Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Breast Density, Ki67 and Larger Extensions of Breast Cancer.

Abstract Background: Studying breast cancer, our data has demonstrated higher occurrence of large extensions and/or multiple synchronic malignant lesions in dense breasts. Following this investigation, we decided to correlate breast density with Ki67 on tumor specimens and disease extent on MRI. Methods: From August 2005 to April 2009, 193 consecutive patients diagnosed with breast cancer were evaluated about number and size of breast malignant lesions, about fibroglandular (FG) density on Mammography and about proliferation marker on immunohistochemistry of tumor cells. Fibroglandular density was classified using criteria: &amp;lt;50%; &amp;gt;50%. All patients had evaluation of hormonal receptors (estrogen and progesterone), HER2/neu and Ki67 on immunohistochemistry of tumor blocks. They were also submitted to bilateral breast MRI in 1.5 T Excite/GE equipment, 5 sequences FSPGR (90 seconds each, 1 preinjection, 4 postinjection of gadolinium 0.16 mM/kg, 3.5/0 thickness) to evaluate size of primary lesion and presence of additional malignant foci. Additional findings were submitted to pathological examination (core or excisional biopsy). Results: Among 193 patients, 66 (34%) presented FG density &amp;lt;50% and 127 (66%) had FG density &amp;gt;50%. Eighty one patients (42%) presented large single tumor (35 cases) and/or multiple synchronic malignant lesions (46 cases), which 16/81 (19%) had FG density &amp;lt;50% and 65/81 (81%) had FB density &amp;gt;50%. In 112/193 patients (58%) with small single tumor on MRI, 66 (59%) had density &amp;gt;50%. Expression of Ki67 was 30% positive or higher in 17/66 patients (25,7%) with FG density &amp;lt;50% and in 70/127 patients (55%) with FB density &amp;gt;50%. Correlation between high expression of Ki67 (30% or higher) and extent was significant for patients with large single tumor (17/35=48,5%), but not for patients with multiple synchronic lesions (11/46=24%). Expression of Ki67 was 30% positive or higher associated with HER2 overexpression (3+) or with triple negative tumors in 95% of both conditions (multiple synchronic or larger single tumors). Conclusions: This study demonstrated that dense breasts are associated with larger extensions of breast cancer and suggests that FB density can be correlated to higher expressions of Ki67 on immunohistochemistry, especially in single tumors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6043.</jats:p

Relaxation and luminescence studies on hydrated bipyridyl- and terpyridyl-based lanthanide complexes

International audienceThe synthesis of the novel ligand L2, based on a 2,2'-bipyridine functionalized by a carboxylate function and a methyleneiminodiacetate group in positions 6 and 6', is described. Its europium complex, [EuL2(H2O)(3)], has been prepared and characterized. The spectroscopic properties of [EuL2(H2O)(3)] were studied by means of absorption, and both steady-state and time-resolved luminescence spectroscopy. Although L2 displays a very good sensitization efficiency (eta(sens.) = 89%), the overall luminescence quantum yield of the complex is rather poor (2.6%). This results from strong non-radiative deactivations due to the presence of three water molecules in the first coordination sphere, as evidenced by luminescence lifetime measurements in H2O and D2O. The relaxation properties of the Gd3+ complexes obtained with ligands L2 and L1, the latter containing an additional pyridine ring in the aromatic core, were assessed by means of O-17 NMR and nuclear magnetic relaxation dispersion (NMRD). The calculated water exchange rates for both complexes are faster than those of currently used contrast agents (k(ex)(298) = 14.0 +/- 1.5 10(6) and 11.1 +/- 1.1 10(6) s(-1) for [GdL1(H2O)(2)] and [GdL2(H2O)(3)], respectively). The rotational correlation time calculated for [GdL1(H2O)(2)] appeared to be long (110 +/- 16 ps vs 65 +/- 5ps for [GdL2(H2O)(3)]), pointing to a hindered rotation due to the larger aromatic frame. Finally, the interaction of the two Gd complexes with hydrogencarbonate and phosphate anions was studied by relaxivity measurements, showing that both anions are able to compete with water molecules as ligands for Gd3+, with HCO3- showing a better affinity