Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

\u2022 La Societ\ue0 Agricola \u201cOfficina del Sole: un esempio di azienda multifunzionale

La Societ\ue0 Agricola \u201cOfficina del Sole\u201d rappresenta un tipico esempio di azienda agricola multifunzionale. Sita a Montegiorgio (FM), si estende su una superficie di circa 40 ha in zona collinare. Acquisita nel 2009 da una giovane imprenditrice locale, l\u2019azienda, dapprima destinata alla quasi totale coltivazione della vite e in parte riservata a seminativo, \ue8 attualmente oggetto di un progetto che coinvolge lo spin-off HORT dell\u2019Universit\ue0 Politecnica delle Marche e il Dipartimento di Colture Arboree della Facolt\ue0 di Agraria di Bologna, i quali hanno curato la progettazione dell\u2019intera area, ponendo particolare attenzione all\u2019analisi del territorio in cui l\u2019azienda si inserisce, riproducendone quindi i tratti distintivi e caratteristici e tenendo conto della vocazionalit\ue0 del territorio per la scelta delle colture. Per queste ragioni, \ue8 stata proposta una ripartizione colturale che ha previsto l\u2019inserimento di vitigni e variet\ue0 di olivo e fruttiferi locali, volti a valorizzare il territorio, in termini di sostenibilit\ue0 ambientale, economica e sociale, in quanto le colture si inseriscono perfettamente nel paesaggio e costituiscono parte integrante di percorsi didattici e socio-ricreativi proposti per incentivare l\u2019offerta turistica della zona. Agriturismo, beauty farm, cantina, frantoio e fattoria didattica sono alcune fra le pi\uf9 importanti attivit\ue0 che l\u2019azienda attiver\ue0

Reduced CD36-dependent tissue sequestration of Plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo

Adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of Plasmodium falciparum malaria. The prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. Irbc of the rodent parasite Plasmodium berghei ANKA sequester in a fashion analogous to P. falciparum by adhering to the host receptor CD36. To experimentally determine the significance of sequestration for parasite growth, we generated a mutant P. berghei ANKA parasite with a reduced CD36-mediated adherence. Although the cognate parasite ligand binding to CD36 is unknown, we show that nonsequestering parasites have reduced growth and we provide evidence that in addition to avoiding spleen removal, other factors related to CD36-mediated sequestration are beneficial for parasite growth. These results reveal for the first time the importance of sequestration to a malaria infection, with implications for the development of strategies aimed at reducing pathology by inhibiting tissue sequestration.Host-parasite interactio

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.Hereditary cancer genetic