Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors.

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy.

Causal identification of single-cell experimental perturbation effects with CINEMA-OT.

Recent advancements in single-cell technologies allow characterization of experimental perturbations at single-cell resolution. While methods have been developed to analyze such experiments, the application of a strict causal framework has not yet been explored for the inference of treatment effects at the single-cell level. Here we present a causal-inference-based approach to single-cell perturbation analysis, termed CINEMA-OT (causal independent effect module attribution + optimal transport).

FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma.

Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role.

Online survey of university students' perception, awareness and adherence to COVID-19 prevention measures.

Background: Determining factors correlated with protective measures against COVID-19 is important to improve public health response. This study describes student opinions related to university COVID-19 preventive measures.

Methods: In fall 2020, 643 US university students completed an online survey on perception, awareness, and adherence to COVID-19 preventive measures.

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.

Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.

Patients And Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330).

Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors.

Background: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells.

Methods: Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment.

B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors.

Background: PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.

Methods: We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy.

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer.

Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice.

Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity.

Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state.

IL-7 plays a critical role for the homeostasis of allergen-specific memory CD4 T cells in the lung and airways.

Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways.

UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model.

Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single-cell clone, we generated a mutagenized model that exhibits high somatic mutation burden.

CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7- and IL-15-dependent niches.

C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection.

Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.

More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1).

Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase.

The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection.

Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin.

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1.

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line.

Comparison of the analytical capabilities of the BAC Datamaster and Datamaster DMT forensic breath testing devices.

The State of Michigan uses the Datamaster as an evidential breath testing device. The newest version, the DMT, will replace current instruments in the field as they are retired from service. The Michigan State Police conducted comparison studies to test the analytical properties of the new instrument and to evaluate its response to conditions commonly cited in court defenses.