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Abstract NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.

ABSTRACT: This paper examines the informativeness of special purpose acquisition company (SPAC) revenue forecasts. We document a positive association between the compound annual growth rate in revenue forecasts and abnormal returns, retail trading, and Twitter activity in the five-day window surrounding the disclosure of a merger announcement. By contrast, we find limited evidence that institutional investors and traditional information intermediaries respond to SPAC revenue forecasts. We also find evidence that SPAC revenue forecasts positively predict future operating underperformance, stock underperformance, and class action lawsuits. Overall, our results affirm the SEC’s concerns about the attractiveness of aggressive revenue projections to retail investors. JEL Classifications: G34; G32; M40; M48.

ABSTRACT The rapidly developing field of oncolytic virus (OV) therapy necessitates the development of new and improved analytical approaches for the characterization of the virus during production and development. Accurate monitoring and absolute quantification of viral proteins are crucial for OV product characterization and can facilitate the understanding of infection, immunogenicity, and development stages of viral replication. Targeted mass spectrometry methods like multiple reaction monitoring (MRM) offer a robust way to directly detect and quantify specific targeted proteins represented by surrogate peptides. We have leveraged the power of MRM by combining ultra-high performance liquid chromatography (UPLC) with a Sciex 6500 triple-stage quadrupole mass spectrometer to develop an assay that accurately and absolutely quantifies the structural proteins of a pseudotyped vesicular stomatitis virus (VSV) intended for use as a new biotherapeutic (designated hereafter as VSV-GP to differentiate it from native VSV). The new UPLC-MRM method provides absolute quantification with the use of heavy-labeled reference standard surrogate peptides. When added in known exact amounts to standards and samples, the reference standards normalize and account for any small perturbations during sample preparation and/or instrument performance, resulting in accurate and precise quantification. Because of the multiplexed nature of MRM, all targeted proteins are quantified at the same time. The optimized assay has been enhanced to quantify the ratios of the processed GP1 and GP2 proteins while simultaneously measuring any remaining or unprocessed form of the envelope protein GP complex (GPC; full-length GPC).IMPORTANCEThe development of oncolytic viral therapy has gained considerable momentum in recent years. Vesicular stomatitis virus glycoprotein (VSV-GP) is a new biotherapeutic emerging in the oncolytic viral therapy platform. Novel analytical assays that can accurately and precisely quantify the viral proteins are a necessity for the successful development of viral vector as a biotherapeutic. We developed an ultra-high performance liquid chromatography multiple reaction monitoring-based assay to quantify the absolute concentrations of the different structural proteins of VSV-GP. The complete processing of GP complex (GPC) is a prerequisite for the infectivity of the virus. The assay extends the potential for quantifying full-length GPC, which provides an understanding of the processing of GPC (along with the quantification of GP1 and GP2 separately). We used this assay in tracking GPC processing in HEK-293-F production cell lines infected with VSV-GP.

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.

Background: The air traffic management (ATM) system has historically coped with a global increase in traffic demand ultimately leading to increased operational complexity. When dealing with the impact of this increasing complexity on system safety it is crucial to automatically analyse the losses of separation (LoSs) using tools able to extract meaningful and actionable information from safety reports. Current research in this field mainly exploits natural language processing (NLP) to categorise the reports,with the limitations that the considered categories need to be manually annotated by experts and that general taxonomies are seldom exploited. Methods: To address the current gaps,authors propose to perform exploratory data analysis on safety reports combining state-of-the-art techniques like topic modelling and clustering and then to develop an algorithm able to extract the Toolkit for ATM Occurrence Investigation (TOKAI) taxonomy factors from the free-text safety reports based on syntactic analysis. TOKAI is a tool for investigation developed by EUROCONTROL and its taxonomy is intended to become a standard and harmonised approach to future investigations. Results: Leveraging on the LoS events reported in the public databases of the Comisión de Estudio y Análisis de Notificaciones de Incidentes de Tránsito Aéreo and the United Kingdom Airprox Board,authors show how their proposal is able to automatically extract meaningful and actionable information from safety reports,other than to classify their content according to the TOKAI taxonomy. The quality of the approach is also indirectly validated by checking the connection between the identified factors and the main contributor of the incidents. Conclusions: Authors' results are a promising first step toward the full automation of a general analysis of LoS reports supported by results on real-world data coming from two different sources. In the future,authors' proposal could be extended to other taxonomies or tailored to identify factors to be included in the safety taxonomies.

Abstract: Introduction: There is evidence to suggest that an association exists between oral infections and coronary heart disease (CHD). Subjects presenting lesions of endodontic origin (LEOs) or pulpal inflammation had an increased risk of developing CHD. However, findings concerning systemic manifestations of apical periodontitis (AP) remain controversial. An association between CD14 gene polymorphisms and atherosclerosis-associated diseases has been shown, but there are no data regarding an association between CD14 polymorphism and AP. This study evaluated associations between clinical oral health status, CD14 polymorphisms, and CHD. Methods: A case-controlled clinical trial was designed to compare middle-aged adults with acute myocardial infarction or unstable angina (n = 51) within 12 months of the acute event defined as first manifestation with healthy controls (n = 49). Participants were matched for age, sex, and socioeconomic status. Indicators of oral disease and compliance were evaluated. CD14 polymorphisms were analyzed by restriction fragment length polymorphism–polymerase chain reaction. Results: CHD subjects had a higher prevalence of oral diseases and lower compliance to oral preventive strategies than healthy controls. Multivariate analysis showed a positive association between missing teeth (odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.02–1.85), the number of LEOs (OR = 4.37; 95% CI, 1.69–11.28), chronic periodontitis (OR = 5.87; 95% CI, 1.17–29.4), and CHD. No statistically significant association emerged between the CD14 C(−260)T and the CD14 C(−159)T polymorphism, endodontic or periodontal disease, and CHD. Conclusions: Chronic oral diseases may increase the risk of CHD and may be an unconventional risk factor for CHD. [Copyright &y& Elsevier]

The article reports on research which was conducted to compare opioid discontinuation and opioid replacement protocols in patients with chronic noncancer pain and coexistent opioid addiction. Researchers evaluated 12 patients. They found that the patients were more likely to adhere to an opioid replacement protocol than to an opioid weaning protocol and that opioid replacement therapy which featured buprenorphine and naloxone was effective and resulted in improved physical functioning.

A letter to the editor is presented that discusses the case of Cogan's syndrome and its treatment.

One of the main requirements for investigation of health risks to environmental pollution is accurate information on population distribution. Although detailed data do exist in many parts of the world, based on national censuses at household or census tract level, in many others the level of spatial aggregation of these data is too coarse to allow reliable population estimates to be derived at the small area scale. Nor do census data typically provide accurate, small-area estimates of changes in population distribution in inter-censual years. One important, but as yet little-used source of information on population distribution is night-time satellite data, such as those provided by the Defense Meteorological Satellite Program (DMSP). These provide complete Earth coverage every night (subject to cloud cover) at a nominal spatial resolution of ca. 500 to 2700 metres. Previous studies have demonstrated strong associations between light emissions and population density at broad (e.g. national) scales, and the capability to use the data to detect and map changes in urban area over periods of a few years. This study assessed the ability to extend the use of these data to give local estimates of population distribution and to detect short-term variations in population as inputs to epidemiological studies. In a European-wide analysis, DMSP data were first linked to detailed land cover data within a Geographical Information System, to enhance their spatial resolution, using a combination of kriging and inverse distance weighting techniques. Associations between light emissions from relevant land cover classes and population numbers at different levels of aggregation were then analysed, both across the European Union and by country. Results showed that country-specific models typically explained 70-90% of variation in population distribution at the regional (e.g. county) scale and 50-85% of variation at the small-area (census tract) scale. DMSP data were also analysed to explore seasonal and year-to-year variations in population in sub-areas of the EU. Clear differences could be detected in both seasonal patterns of activity and long-term urban growth. Further exploration and use of these data as part of epidemiological investigations is therefor warranted. [ABSTRACT FROM AUTHOR]

Reports on a study of 11 cases of immunoglobulin E (IgE)-mediated urticaria/angioedema caused by mussels. Allergic reactions after ingestion of raw and/or cooked mussels; Skin-prick tests; Possible significance of cooking procedure in the incidence of positive skin tests to unprepared cooked mussel and/or clam preparations; Poor relationship between clinical symptoms and test results.