Analysis of radiation patterns of interaction tones generated by inlet rods in the JT15D engine

Interaction tones were intentionally generated by circumferential arrays of equally spaced rods that protrude radially from the inlet wall near the face of the 28-blade fan. Arrays of 28 and 41 rods, selected to give specific far field radiation properties, were tested. The expected properties were readily apparent in the measured radiation patterns. A more detailed analysis of the test data showed both the precision and limitations of the applied acoustic theory. Rods protruding 23 percent of the radius predominantly generated only lowest radial order modes, as expected. Measured and predicted radiation patterns were generally in good agreement. The agreement, however, depended on a significant degree of implied refraction due to inlet velocity gradients. Refraction, if present, would impact static-flight noise comparisons

Law Professor Comment Letter on Harmonization of Private Offering Rules

Comment letter filed on Sept. 24, 2019. File No. S7-08-19 We are fifteen law professors whose scholarship and teaching focuses on securities regulation. We appreciate the opportunity to comment on the U.S. Securities and Exchange Commission’s (“SEC” or the “Commission”) Concept Release on Harmonization of Securities Offering Exemptions (the “Concept Release”)

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR 12]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I\u2013III invasive early BC at age 6440 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60\u20130.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94\u20132.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients\u2019 counseling on treatment, prevention, and surveillance strategies

Proportions of CD4+ memory T cells are altered in individuals chronically infected with Schistosoma haematobium

Characterisation of protective helminth acquired immunity in humans or experimental models has focused on effector responses with little work conducted on memory responses. Here we show for the first time, that human helminth infection is associated with altered proportions of the CD4+ memory T cells, with an associated alteration of TH1 responses. The reduced CD4+ memory T cell proportions are associated with a significantly lower ratio of schistosome-specific IgE/IgG4 (marker for resistance to infection/re-infection) in uninfected older people. Helminth infection does not affect the CD8+ memory T cell pool. Furthermore, we show for the first time in a helminth infection that the CD4+ memory T cell proportions decline following curative anti-helminthic treatment despite increased CD4+ memory cell replication. Reduced accumulation of the CD4+ memory T cells in schistosome-infected people has implications for the development of natural or vaccine induced schistosome-specific protective immunity as well as for unrelated pathogens

Multi-omics comparison of malignant and normal uveal melanocytes reveals molecular features of uveal melanoma.

Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with the upregulation of PRAME, an independent prognostic biomarker in UM, and a potential therapeutic target. Our findings illustrate how multi-omics approaches can improve our understanding of tumorigenesis and reveal two distinct mechanisms of gene expression dysregulation in UM

A Schistosome cAMP-Dependent Protein Kinase Catalytic Subunit Is Essential for Parasite Viability

Eukaryotes, protozoan, and helminth parasites make extensive use of protein kinases to control cellular functions, suggesting that protein kinases may represent novel targets for the development of anti-parasitic drugs. Because of their central role in intracellular signaling pathways, cyclic nucleotide–dependent kinases such as cAMP-dependent protein kinase (PKA) represent promising new targets for the treatment of parasitic infections and neoplastic disorders. However, the role of these kinases in schistosome biology has not been characterized and the genes encoding schistosome PKAs have not been identified. Here we provide biochemical evidence for the presence of a PKA signaling pathway in adult Schistosoma mansoni and show that PKA activity is required for parasite viability in vitro. We also provide the first full description of a gene that encodes a PKA catalytic subunit in S. mansoni, named SmPKA-C. Finally we demonstrate, through RNA interference, that SmPKA-C contributes to the PKA activity we detected biochemically and that inhibition of SmPKA-C expression in adult schistosomes results in parasite death. Together our data show that SmPKA-C is a critically important gene product and may represent an attractive therapeutic target for the treatment and control of schistosomiasis

Regulatory and Activated T Cells in Human Schistosoma haematobium Infections

Acquired immunity against helminths is characterised by a complex interplay between the effector Th1 and Th2 immune responses and it slowly manifests with age as a result of cumulative exposure to parasite antigens. Data from experimental models suggest that immunity is also influenced by regulatory T cells (Treg), but as yet studies on Treg in human schistosome infections are limited

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P &lt; 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors