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Background: Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. Objectives: To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an antieinterleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. Methods: This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4: 1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. Results: The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. Limitations: Interpretation of efficacy data is limited by the small sample size. Conclusion: Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis.

Homozygosity mapping is a well-known technique to identify runs of

Ewing sarcoma is characterized by a pathognomonic chromosomal translocation that generates the EWSR1-FLI1 chimeric transcription factor. The transcriptional targets of EWSR1-FLI1 that are essential for tumorigenicity are incompletely defined. Here, we found that EWSR1-FLI1 modulates the expression of cancer/testis (CT) antigen genes, whose expression is biased to the testes but is also activated in cancer. Among these CT antigens, fetal and adult testis expressed 1 (FATE1) is most robustly induced. EWSR1-FLI1 associates with the GGAA repeats in the proximal promoter of FATE1, which exhibits accessible chromatin exclusively in mesenchymal progenitor cells (MPCs) and Ewing sarcoma cells. Expression of EWSR1-FLI1 in non-Ewing sarcoma cells and in MPCs enhances FATE1 mRNA and protein expression. Conversely, depletion of EWSR1-FLI1 in Ewing sarcoma cells leads to a loss of FATE1 expression. Importantly, we found that FATE1 is required for survival and anchorage-independent growth in Ewing sarcoma cells via attenuating the accumulation of BNIP3L, a BH3-only protein that is toxic when stabilized. This action appears to be mediated by the E3 ligase RNF183. We propose that engaging FATE1 function can permit the bypass of cell death mechanisms that would otherwise inhibit tumor progression.

Female Aedes aegypti mosquitoes use multiple sensory modalities to hunt human hosts and obtain a blood meal for egg production. Attractive cues include carbon dioxide (CO2), a major component of exhaled breath [1, 2]; heat elevated above ambient temperature, signifying warmblooded skin [3, 4]; and dark visual contrast [5, 6], proposed to bridge long-range olfactory and short-range thermal cues [7]. Any of these sensory cues in isolation is an incomplete signal of a human host, and so a mosquito must integrate multimodal sensory information before committing to approaching and biting a person [8]. Here, we study the interaction of visual cues, heat, and CO2 to investigate the contributions of human-associated stimuli to host-seeking decisions. We show that tethered flying mosquitoes strongly orient toward dark visual contrast, regardless of CO2 stimulation and internal host-seeking status. This suggests that attraction to visual contrast is general and not contingent on other host cues. In free-flight experiments with CO2, adding a dark contrasting visual cue to a warmed surface enhanced attraction. Moderate warmth became more attractive to mosquitoes, and mosquitoes aggregated on the cue at all non-noxious temperatures. Gr3 mutants, unable to detect CO2, were lured to the visual cue at ambient temperatures but fled and did not return when the surface was warmed to host-like temperatures. This suggests that attraction to thermal cues is contingent on the presence of the additional sensory cue CO2. Our results illustrate that mosquitoes integrate general attractive visual stimuli with context-dependent thermal stimuli to seek promising sites for blood feeding.

Over the past 50 years, the use of mathematical models, derived from

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10(S55L) mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10(S55L) mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10(S55L)-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10(S55L) mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.

I never thought I would spend so much of my time and money setting up still-life–worthy displays of flaky croissants and shiny fruit for people who are judging my science, and that of my colleagues. Yet that's the expectation: At my university, and many others, students bring food to our thesis committee meetings and defenses, adding to the already sky-high pressure. My first taste of it came 5 years ago, for my first committee meeting. I prepared furiously. I meticulously proofread my written proposal and aligned all the figures. My slides all used the same font. I had even prepared some extra slides to address possible questions my judges might ask. Even so, I was sure the meeting was doomed—because I didn't know how to make coffee.

Biased ligands preferentially activate certain signaling pathways downstream of their target receptor, leading to differential physiological or behavioral responses downstream. The kappa opioid receptor (KOR) is a drug target for diseases involving mood and reward, such as depression and addiction. Biased KOR ligands offer the potential to overcome negative side effects that have previously hampered the therapeutic development of KOR agonists by preferentially activating certain signaling pathways. Understanding relationships between ligand bias and behavior is difficult, however, because differences in cellular context and bias quantification methods lead to variation between studies. Here, a set of 21 structurally diverse KOR ligands were tested in parallel, to systematically quantify ligand bias at the KOR. Compounds included the endogenous peptide ligand Dynorphin A(1-17), two novel compounds synthesized for our research, and 18 additional compounds of different structural classes, including morphinans and the natural product Salvinorin A. Compounds were tested for their activity in early KOR signaling pathways (G-protein and β-arrestin recruitment) in KOR-expressing U2OS cells, and ligand bias was calculated. A subset of compounds was tested for sedative properties in the rotarod assay in mice. We found that rotarod sedation significantly correlated with β-arrestin signaling in this system, indicating that this in vitro system can be used to accurately describe this in vivo behavior caused by KOR agonists. Additionally, downstream signaling pathways ERK1/2 and mTOR were evaluated, and we determined that signaling via both of these pathways could diverge from KOR-mediated G-protein and arrestin signaling in this system.

Purpose of ReviewIn this review, we summarize the recent literature regarding the incidence and treatment of seizures arising after ischemic and hemorrhagic strokes. Additionally, we identify open questions in guidelines and standard clinical care to aid future studies aiming to improve management of seizures in post-stroke patients.Recent FindingsStudies demonstrate an increasing prevalence of seizures following strokes, probably a consequence of advances in post-stroke management and expanding use of continuous EEG monitoring. Post-stroke seizures are associated with longer hospitalization and increased mortality; therefore, prevention and timely treatment of seizures are important. The standard of care is to treat recurrent seizures with anti-epileptic drugs (AEDs) regardless of the etiology. However, there are no established guidelines currently for prophylactic use of AEDs following a stroke.SummaryThe prevalence of post-stroke seizures is increasing. Further studies are needed to determine the risk factors for recurrent seizures and epilepsy after strokes and optimal treatment strategies.

Background Patients who receive autologous hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies are at risk of serious adverse outcomes including infections and death. Hyperglycemia following the HCT is associated with increased risk of these adverse outcomes. However, limited information is available on demographic and clinical characteristics that contribute to changes in blood glucose levels following HCT. Objective The objective of this study was to determine the trajectories of fasting blood glucose (FBG) levels as well as the demographic and clinical characteristics that predicted interindividual differences in these FBG trajectories. Methods A sample of adult patients with hematologic malignancies who were scheduled to receive autologous HCT (n = 53) was enrolled in the study. Patients with preexisting diabetes were excluded. Demographic and clinical characteristics were abstracted from electronic medical records. Morning fasting laboratory tests (ie, FBG and absolute neutrophil counts) were obtained. Data were analyzed using hierarchical linear modeling from the day of HCT (day 0) through 14 days post-HCT. Results Among 8 characteristics evaluated, pre-HCT FBG was associated with variability in both the initial levels and the trajectories of FBG. Body mass index was only associated with initial levels of FBG. Conclusions The large amount of interindividual variability in the trajectories of FBG levels following autologous HCT suggests that glucose control in these patients warrants ongoing assessments and preemptive tailoring.