The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

On the basis of these results, public education about importance of breast cancer screening and health promoting behavior should be strongly advocated by health professionals and mass media in China.

Fatty acid synthase (FASN) is a potential therapeutic target for treatment of cancer and obesity, and is highly elevated in 30% of HER2-overexpressing breast cancers. Considerable interest has developed in searching for novel FASN inhibitors as therapeutic agents in treatment of HER2-overexpressing breast cancers. Amentoflavone was found to be effective in suppressing FASN expression in HER2-positive SKBR3 cells. Pharmacological inhibition of FASN by amentoflavone specifically down-regulated HER2 protein and mRNA, and caused an up-regulation of PEA3, a transcriptional repressor of HER2. In addition, pharmacological blockade of FASN by amentoflavone preferentially decreased cell viability and induced cell death in SKBR3 cells. Palmitate reduced the cytotoxic effect of amentoflavone, as the percentage of viable cells was increased after the addition of exogenous palmitate. Amentoflavone-induced FASN inhibition inhibited the translocation of SREBP-1 in SKBR3 cells. Amentoflavone inhibited phosphorylation of AKT, mTOR, and JNK. The use of pharmacological inhibitors revealed that the modulation of AKT, mTOR, and JNK phosphorylation required synergistic amentoflavone-induced FASN inhibition and HER2 activation in SKBR3 cells. These results suggest that amentoflavone modulated FASN expression by regulation of HER2-pathways, and induced cell death to enhance chemopreventive or chemotherapeutic activity in HER2-positive breast cancers.

PurposeThe aim of this study was to evaluate the correlation between central lymph node (CLN) metastasis and clinicopathologic characteristics of papillary thyroid cancer (PTC). In addition, we investigated the incidence and risk factors for contralateral CLN metastasis in unilateral PTC. This study suggests the appropriate surgical extent for CLN dissection.MethodsA prospective study of 500 patients with PTC who underwent total thyroidectomy and prophylactic bilateral CLN dissection was conducted.ResultsOf 500 patients, 255 had CLN metastases. The rate of CLN metastasis was considerably higher in cases of younger patients (<45 years old) (P < 0.001; odds ratio [OR], 2.357) and of a maximal tumor size greater than 1 cm (P < 0.001; OR, 3.165). Ipsilateral CLN metastasis was detected in 83.1% of cases (133/160) of unilateral PTC, only contralateral CLN metastases in 3.7% of cases (6/160), and bilateral CLN metastases in 13.1% of cases (21/160). The rate of contralateral CLN metastasis was considerably higher in cases of PTC with a large tumor size (≥1 cm) (P = 0.019; OR, 4.440) and with ipsilateral CLN metastasis (P = 0.047; OR, 2.613).ConclusionYounger age (<45 years old) and maximal tumor size greater than 1 cm were independent risk factors for CLN metastasis. Maximal tumor size greater than 1 cm and presence of ipsilateral CLN macrometastasis were independent risk factors for contralateral CLN metastasis. Therefore, both CLN dissections should be considered for unilateral PTC with a maximal tumor size greater than 1 cm or presence of ipsilateral CLN macrometastasis.

PurposeThe purpose of this study is to evaluate imaging and histopathologic findings including the immunohistochemical characteristics of invasive micropapillary carcinoma (IMPC) of the breast.MethodsTwenty-nine patients diagnosed with IMPC were included in the present study. Mammographic, sonographic, and magnetic resonance imaging (MRI) findings were analyzed retrospectively according to the American College of Radiology Breast Imaging Reporting and Data System lexicon. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings were also evaluated. Microscopic slides of surgical specimens were reviewed in consensus by two pathologists with a specialty in breast pathology.ResultsMost IMPCs presented as a high density irregular mass with a non-circumscribed margin associated with microcalcifications on mammography, as an irregular hypoechoic mass with a spiculated margin on ultrasound, and as irregular spiculated masses with washout patterns on MRI. PET-CT showed a high maximum standardized uptake value (SUVmax) (mean, 11.2). Axillary nodal metastases were identified in 65.5% of the patients. Immunohistochemical studies showed high positivities for estrogen receptor and c-erbB-2 (93.1% and 51.7µ, respectively).ConclusionEven though the imaging characteristics of IMPCs are not distinguishable from typical invasive ductal carcinomas, this tumor type frequently results in nodal metastases and high positivities for both estrogen receptor and c-erbB-2. The high SUVmax value that is apparent on PET-CT might be helpful in the diagnosis of IMPC.