Lynggaardshepherd2622

These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity 1-3 days postlesioning, suggesting disease-modifying properties and translational potential for PD. SIGNIFICANCE STATEMENT Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier. Epigenetic phosphorylation Both compounds significantly attenuated dopamine depletion, cytokine production, microglial activation, dopaminergic neuronal loss, oxidative/nitrative stress indices, and behavioral abnormality in a Parkinson disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties that may be useful in treating Parkinson disease.Until 1990, it was illegal for transnational tobacco companies (TTCs) to sell cigarettes in Thailand. We reviewed and analysed internal tobacco industry documents relevant to the Thai market during the 1980s. TTCs' attempts to access the Thai cigarette market during the 1980s concentrated on political lobbying, advertising and promotion of the foreign brands that were illegal to sell in Thailand at the time. They sought to take advantage of the Thai Tobacco Monopoly's (TTM) inefficiency to propose licencing agreements and joint ventures with TTM and took advantages of unclear regulations about cigarette marketing to promote their products through advertising and sponsorship activities. After their initial efforts failed, they successfully lobbied the US to impose trade sanctions to liberalise Thailand's market. Similar to the situation for cigarettes in the 1980s, since 2017, Philip Morris International has worked in parallel with a pro-e-cigarette group to pressure Thailand's government to allow sales of electronic nicotine delivery systems (ENDS; including e-cigarettes and heated tobacco products), knowing the products were illegal under Thai law. Health advocates and government authorities should be aware of past TTCs' tactics for cigarettes and anticipate that TTCs will attempt to use international trade law to force markets open for ENDS if their domestic efforts fail.Many have called for greater inclusion of researchers from low- and middle-income countries (LMICs) in the conduct of global health research, yet the extent to which this occurs is unclear. Prior studies are journal-, subject-, or region-specific, largely rely on manual review, and yield varying estimates not amenable to broad evaluation of the literature. We conducted a large-scale investigation of the contribution of LMIC-affiliated researchers to published global health research and examined whether this contribution differed over time. We searched titles, abstracts, and keywords for the names of countries ever classified as low-, lower middle-, or upper middle-income by the World Bank, and limited our search to items published from 2000 to 2017 in health science-related journals. Publication metadata were obtained from Elsevier/Scopus and analysed in statistical software. We calculated proportions of publications with any, first, and last authors affiliated with any LMIC as well as the same LMIC(s) identified in the title/abstract/keywords, and stratified analyses by year, country, and countries' most common income status. We analysed 786 779 publications and found that 86.0% included at least one LMIC-affiliated author, while 77.2% and 71.2% had an LMIC-affiliated first or last author, respectively; however, analagous proportions were only 58.7%, 36.8%, and 29.1% among 100 687 publications about low-income countries. Proportions of publications with LMIC-affiliated authors increased over time, yet this observation was driven by high research activity and representation among upper middle-income countries. Between-country variation in representation was observed, even within income status categories. We invite comment regarding these findings, particularly from voices underrepresented in this field.

In contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides (

).

Phage libraries displaying

were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40

were chemically conjugated to tumor antigen

with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW <8 kDa). The TICAs were evaluated in a suite of

and

assays to characterize their pharmacology and mechanism of action.

Linking

against costimulatory receptors (e.g., CD137) to

against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presenceafforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.

Pancreatic cancer remains one of the most lethal cancers and is refractory to immunotherapeutic interventions. Oncolytic viruses are a promising new treatment option, but current platforms demonstrate limited efficacy, especially for inaccessible and metastatic cancers that require systemically deliverable therapies. We recently described an oncolytic vaccinia virus (VV), VVLΔTKΔN1L, which has potent antitumor activity, and a regime to enhance intravenous delivery of VV by pharmacological inhibition of pharmacological inhibition of PI3 Kinase δ (PI3Kδ) to prevent virus uptake by macrophages. While these platforms improve the clinical prospects of VV, antitumor efficacy must be improved.

VVLΔTKΔN1L was modified to improve viral spread within and between tumors via viral B5R protein modification, which enhanced production of the extracellular enveloped virus form of VV. Antitumor immunity evoked by viral treatment was improved by arming the virus with interleukin-21, creating VVL-21. Efficacy, functional activity and synergy with α-programmed cell death protein 1 (α-PD1) were assessed after systemic delivery to murine and Syrian hamster models of pancreatic cancer.