Hashimoto's Encephalopathy with Use of Intravenous Immunoglobulin as First-Line Therapy.

Hashimoto's encephalopathy is an uncommon cause of altered mental status in hospitalized patients and is challenging to diagnose, particularly in the presence of other psychiatric comorbidities. Corticosteroids are the primary treatment. Here, we present a patient with history of post-traumatic stress disorder and prior substance abuse admitted with profound altered mental status and agitation requiring admission to the intensive care unit and mechanical ventilation. He was treated with intravenous immunoglobulin (IVIG) instead of the standard steroid course because of concerns for worsening agitation. The patient had improvement with IVIG infusions, returned to a functional state, and has remained on IVIG therapy monthly since the initial episode without any disease recurrence.

Griseofulvin Radiosensitizes Non-Small Cell Lung Cancer Cells and Activates cGAS.

Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.

Systems thinking as a pathway to global warming beliefs and attitudes through an ecological worldview.

Prior research has found that systems thinking, the tendency to perceive phenomena as interconnected and dynamic, is associated with a general proenvironmental orientation. However, less is known about its relationship with public understanding of climate change and/or whether this relationship varies across people with different political views. Because climate change is a highly politicized issue, it is also important to understand the extent to which systems thinking can foster acceptance of climate science across political lines. Using an online sample of US adults (n = 1,058), we tested the degree to which systems thinking predicts global warming beliefs and attitudes (e.g., believing that global warming is happening, that it is human-caused, etc.), independent of an ecological worldview (i.e., the New Ecological Paradigm). We found that although systems thinking is positively related to global warming beliefs and attitudes, the relationships are almost fully explained by an ecological worldview. Indirect effects of systems thinking are consistently strong across political ideologies and party affiliations, although slightly stronger for conservatives and Republicans than for liberals and Democrats, respectively. We did not find evidence of the converse: Systems thinking does not seem to mediate the relationship between an ecological worldview and global warming beliefs and attitudes. Together, these findings suggest that systems thinking may support the adoption of global warming beliefs and attitudes indirectly by helping to develop an ecological ethic that people should take care of and not abuse the environment.

Diverse segments of the US public underestimate the environmental concerns of minority and low-income Americans.

In a nationally representative survey experiment, diverse segments of the US public underestimated the environmental concerns of nonwhite and low-income Americans and misperceived them as lower than those of white and more affluent Americans. Moreover, both whites and nonwhites and higher- and lower-income respondents associated the term "environmentalist" with whites and the well-educated, suggesting that shared cultural stereotypes may drive these misperceptions. This environmental belief paradox-a tendency to misperceive groups that are among the most environmentally concerned and most vulnerable to a wide range of environmental impacts as least concerned about the environment-was largely invariant across demographic groups and also extended to the specific issue of climate change. Suggesting these beliefs are malleable, exposure to images of a racially diverse (vs. nondiverse) environmental organization in an embedded randomized experiment reduced the perceived gap between whites' and nonwhites' environmental concerns and strengthened associations between nonwhites and the category "environmentalists" among minority respondents. These findings suggest that stereotypes about others' environmental attitudes may pose a barrier to broadening public engagement with environmental initiatives, particularly among populations most vulnerable to negative environmental impacts.

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis.

Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked ß-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.

ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation.

DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage-signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.

Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.

Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/ß-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.

Ganetespib radiosensitization for liver cancer therapy.

Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33-1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.