Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6 natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.
Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long-term outcomes, including suicide, and poor treatment response. Because extant psychological and pharmacological treatments are relatively ineffective for anhedonia, there is an unmet therapeutic need for this high-risk symptom. Current psychological and drug treatments for anxiety and depression focus largely on reducing excesses in negative affect rather than improving deficits in positive affect. Recent advances in affective neuroscience posit that anhedonia is associated with deficits in the appetitive reward system, specifically the anticipation, consumption, and learning of reward. In this paper, we review the evidence for positive affect as a symptom cluster, and its neural underpinnings, and introduce a novel psychological treatment for anxiety and depression that targets appetitive responding. First, we review anhedonia in relation to positive and negative valence systems and current treatment approaches. Second, we discuss the evidence linking anhedonia to biological, experiential, and behavioral deficits in the reward subsystems. Third, we describe the therapeutic approach for Positive Affect Treatment (PAT), an intervention designed to specifically target deficits in reward sensitivity.
Objective: Loss of pleasure or interest in activities (i.e., anhedonia) is a risk factor for suicidality, treatment nonresponse, and relapse. Extant treatments that focus on reducing negative affect have limited effects upon positive affect (a core feature of anhedonia). We investigated whether a novel intervention aimed at increasing reward sensitivity was more efficacious for positive affect than a cognitive–behavior treatment aimed at reducing threat sensitivity, in individuals with clinically severe symptoms of depression or anxiety, and functional impairment. Method: The Treatment for Affective Dimensions trial was offered in a 2-site randomized study at outpatient treatment centers in Los Angeles and Dallas. Ninety-six patients were randomized to 15 weekly, individual sessions of Positive Affect Treatment (PAT) or Negative Affect Treatment (NAT). The primary outcome was improvement in positive affect (Positive and Negative Affect Schedule–Positive) from pretreatment to 6-month follow-up (6MFU). Secondary outcomes were improvements in negative affect (Positive and Negative Affect Schedule–Negative), suicidal ideation, and symptoms (Depression Anxiety Stress Scales). Results: PAT resulted in greater improvements in positive affect, p = .009, d = .52, and higher positive affect at 6MFU, p = .002, d = .67, than NAT. Participants in PAT also reported lower negative affect, p = .033, d = .52, and lower symptoms of depression, p = .035, d = .34, anxiety, p < .018, d = .30, and stress, p = .006, d = .43 at 6MFU. Finally, probability of suicidal ideation at 6MFU was lower in PAT than NAT (1.7% vs. 12.0%), p < .001. Conclusions: Compared to NAT, PAT demonstrated better outcomes (at 6MFU) on positive affect, depression, anxiety, stress, and suicidal ideation, for patients with symptomatic pretreatment levels of these outcomes.
Various emotional states and stress increase oscillatory resistance largely independently of concurrent increases in autonomic or ventilatory activity. The particular sensitivity of asthmatics to passive coping demand requires additional research.
Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis.
Targeted nanomedicine holds enormous potential for advanced diagnostics and therapy. Although it is known that nanoparticles accumulate in liver in vivo, the impact of cell-targeting particles on the liver, especially in disease conditions, is largely obscure. We had previously demonstrated that peptide-conjugated nanoparticles differentially impact macrophage activation in vitro. We thus comprehensively studied the distribution of gold nanorods (AuNR) in mice in vivo and assessed their hepatotoxicity and impact on systemic and hepatic immune cells in healthy animals and experimental liver disease models. Gold nanorods were stabilized with either cetyltrimethylammonium bromide or poly(ethylene glycol) and additional bioactive tripeptides RGD or GLF. Gold nanorods mostly accumulated in liver upon systemic injection in mice, as evidenced by inductively coupled plasma mass spectrometry from different organs and by non-invasive microcomputerized tomography whole-body imaging. In liver, AuNR were only found in macrophages by seedless deposition and electron microscopy. In healthy animals, AuNR did not cause significant hepatotoxicity as evidenced by biochemical and histological analyses, even at high AuNR doses. However, flow cytometry and gene expression studies revealed that AuNR polarized hepatic macrophages, even at low doses, dependent on the respective peptide sequence, toward M1 or M2 activation. While peptide-modified AuNR did not influence liver scarring, termed fibrosis, in chronic hepatic injury models, AuNR-induced preactivation of hepatic macrophages significantly exacerbated liver damage and disease activity in experimental immune-mediated hepatitis in mice. Bioactively targeted gold nanoparticles are thus potentially harmful in clinically relevant settings of liver injury, as they can aggravate hepatitis severity.
Background-Given growing evidence that respiratory dysregulation is a central feature of panic disorder (PD) interventions for panic that specifically target respiratory functions could prove clinically useful and scientifically informative. We tested the effectiveness of a new, brief, capnometry-assisted breathing therapy (BRT) on clinical and respiratory measures in PD.Methods-Thirty-seven participants with PD with or without agoraphobia were randomly assigned to BRT or to a delayed-treatment control group. Clinical status, respiration rate, and end-tidal pCO 2 were assessed at baseline, posttreatment, 2-month and 12-month follow-up. Respiratory measures were also assessed during homework exercises using a portable capnometer as a feedback device.Results-Significant improvements (in PD severity, agoraphobic avoidance, anxiety sensitivity, disability, and respiratory measures) were seen in treated but not untreated patients, with moderate to large effect sizes. Improvements were maintained at follow-up. Treatment compliance was high for session attendance and homework exercises; dropouts were few.Conclusions-The data provide preliminary evidence that raising end-tidal pCO 2 by means of capnometry feedback is therapeutically beneficial for panic patients. Replication and extension will be needed to verify this new treatment's efficacy and determine its mechanisms.
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