Targeting antigen to bone marrow stromal cell‐2 expressed by conventional and plasmacytoid dendritic cells elicits efficient antigen presentation

Bone marrow stromal cell‐2 (BST‐2) has major roles in viral tethering and modulation of interferon production. Here we investigate BST‐2 as a receptor for the delivery of antigen to dendritic cells (DCs). We show that BST‐2 is expressed by a panel of mouse and human DC subsets, particularly under inflammatory conditions. The outcome of delivering antigen to BST‐2 expressed by steady state and activated plasmacytoid DC (pDC) or conventional CD8⁺ and CD8^? DCs was determined. T‐cell responses were measured for both MHC class I (MHCI) and MHC class II (MHCII) antigen presentation pathways in vitro. Delivering antigen via BST‐2 was compared with that via receptors DEC205 or Siglec‐H. We show that despite a higher antigen load and faster receptor internalisation, when antigen is delivered to steady state or activated pDC via BST‐2, BST‐2‐targeted activated conventional DCs present antigen more efficiently. Relative to DEC205, BST‐2 was inferior in its capacity to deliver antigen to the MHCI cross‐presentation pathway. In contrast, BST‐2 was superior to Siglec‐H at initiating either MHCI or MHCII antigen presentation. In summary, BST‐2 is a useful receptor to target with antigen, given its broad expression pattern and ability to access both MHCI and MHCII presentation pathways with relative efficiency.     

Performances,feasibility and acceptability of nasopharyngeal swab,saliva and oral-self sampling swab for the detection of severe acute respiratory syndrome coronavirus 2

European Journal of Clinical Microbiology & Infectious Diseases - Molecular diagnosis on nasopharyngeal swabs (NPS) is the current standard for COVID-19 diagnosis, but saliva may be an...     

Longitudinal Analysis of Inflammatory Response to SARS-CoV-2 in the Upper Respiratory Tract Reveals an Association with Viral Load,Independent of Symptoms

Background

SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches.

Methods

SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms.

Results

Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG.

Conclusion

The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.

     

Timing of dental extractions in patients undergoing radiotherapy and the incidence of osteoradionecrosis: a systematic review and meta-analysis

This systematic review aimed to examine whether the incidence of osteonecrosis differed between patients who have dental extractions before or after radiotherapy (RT). The reported incidence of osteoradionecrosis (ORN) of the jaws following RT to the head and neck varies widely in the literature. Currently, for patients with head and neck cancer there are no universally accepted guidelines on the optimal timing of dental surgery relative to RT to minimise incident ORN. A literature review was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) criteria. A search of PubMed, EMBASE, Evidence-Based Medicine, and Web of Science databases targeted literature published up to and including 10 April 2020. Two independent reviewers assessed studies for eligibility against inclusion criteria. An assessment of bias was conducted for each of the included studies and relevant data extracted. A meta-analysis was undertaken using the statistical methods described. Twenty-four of 708 studies were included. They were heterogeneous and included a wide variation of RT methods, head and neck malignancies, and comorbidities. While some concluded that the incidence of ORN was dependent on the timing of dental extractions in relation to RT, with regard to the risk of its development, others reported additional factors such as age, comorbidities, extent of surgical resection, and dose and field of radiation, as more important predictors than timing. In many there was consistent lack of detail around the timing of dental procedures in relation to the delivery of RT. From 21 studies including 36,294 patients, of whom 14,389 had extractions before RT, the pooled incidence of ORN was 5.5% (95% CI: 2.1% to 10.1%). Significant heterogeneity was found in Cochran’s Q-test (p < 0.001) and Higgins I² = 98.0%. From 21 studies including 37,805 patients, of whom 6030 had extractions after RT, the pooled incidence of ORN was 5.3% (95% CI: 2.9% to 8.2%). Significant heterogeneity was found in Cochran’s Q-test (p < 0.001) and Higgins I² = 80.0%. There was no statistically significant difference between these two groups (random-effects model Q=0.12, p=0.73). Large, longitudinal studies with a priori-specified methods are needed to identify, recruit, and prospectively follow patients with head and neck cancer for the onset of ORN after dental surgery. This will allow clinical guidelines to be established to assist clinicians to plan treatment when extractions are indicated in patients undergoing RT to the head and neck.     

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogen-activated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP^−/−, and TxNIP^+/− mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP^−/− mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP^−/− mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-β1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1β mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms’ tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP^−/− mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O₂⁻ generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.     

Is shared decision-making vanishing at the end-of-life? A descriptive and qualitative study of advanced cancer patients’ involvement in specific therapies decision-making

Background

Little is known about what is at stake at a subjective level for the oncologists and the advanced cancer patients when they face the question whether to continue, limit or stop specific therapies. We studied (1) the frequency of such questioning, and (2) subjective determinants of the decision-making process from the physicians’ and the patients’ perspectives.

Methods

(1) All hospitalized patients were screened during 1 week in oncology and/or hematology units of five institutions. We included those with advanced cancer for whom a questioning about the pursuit, the limitation or the withholding of specific therapies (QST) was raised. (2) Qualitative design was based on in-depth interviews.

Results

In conventional units, 12.8 % of cancer patients (26 out of 202) were concerned by a QST during the study period. Interviews were conducted with all physicians and 21 advanced cancer patients. The timing of this questioning occurred most frequently as physicians estimated life expectancy between 15 days and 3 months. Faced with the most frequent dilemma (uncertain risk-benefit balance), physicians showed different ways of involving patients. The first two were called the “no choice” models: 1) trying to resolve the dilemma via a technical answer or a “wait-and-see” posture, instead of involving the patients in the questioning and the thinking; and 2), giving a “last minute” choice to the patients, leaving to them the responsibility of the decision. In a third model, they engaged early in shared reflections and dialogue about uncertainties and limits with patients, proxies and care teams. These schematic trends influenced patients’ attitudes towards uncertainty and limits, as they were influenced by these ones. Individual and systemic barriers to a shared questioning were pointed out by physicians and patients.

Conclusions

This study indicate to what extent these difficult decisions are related to physicians’ and patients’ respective and mutually influenced abilities to deal with and share about uncertainties and limits, throughout the disease trajectory. These insights may help physicians, patients and policy makers to enrich their understanding of underestimated and sensitive key issues of the decision-making process.