple species, suggesting different evolutionary processes act at different times during a radiation of species. These results set the stage for additional mutagenesis studies that could explicitly link selection, drift, and constraint to the evolution of phenotypic diversification.
see also the Perspective by Danielle M. DeLeo and Heather D. Bracken#x02010;Grissom.
Respiratory syncytial virus (RSV), a major cause of illness and death in infants worldwide, could be prevented by vaccination during pregnancy. The efficacy, immunogenicity, and safety of a bivalent ...RSV prefusion F protein-based (RSVpreF) vaccine in pregnant women and their infants are uncertain.
In a phase 2b trial, we randomly assigned pregnant women, at 24 through 36 weeks' gestation, to receive either 120 or 240 μg of RSVpreF vaccine (with or without aluminum hydroxide) or placebo. The trial included safety end points and immunogenicity end points that, in this interim analysis, included 50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical-cord blood, as well as maternal-to-infant transplacental transfer ratios.
This planned interim analysis included 406 women and 403 infants; 327 women (80.5%) received RSVpreF vaccine. Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminum hydroxide than among those who received RSVpreF vaccine without aluminum hydroxide. The incidences of adverse events in the women and infants were similar in the vaccine and placebo groups; the type and frequency of these events were consistent with the background incidences among pregnant women and infants. The geometric mean ratios of 50% neutralizing titers between the infants of vaccine recipients and those of placebo recipients ranged from 9.7 to 11.7 among those with RSV A neutralizing antibodies and from 13.6 to 16.8 among those with RSV B neutralizing antibodies. Transplacental neutralizing antibody transfer ratios ranged from 1.41 to 2.10 and were higher with nonaluminum formulations than with aluminum formulations. Across the range of assessed gestational ages, infants of women who were immunized had similar titers in umbilical-cord blood and similar transplacental transfer ratios.
RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns. (Funded by Pfizer; ClinicalTrials.gov number, NCT04032093.).
Background & Aims Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by ...incorporating information from common genetic susceptibility loci. Methods By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States. Results We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 ( P = .0028) for men and from 0.52 to 0.56 ( P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women. Conclusions By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.
Abstract
Background
Protection against human respiratory syncytial virus (RSV) remains an unmet need potentially addressable by maternal immunization. This phase 1/2 study evaluated a bivalent ...prefusion F vaccine (RSVpreF) with antigens from RSV subgroups A and B.
Methods
Adults 18–49 years old (N = 618) were randomized to receive placebo or 60, 120, or 240 µg RSVpreF with or without Al(OH)3. Safety and immunogenicity were evaluated.
Results
RSVpreF recipients more frequently reported local reactions and systemic events than placebo recipients; these were mostly mild or moderate. No vaccine-related serious adverse events occurred through 12 months postvaccination. All RSVpreF formulations induced 1-month postvaccination virus-neutralizing titers higher than those associated with protection of high-risk infants by palivizumab, the only prophylactic currently available for RSV. Geometric mean fold rises (GMFRs) across RSVpreF doses/formulations were 10.6–16.9 for RSV A and 10.3–19.8 for RSV B at 1 month postvaccination, greater than those historically elicited by postfusion F vaccines. GMFRs were 3.9–5.2 and 3.7–5.1, respectively, at 12 months postvaccination.
Conclusions
RSVpreF formulations were safe, well tolerated, and induced robust neutralizing responses in adults. These findings support development of RSVpreF, which is being evaluated in a pivotal phase 3 study for maternal immunization.
Clinical Trials Registration
NCT03529773.
Respiratory syncytial virus stabilized prefusion F subunit vaccine (RSVpreF) formulations were well tolerated and highly immunogenic in younger adults. These findings support further development of RSVpreF in a pivotal phase 3 study for maternal immunization.
Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive ...material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants.
In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds.
Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 μg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 μg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation.
GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).
Curiosity can be a powerful motivator to learn and retain new information. Evidence shows that high states of curiosity elicited by a specific source (i.e., a trivia question) can promote memory for ...incidental stimuli (non-target) presented close in time. The spreading effect of curiosity states on memory for other information has potential for educational applications. Specifically, it could provide techniques to improve learning for information that did not spark a sense of curiosity on its own. Here, we investigated how high states of curiosity induced through trivia questions affect memory performance for unrelated scholastic facts (e.g., scientific, English, or historical facts) presented in close temporal proximity to the trivia question. Across three task versions, participants viewed trivia questions closely followed in time by a scholastic fact unrelated to the trivia question, either just prior to or immediately following the answer to the trivia question. Participants then completed a surprise multiple-choice memory test (akin to a pop quiz) for the scholastic material. In all three task versions, memory performance was poorer for scholastic facts presented after trivia questions that had elicited high versus low levels of curiosity. These results contradict previous findings showing curiosity-enhanced memory for incidentally presented visual stimuli and suggest that target information that generates a high-curiosity state interferes with encoding complex and unrelated scholastic facts presented close in time.
Abstract
Background
Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults and adults with comorbidities. An effective vaccine is needed. An investigational ...bivalent prefusion F vaccine (RSVpreF) was assessed in healthy adults.
Methods
This phase 1/2 study randomized adults 18–85 years old to receive placebo or 60, 120, or 240 µg RSVpreF (with or without aluminum hydroxide) alone or concomitantly with seasonal inactivated influenza vaccine (SIIV). Safety and immunogenicity were assessed.
Results
In older adults, reactogenicity events were predominantly mild or moderate among RSVpreF recipients; adverse events through 1 month postvaccination were similar across formulations. Coadministration with SIIV did not appear to affect safety among younger or older adults. All RSVpreF formulations with or without concomitant SIIV elicited robust RSV serum-neutralizing responses in adults aged 50–85 years 1 month postvaccination. Neutralizing titers 1 and 12 months postvaccination were 6.9–14.9 and 2.9–4.5 times, respectively, those before vaccination. SIIV immune responses trended lower when coadministered with RSVpreF.
Conclusions
RSVpreF formulations administered alone or with SIIV were well tolerated and highly immunogenic in older adults, supporting the potential for RSVpreF to protect older adults from RSV disease.
Clinical Trials Registration
NCT03529773.
Respiratory syncytial virus stabilized prefusion F subunit vaccine (RSVpreF) formulations administered alone or with seasonal inactivated influenza vaccine were well tolerated and highly immunogenic in older adults, suggesting that RSVpreF may protect older adults from respiratory syncytial virus disease.
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