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Open-system electronic nicotine delivery systems (ENDS) permit modifications to device characteristics such as power, potentially increasing nicotine and toxicant delivery. Limiting liquid nicotine concentration may carry unintended consequences by prompting users to increase device power to increase nicotine delivery. This study examined the abuse liability of ENDS across nicotine concentration and power settings. In a clinical laboratory study, n = 19 exclusive ENDS users and n = 13 dual ENDS/cigarette users, aged 21-55 completed four Latin-square ordered conditions that varied by liquid nicotine concentration (10 mg/ml [low], 30 mg/ml [high]) and device power (15 watts [low], 30 watts [high]), that were followed by a fifth own brand (OB) condition. A progressive ratio task (PRT) using bar presses to earn ENDS puffs was used to assess abuse liability and compare between conditions using mixed effects linear regressions. The low nicotine/high watt condition was associated with a significantly higher number of bar presses and puffs earned relative to the OB ENDS, high nicotine/high watt, and high nicotine/low watt conditions (p < .05). Findings appeared to be driven largely by exclusive ENDS users; most comparisons were not significant among dual users. Participants worked significantly harder for puffs of low nicotine/high watt ENDS, highlighting previous findings that suggest limiting liquid nicotine concentration without addressing power settings may be insufficient to reduce the abuse liability of ENDS. (PsycInfo Database Record (c) 2021 APA, all rights reserved). more...

Objective: In this paper, we characterize how potential policies restricting access to tobacco products may impact use behaviors among adult, past 30-day, smokers and e-cigarette users. Methods: We conducted an online experiment with 820 smokers, e-cigarette users, and dual users (April 27-June 8, 2020). We randomized participants to one of 4 hypothetical access scenarios: (1) tobacco retail stores open + pharmacies open (TOPO); (2) tobacco stores open but favorite brand unavailable + pharmacies open (TOPO-NFB); (3) tobacco stores closed + pharmacies open (TCPO); and (4) tobacco stores closed + pharmacies closed (TCPC). Outcomes (measured on 0-100 visual analog scales) included the likelihood of quitting, reducing, switching brands or products, and finding another source of tobacco products. Seemingly unrelated regressions tested for associations between access scenarios and prospective tobacco use behaviors. Results: Participants in the TCPO and TOPO-NFB scenarios were more likely to reduce use, switch brands/products, and find another source (ps < .001) than those in the TOPO scenario. Dual and flavored product users were more likely to switch products (ps < .01). Conclusions: When tobacco retailers are closed, tobacco users may be more likely to quit and/or reduce use compared to when retailers are open. However, access restrictions could prompt users to switch tobacco brands/products or sources. more...

Although adjuvants and formulations are often either empirically derived, or at best judged by their ability to elicit broad inflammation, it would be ideal if specific innate correlates of adaptive immunity could be identified to set a universally applicable benchmark for adjuvant evaluation. Using an IL-27 reporter transgenic mouse model, we show in this study that conventional type 1 dendritic cell IL-27 production in the draining lymph node 12 h after s.c. vaccination directly correlates with downstream CD8+ T cell memory and protective immunity against infectious challenge. This correlation is robust, reproducible, predictive, entirely unique to vaccine biology, and is the only innate correlate of CD8+ T cell immune memory yet to be identified. Our results provide new insights into the basic biology of adjuvant-elicited cellular immunity and have clear implications for the screening and evaluation of novel adjuvants. more...

