The role of poly (ADP-ribose) polymerase 1 (PARP1) in cancer has been extensively studied in the context of DNA repair, leading to clinical trials of PARP1 inhibitors in cancers defective in ...homologous recombination. However, the DNA repair-independent roles of PARP1 in carcinogenesis and metastasis, particularly in lung cancer metastasis, remain largely uncharacterized. Here, we report that PARP1 promotes lung adenocarcinoma relapse to the brain and bones by regulating several steps of the metastatic process in a DNA repair-independent manner. We find that PARP1 expression is associated with overall and distant metastasis-free survival in lung adenocarcinoma patients. Consistent with this, genetic knockdown and pharmacological inhibition of PARP1 significantly attenuated the metastatic potential of lung adenocarcinoma cells. Further investigation revealed that PARP1 potentiates lung adenocarcinoma metastasis by promoting invasion, anoikis resistance, extravasation and self-renewal of lung adenocarcinoma cells and also by modifying the brain microenvironment. Finally, we identified S100A4 and CLDN7 as novel transcriptional targets and clinically relevant effectors of PARP1. Collectively, our study not only revealed previously unknown functions of PARP1 in lung adenocarcinoma metastasis but also delineated the molecular mechanisms underlying the pro-metastatic function of PARP1. Furthermore, these findings provide a foundation for the potential use of PARP1 inhibitors as a new treatment option for lung adenocarcinoma patients with elevated PARP1 expression.
Background
Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.
Objective
To evaluate whether inhalation ...of S. aureus‐derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.
Methods
Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).
Results
Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF‐α) and interleukin 6 (IL‐6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL‐6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll‐like receptor 2 (TLR2)‐dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN‐γ) or IL‐17.
Conclusion
Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2‐dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.
We report an improved measurement of the free neutron lifetime τn using the UCN τ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38 × 106 surviving ultracold ...neutrons (UCNs) after storing in UCN τ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τn from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τn measurements and by performing a global likelihood fit to all data while self-consistently incorporating the β -decay lifetime. Both techniques achieve consistent results and find a value τn = 877.75 ± 0.2 8stat + 0.22/−0.16syst s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.
In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown.
At Kaiser Permanente Northern ...California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000-2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure.
Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02).
Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.
Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the ...characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade.
We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations.
Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history.
EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.
Tendon healing follows a complex series of coordinated events, which ultimately produces a mechanically inferior tissue more scar‐like than native tendon. More regenerative healing occurs when ...anti‐inflammatory M2 macrophages play a more dominant role. Mesenchymal stromal/stem cells (MSCs) are able to polarize macrophages to an M2 immunophenotype via paracrine mechanisms. We previously reported that coculture of CD14+ macrophages (MQs) with MSCs resulted in a unique M2‐like macrophage. More recently, we generated M2‐like macrophages using only extracellular vesicles (EVs) isolated from MSCs creating “EV‐educated macrophages” (also called exosome‐educated macrophages EEMs), thereby foregoing direct use of MSCs. For the current study, we hypothesized that cell therapy with EEMs would improve in vivo tendon healing by modulating tissue inflammation and endogenous macrophage immunophenotypes. We evaluated effects of EEMs using a mouse Achilles tendon rupture model and compared results to normal tendon healing (without any biologic intervention), MSCs, MQs, or EVs. We found that exogenous administration of EEMs directly into the wound promoted a healing response that was significantly more functional and more regenerative. Injured tendons treated with exogenous EEMs exhibited (a) improved mechanical properties, (b) reduced inflammation, and (c) earlier angiogenesis. Treatment with MSC‐derived EVs alone were less effective functionally but stimulated a biological response as evidenced by an increased number of endothelial cells and decreased M1/M2 ratio. Because of their regenerative and immunomodulatory effects, EEM treament could provide a novel strategy to promote wound healing in this and various other musculoskeletal injuries or pathologies where inflammation and inadequate healing is problematic. Stem Cells 2019;37:652–662
Extracellular vesicles (EVs) were isolated from bone marrow derived mesenchymal stem/stromal cells (BMMSCs) via ultracentrifugation. CD14+ monocytes were obtained from peripheral blood, cultured, activated to CD14+ macrophages, and educated with MSC‐derived EVs, producing EV‐educated macrophages (EEMs). Treatment with EEMs using a mouse Achilles tendon injury model accelerated healing as indicated by reduced inflammation, early angiogenesis, and improved strength and modulus.
Background
Chronic rhinosinusitis (CRS) is an inflammatory process in the nasal cavity and paranasal sinuses, and bacteria have been considered to be a cause. Indeed, recent evidence indicates that ...bacteria‐derived extracellular vesicles (EV) appear to be an important causative agent of inflammatory diseases. Here, we aimed to evaluate the diversity of nasal microbiota and their secreted EV in patients with CRS.
Methods
Nasal lavage (NAL) fluid samples were obtained from five patients with CRS with polyposis, three patients with CRS without polyposis, and three non‐CRS controls. After preparation of bacteria and EV from samples using differential centrifugation, genomic DNA was extracted and 16S‐rDNA amplicons were subjected to high‐throughput pyrosequencing on a Roche 454 GS‐FLX platform.
Results
Metagenomics showed that bacteria composition was positively correlated with EV composition. Samples from patients with CRS had greater bacterial abundance and lower diversity, both from bacteria and the EV portion of samples, compared with non‐CRS samples. At each phylogenetic level, Bacteroidetes decreased while Proteobacteria increased in the CRS group at the phylum level. At the genus level, Prevotella spp. decreased in the CRS group, while Staphylococcus spp. increased from both bacteria and EV. Moreover, Staphylococcus aureus and its secreting EV compositions were higher in samples from CRS with polyps compared with CRS without polyps.
Conclusions
These results suggest that patients with CRS have altered nasal microbiota and decreased diversity in bacterial compositions as well as increased S. aureus abundance in those patients with polyps.
Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that ...irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.
How well do serum samples from persons vaccinated with the mRNA-1273 vaccine neutralize the P.1 lineage, the B.1.1.7 lineage, the B.1.1.7 lineage plus the E484K mutation, the B.1.351 lineage, and the ...B.1.427/B.1.429 lineage of SARS-CoV-2? This study provides an answer.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to growing concerns over increased transmissibility and the ability of some variants to partially escape ...immunity. Sera from participants immunized on a prime-boost schedule with the mRNA-1273 COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants, including variants of concern (VOCs) and variants of interest (VOIs), compared to neutralization of the wild-type SARS-CoV-2 virus (designated D614G). Results showed minimal, statistically nonsignificant effects on neutralization titers against the B.1.1.7 (Alpha) variant (1.2-fold reduction compared with D614G); other VOCs, such as B.1.351 (Beta, including B.1.351-v1, B.1.351-v2, and B.1.351-v3), P.1 (Gamma), and B.1.617.2 (Delta), showed significantly decreased neutralization titers ranging from 2.1-fold to 8.4-fold reductions compared with D614G, although all remained susceptible to mRNA-1273-elicited serum neutralization. IMPORTANCE In light of multiple variants of SARS-CoV-2 that have been documented globally during the COVID-19 pandemic, it remains important to continually assess the ability of currently available vaccines to confer protection against newly emerging variants. Data presented herein indicate that immunization with the mRNA-1273 COVID-19 vaccine produces neutralizing antibodies against key emerging variants tested, including variants of concern and variants of interest. While the serum neutralization elicited by mRNA-1273 against most variants tested was reduced compared with that against the wild-type virus, the level of neutralization is still expected to be protective. Such data are crucial to inform ongoing and future vaccination strategies to combat COVID-19.
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