Influenza Virus Non-Structural Protein 1 (NS1) Disrupts Interferon Signaling

Type I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β. Here we show that expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. In support of this NS1-mediated inhibition, we observed a reduction in expression of ifnar1 in ex vivo human non-tumor lung tissues infected with H5N1 and H1N1 viruses. Moreover, H1N1 and H5N1 virus infection of human monocyte-derived macrophages led to inhibition of both ifnar1 and ifnar2 expression. In addition, NS1 expression induces up-regulation of the JAK/STAT inhibitors, SOCS1 and SOCS3. By contrast, treatment of ex vivo human lung tissues with IFN-α results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections

Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

A Registry-Based Study on The Association between Human Salmonellosis And Routinely Collected Parameters in Michigan, 1995–2001

Purpose: Salmonella serotypes are among the most common bacterial causes of foodborne gastroenteritis in the United States, associated with ∼1.4 million human illnesses annually. Studies on trends of the serotypes and host-related factors are necessary for the development of effective prevention plans for foodborne diseases caused by these pathogens. Materials and Methods: To determine the epidemiologic trends of human infections with the most common Salmonella serotypes in Michigan, we analyzed cases of culture-confirmed salmonellosis at the Michigan Department of Community Health (MDCH) from 1995 to 2001. Results: A total of 6797 cases were reported, with an average annual incidence per 100,000 population (AAI) of 9.9. Among cases for which information on Salmonella serotype were available (6292 cases), the most common serotypes were S. Typhimurium (1596 cases, 26%), followed by S. Enteritidis (1309, 22%), S. Heidelberg (466, 8%) and S. Newport (222, 4%). From 1998 to 2001, the incidence of S. Typhimurium and S. Enteritidis decreased significantly by 39% (95% confidence interval [CI], 49% to 26% decrease) and 32% (95% CI, 44% to 18% decrease) respectively. Whereas the incidence of S. Newport increased by 101% (95% CI, 25% to 225% increase) and S. Heidelberg remained stable. Infection with these serotypes frequently occurred in the summer months. As a group, infants had the highest AAI for all Salmonella serotypes (75.0), S. Typhimurium (21.9), S. Enteritidis (14.0), S. Heidelberg (5.4), and S. Newport (1.7). Among patients whose race was known, blacks had a significantly higher AAI compared to whites for S. Typhimurium (2.5 vs. 1.3; RR = 2.3, 95% CI, 1.6–3.3), S. Enteritidis (1.4 vs. 1.1; relative rate (RR) = 1.4; 95% CI, 1.1–1.6), S. Heidelberg (0.8 vs. 0.3; RR = 3.6; 95% CI, 2.8–4.6), and S. Newport (0.3 vs. 0.1; RR = 2.8; 95% CI, 1.9–4.2). Among patients whose ethnicity was known, Hispanics had a significantly higher AAI for S. Enteritidis compared to non-Hispanics (1.0 vs. 0.5; RR = 1.9; 95% CI, 1.2–3.0), but not different significantly for S. Typhimurium, S. Heidelberg, and S. Newport. Conclusion: This study revealed the emergence of S. Newport and the high incidence of the most common Salmonella serotypes among infants, people of African descent, and Hispanics. This information can be used by the state and local health departments of Michigan to enhance salmonellosis prevention efforts by rationalizing the allocation of appropriate public health resources and personnel.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63353/1/fpd.2006.48.pd

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.

Background Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.Methods We conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.Results From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.Conclusions Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.)