Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. ...Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8+ T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8+ T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8+ T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.
•Pharmacologic inhibition of MEK potentiates rather than hinders anti-tumor T cells•MEK inhibitors nonetheless suppress anti-tumor priming in lymph nodes in vivo•MEK inhibitors potentiate anti-tumor T cells by impairing TCR-driven apoptosis•MEK inhibition combines with anti-PD-L1 treatment to yield durable tumor regression
MEK is a critical signaling component for both Ras-pathway-mutated tumors and normal T cells. Mellman and colleagues demonstrate that MEK inhibitors potentiate rather than suppress T-cell-based anti-tumor immunity and can combine successfully with anti-PD-L1 immunotherapy.
We propose that the temporal dimension is fragile in that choices are insufficiently sensitive to it, and second, such sensitivity as exists is exceptionally malleable, unlike other dimensions such ...as money, which are attended by default. To test this, we axiomatize a "constant-sensitivity" discount function, and in four studies, we show that the degree of time-sensitivity is inadequate relative to the compound discounting norm, and strongly susceptible to manipulation. Time-sensitivity is increased by a comparative within-subject presentation (Experiment 1), direct instruction (Experiment 3), and provision of a visual cue for time duration (Experiment 4); time-sensitivity is decreased using a time pressure manipulation (Experiment 2). In each study, the sensitivity manipulation has an opposite effect on near-future and far-future valuations: Increased sensitivity decreases discounting in the near future and increases discounting in the far future. In contrast, such sensitivity manipulations have little effect on the money dimension.
Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if ...patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
CAD/CAM milling systems provide a rapid and individual method for the manufacturing of zirconia dental restorations. However, the disadvantages of these systems include limited accuracy, possible ...introduction of microscopic cracks, and a waste of material due to the principle of the ‘subtractive process’. The hypothesis of this study was that these issues can be overcome by a novel generative manufacturing technique, direct inkjet printing. A tailored zirconia-based ceramic suspension with 27 vol% solid content was synthesized. The suspension was printed on a conventional, but modified, drop-on-demand inkjet printer. A cleaning unit and a drying device allowed for the build-up of dense components of the size of a posterior crown. A characteristic strength of 763 MPa and a mean fracture toughness of 6.7 MPam0.5 were determined on 3D-printed and subsequently sintered specimens. The novel technique has great potential to produce, cost-efficiently, all-ceramic dental restorations at high accuracy and with a minimum of materials consumption.
Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. ...Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.
We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain ...coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
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•Analysis of 2,114 postmortem samples reveals the Alzheimer’s brain transcriptome•Overlap with mouse models pinpoints age-, sex-, and pathology-induced changes•Cross-species resource highlights conserved transcriptional networks in disease
Wan et al. develop a consensus atlas of the human brain transcriptome in Alzheimer’s disease, based on 2,114 postmortem samples, and examine overlap with 251 expression signatures from mouse brain RNA sequencing experiments, including many neurodegenerative disease models.
This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans.
Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent ...electrocardiography, measured arterial, central venous CVP and pulmonary artery PAP pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide ETCO2, respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml).
The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged.
Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.
Abstract Autism is a severe disorder that involves both genetic and environmental factors. Expression profiling of the superior temporal gyrus of six autistic subjects and matched controls revealed ...increased transcript levels of many immune system-related genes. We also noticed changes in transcripts related to cell communication, differentiation, cell cycle regulation and chaperone systems. Critical expression changes were confirmed by qPCR ( BCL6 , CHI3L1 , CYR61 , IFI16 , IFITM3 , MAP2K3 , PTDSR , RFX4 , SPP1 , RELN , NOTCH2 , RIT1 , SFN , GADD45B , HSPA6 , HSPB8 and SERPINH1 ). Overall, these expression patterns appear to be more associated with the late recovery phase of autoimmune brain disorders, than with the innate immune response characteristic of neurodegenerative diseases. Moreover, a variance-based analysis revealed much greater transcript variability in brains from autistic subjects compared to the control group, suggesting that these genes may represent autism susceptibility genes and should be assessed in follow-up genetic studies.
Understanding the relationship between protein structural dynamics and function is crucial for both basic research and biotechnology. However, methods for studying the fast dynamics of structural ...changes are limited. Here, we introduce fluorescent nanoantennas as a spectroscopic technique to sense and report protein conformational changes through noncovalent dye-protein interactions. Using experiments and molecular simulations, we detect and characterize five distinct conformational states of intestinal alkaline phosphatase, including the transient enzyme-substrate complex. We also explored the universality of the nanoantenna strategy with another model protein, Protein G and its interaction with antibodies, and demonstrated a rapid screening strategy to identify efficient nanoantennas. These versatile nanoantennas can be used with diverse dyes to monitor small and large conformational changes, suggesting that they could be used to characterize diverse protein movements or in high-throughput screening applications.
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