Introduction Coronavirus Disease 2019 (COVID-19) is a public health crisis, but its effects on tobacco users remain ill-defined. This report aimed to assess the relationship between tobacco product-specific risk perceptions for COVID-19 and changes in tobacco use since the start of the pandemic. Methods A sample (n = 776) of past-30 day exclusive smokers (n = 238), exclusive e-cigarette users (n = 143), and dual users (n = 395) residing in the US and aged 18 or older were collected using Mechanical Turk from April 27 to June 8, 2020. Adjusted associations between tobacco product-specific COVID-19 risk perceptions (ie risk that smokers/vapers are at for COVID-19 relative to non-smokers/non-vapers) and changes in tobacco use since the pandemic began were assessed using partial proportional odds models. Results A majority of those who used cigarettes (63.7%) and e-cigarettes (56.1%) felt that the risk of COVID-19 was greater for users of their tobacco product than for non-users. Twenty-four percent of smokers had increased their cigarette use since the start of the pandemic and 28.0% had decreased. Similarly, 27.3% of e-cigarette users had increased their e-cigarette use since the start of the pandemic and 23.8% had decreased. Higher risk perceptions for COVID-19 were associated with reductions in tobacco use since the pandemic began for exclusive e-cigarette users and dual users. Conclusions These findings provide the support that tobacco product-specific COVID-19 risk perceptions may be an important correlate of changes in tobacco use during the pandemic. Targeted information to inform tobacco users regarding their risks for COVID-19 is needed during this public health crisis. Implications Few published studies have investigated the relationship between tobacco product-specific risk perceptions for COVID-19 and changes in tobacco product use since the pandemic began. This study enhances the current literature by providing evidence that higher tobacco product-specific risk perceptions for COVID-19 are associated with reductions in tobacco use since the pandemic began for exclusive e-cigarette users and dual users of cigarettes and e-cigarettes. Additionally, daily tobacco users may be more likely to have increased their tobacco use than non-daily users. These findings emphasize the importance of disseminating targeted health information to tobacco users regarding COVID-19 risks. more...

IDH1-mutated gliomas are slow growing brain tumours, which progress into high-grade gliomas. They present intra-tumoural cell heterogeneity, but no good markers are available to distinguish the different cell subtypes. The molecular mechanisms underlying the formation of this cell diversity is also ill defined. Here we report that the SOX9 and OLIG1 transcription factors, which specifically label astrocytes and oligodendrocytes in the normal brain, reveal the presence of two largely non-overlapping tumoural populations in IDH1-mutated oligodendrogliomas and astrocytomas. Astro-like SOX9+ cells additionally stain for APOE, CRYAB, ID4, KCNN3, while oligo-like OLIG1+ cells stain for ASCL1, EGFR, IDH1, PDGFRA, PTPRZ1, SOX4, and SOX8. GPR17, an oligodendrocytic marker, was expressed by both cells. These two sub-populations appear to have distinct BMP, NOTCH1, and MAPK active pathways as stainings for BMP4, HEY1, HEY2, p-SMAD1/5 and p-ERK were higher in SOX9+ cells. We used primary cultures and a new cell line to explore the influence of NOTCH1 activation and BMP treatment on low-grade glioma cell phenotype. This revealed that NOTCH1 globally reduced oligodendrocytic markers and IDH1 expression while upregulating APOE, CRYAB, HEY1/2 and an electrophysiologically Ca2+-activated apamin-sensitive K+ channel (KCNN3/SK3). This was accompanied by reduction in proliferation. Similar effects of NOTCH1 activation were observed in non-tumoural human oligodendrocytic cells, which additionally induced strong SOX9 expression. BMP treatment reduced OLIG1/2 expression and strongly upregulated CRYAB and NOGGIN, a negative regulator of BMP. The presence of astro-like SOX9+ and oligo-like OLIG1+ cells in diffuse low-grade gliomas raise new questions about their role in the pathology. more...

The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3&beta, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3&beta, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1. more...

Simple Summary CXCR4 is critically involved in triple-negative breast cancer metastasis. LASP1 was previously found to be necessary for CXCR4-dependent tumor cell invasion. Here we aimed to understand how LASP1 can have such a powerful role this process that is critical to metastasis. We found Ago2, a master regulator protein, to associate with LASP1 in response to CXCR4 activity. Furthermore, we found that this association was responsible for affecting the expression of proteins regulated by Ago2. Abstract The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells. more...

