PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in understanding of how to rationally leverage the therapeutic activity. PD-L1 is widely expressed in tumor cells but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro. As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. A comparative microarray analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also elevated mTORC1 activity and augmented the anti-proliferative effects of the mTORC1 inhibitor rapamycin. PD-L1 cells were also relatively deficient in metastasis to the lung and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or tissue-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate non-immune effects of anti-PD-L1 immunotherapy and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses.

Mental health problems are endemic across the globe, and suicide, a strong corollary of poor mental health, is a leading cause of death. Classic psychedelic use may occasion lasting improvements in mental health, but the effects of classic psychedelic use on suicidality are unknown. We evaluated the relationships of classic psychedelic use with psychological distress and suicidality among over 190,000 USA adult respondents pooled from the last five available years of the National Survey on Drug Use and Health (2008-2012) while controlling for a range of covariates. Lifetime classic psychedelic use was associated with a significantly reduced odds of past month psychological distress (weighted odds ratio (OR)=0.81 (0.72-0.91)), past year suicidal thinking (weighted OR=0.86 (0.78-0.94)), past year suicidal planning (weighted OR=0.71 (0.54-0.94)), and past year suicide attempt (weighted OR=0.64 (0.46-0.89)), whereas lifetime illicit use of other drugs was largely associated with an increased likelihood of these outcomes. These findings indicate that classic psychedelics may hold promise in the prevention of suicide, supporting the view that classic psychedelics' most highly restricted legal status should be reconsidered to facilitate scientific study, and suggesting that more extensive clinical research with classic psychedelics is warranted.

It has been suggested that there are two forms of narcissism: a grandiose subtype and a vulnerable subtype. Although these forms of narcissism share certain similarities, it is believed that these subtypes may differ in the domains upon which their self-esteem is based. To explore this possibility, the present study examined the associations between these narcissistic subtypes and domain-specific contingencies of self-worth. The results show that vulnerable narcissism was positively associated with contingencies of self-worth across a variety of domains. In contrast, the associations between grandiose narcissism and domain-specific contingencies of self-worth were more complex and included both positive and negative relationships. These results provide additional support for the distinction between grandiose and vulnerable narcissism by showing that the domains of contingent self-esteem associated with grandiose narcissism may be more limited in scope than those associated with vulnerable narcissism.

IntroductionRecent studies from our laboratory 1,2 and others 3,4 have shown that factor VIIa (FVIIa), a clotting protease that binds to tissue factor (TF) and initiates the activation of the coagulation cascade, also binds to the endothelial cell protein C receptor (EPCR), a receptor for anticoagulant protein C/activated protein C (APC). EPCR controls coagulation by promoting the activation of protein C by thrombin-thrombomodulin complexes. 5 In addition to controlling coagulation, EPCR has been shown to modulate several nonhemostatic functions by supporting APC-induced protease activated receptor-1 (PAR1)-mediated cell signaling. [6][7][8][9][10][11][12][13] Although direct evidence for an association of FVIIa with EPCR in vivo is yet to come, several recent observations are a strong indication that FVIIa does in fact interact with EPCR in vivo. Both human and murine FVIIa administered to mice were shown to associate with endothelium, and blockade of EPCR with EPCR-specific antibodies was shown to prolong the human FVIIa circulatory-half life in mice. 2,14 Analysis of FVII, FVIIa, and soluble EPCR levels in a large group of healthy individuals revealed that those with the EPCR Gly variants, whose circulating levels of soluble EPCR were higher, had higher levels of circulating FVII and FVIIa, suggesting that EPCR in vivo serves as a reservoir for FVII. 15,16 At present, the physiologic importance of FVIIa's interaction with EPCR is not entirely clear. Our recent studies suggest that EPCR may play a role in the clearance and/or transport of FVIIa. 2 Although we are unable to find evidence for the modulation of FVIIa's coagulant activity by EPCR, 1 others have shown that FVIIa binding to EPCR on endothelial cells downregulates FVIIa's coagulant activity. 4 Similarly, EPCR was shown to down-regulate FVIIa generation on endothelial cells by reducing FVII accessibility to phospholipids at the cell surface. 17 Despite divergent views on the potential mechanisms by which APC binding to EPCR provides cytoprotective activity through PAR1-mediated cell signaling, it is generally believed that complex formation of APC with EPCR potentiates APC cleavage of PAR1, and that PAR1 activation is responsible for eliciting protective signaling responses. 6,13,[18][19][20] In agreement with this notion, APC was shown to cleave PAR1 on endothelial cells, and EPCRblocking antibodies that prevent APC binding to EPCR inhibited APC cleavage of PAR1. 18 In studies performed in a heterologous cell model system expressing transfected EPCR and PAR1 or PAR2 reporter constructs, we found no evidence that the FVIIa bound to EPCR was capable of cleaving either PAR1 or PAR2 or of inducing cell signaling. 1 In earlier studies, APC was shown to cleave PAR1 reporter constructs expressed in endothelial cells (EA.hy926 cells), but this cleavage required high concentrations of APC (75nM or higher) and was EPCR independent. 10,21 In the same studies, an APC-mediated protective effect was seen with much lower concentrations of APC, and this effect was E...

It is recommended that researchers and clinicians adopt a more stringent CO cutoff in the range of 3-4 ppm when complete abstinence from smoking is the goal.

As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor initiating cells (TIC) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TIC express more PD-L1 versus non-TIC. Silencing PD-L1 in B16 and ID8agg cells by shRNA (“PD-L1lo”) reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression, and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses.

Hallucinogen-based interventions may benefit substance use populations, but contemporary data informing the impact of hallucinogens on addictive behavior are scarce. Given that many individuals in the criminal justice system engage in problematic patterns of substance use, hallucinogen treatments also may benefit criminal justice populations. However, the relationship between hallucinogen use and criminal recidivism is unknown. In this longitudinal study, we examined the relationship between naturalistic hallucinogen use and recidivism among individuals under community corrections supervision with a history of substance involvement (n=25,622). We found that hallucinogen use predicted a reduced likelihood of supervision failure (e.g. noncompliance with legal requirements including alcohol and other drug use) while controlling for an array of potential confounding factors (odds ratio (OR)=0.60 (0.46, 0.79)). Our results suggest that hallucinogens may promote alcohol and other drug abstinence and prosocial behavior in a population with high rates of recidivism.

BackgroundRecent studies show that activated factor VII (FVIIa) binds to the endothelial cell protein C receptor (EPCR) on the vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown.ObjectiveThe aim of the present study was to investigate the role of the FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues.MethodsWild-type, EPCR-deficient or ECPR-over-expressing mice were injected with human recombinant (r)FVIIa (120 μg kg−1 body weight) via the tail vein. At varying time intervals after rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR.ResultsThe data reveal that, after intravenous (i.v.) injection, rFVIIa rapidly disappears from the blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that the association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. The FVIIa association with the endothelium was undetectable at time points exceeding 24 h post-FVIIa administration. The levels of rFVIIa accumulated in tissue correlate with expression levels of EPCR in mice and FVIIa associated with tissues remained functionally active for periods of at least 7 days.ConclusionsThe observation that an EPCR-dependent association of FVIIa with the endothelium is most pronounced soon after rFVIIa administration and subsequently declines temporally, combined with the retention of functionally active FVIIa in tissue homogenates for extended periods, indicates that FVIIa binding to EPCR on the endothelium facilitates the transport of FVIIa from circulation to extravascular tissues where TF resides.