Background: Argatroban, a synthetic, parenteral, nonheparin anticoagulant, is a direct thrombin inhibitor indicated for the prophylaxis or treatment of venous thromboembolism (VTE) in patients with heparin-induced thrombocytopenia with thrombosis (HITT) and for use during percutaneous coronary intervention (PCI) in patients who have or are at risk for developing HITT. Although heparin resistance occurs in approximately 0.5% to 5% of heparin-treated patients and is well documented in the literature, argatroban resistance is limited to a single case report. The objective of this case is to describe a case in which argatroban resistance was suspected in a patient with critical limb ischemia. Methods: This is a case report of a single patient. Results: A 68-year-old female admitted for critical limb ischemia requiring vascular intervention was treated for presumed HITT with argatroban. A therapeutic activated partial thromboplastin time (aPTT) was not attained (31 seconds) despite multiple uptitrations of the dose to 2.8 μg/kg/min (adjusted based on the institutional protocol and with consideration of organ dysfunction). A coagulopathy workup revealed a high level of factor VIII (265%). Conclusion: This case supports early assessment of factor VIII levels and the consideration of argatroban resistance and in patients who have a subtherapeutic aPTT, despite multiple increases in dose with an elevated factor VIII level. Early identification should prompt the use of an alternative anticoagulant to ensure efficacy. more...

It is well accepted that the innate response is a necessary prerequisite to the formation of the adaptive response. This is true for T cell responses against infections or adjuvanted subunit vaccination. However, specific innate parameters with predictive value for the magnitude of an adjuvant-elicited T cell response have yet to be identified. We previously reported how T cell responses induced by subunit vaccination were dependent on the cytokine IL-27. These findings were unexpected, given that T cell responses to an infection typically increase in the absence of IL-27. Using a novel IL-27p28–eGFP reporter mouse, we now show that the degree to which an adjuvant induces IL-27p28 production from dendritic cells and monocytes directly predicts the magnitude of the T cell response elicited. To our knowledge, these data are the first to identify a concrete innate correlate of vaccine-elicited cellular immunity, and they have significant practical and mechanistic implications for subunit vaccine biology. more...

While adjuvants and formulations are often either empirically derived, or at best judged by their ability to elicit broad inflammation, it would be ideal if specific innate correlates of adaptive immunity could be identified, in order to set a universally applicable benchmark for adjuvant evaluation. Using an IL-27 reporter transgenic mouse model, we show here that cDC1 IL-27 production in the draining lymph node 12 hours after subcutaneous vaccination directly correlates with downstream CD8+ T cell memory and protective immunity against infectious challenge. This correlation is robust, reproducible, predictive, entirely unique to vaccine biology, and is the only innate correlate of CD8+ T cell immune memory yet to be identified. Our results provide new insights into the basic biology of adjuvant-elicited cellular immunity and have clear implications for the screening and evaluation of novel adjuvants. more...

Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC). RocA specifically targets the pool of eIF4A bound to the oncogenic mRNAs that requires its helicase activity for their translation. This property enables specific targeting of tumor cells. The efficacy of RocA against BCSCs is unknown. In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSCs, and hence targeting eIF4A may eliminate BCSCs. Therefore, we isolated BCSCs from two TNBC cell lines: MDA-Bone-Un and SUM-159PT. Following RocA treatment, the self-renewal ability of the BCSCs was significantly reduced as determined by the efficiency of the formation of primary and secondary mammospheres. This was accompanied by a reduction in the levels of NANOG, OCT4, and drug transporters. Exposure to RocA also induced cell death of the BCSCs as evaluated by DRAQ7 and cell viability assays. RocA treatment induced apoptosis with increased levels of cleaved caspase-3. Overall, we identified that RocA is effective in targeting BCSCs, and eIF4A is an actionable molecular target in both BCSCs and bulk tumor cells. Therefore, anti-eIF4A inhibitors could potentially be combined synergistically with existing chemo-, radio- and/or immunotherapies. more...