Tantalum strength at extreme strain rates from impact-driven Richtmyer-Meshkov instabilities.

Recently, Richtmyer-Meshkov instability (RMI) experiments driven by high explosives and fielded with perturbations on a free surface have been used to study strength at extreme strain rates and near zero pressure. The RMI experiments reported here used impact loading, which is experimentally simpler, more accurate to analyze, and which also allows the exploration of a wider range of conditions. Three experiments were performed on tantalum at shock stresses from 20 to 34 GPa, with six different perturbation sizes at each shock level, making this the most comprehensive set of strength-focused RMI experiments reported to date on any material. The resulting estimated average strengths of 1200-1400 MPa at strain rates of 10^{7}/s exceeded, by 40% or more, a common power law extrapolation from data at strain rates below 10^{4}/s. Taken together with other data in the literature that show much higher strength at simultaneous high rates and high pressure, these RMI data isolated effects and indicated that, in the range of conditions examined, the pressure effects are more significant than rate effects.

Evaluation of thymosin α 1 in nonclinical models of the immune-suppressing indications melanoma and sepsis.

OBJECTIVES: Recent understanding of the complex pathophysiology of melanoma and severe sepsis suggests that immune-modulating compounds such as thymosin alpha 1 (INN: thymalfasin; abbreviated Ta1) could be useful in the treatment of these two unrelated immune-suppressing indications. RESEARCH DESIGN AND METHODS: Three nonclinical murine models were utilized, including: i) a lung metastasis B16 model; ii) a B16-based tumor growth model; and iii) a cecal-ligation and puncture (CLP) sepsis model. RESULTS: In the lung metastasis model, Ta1 treatment alone led to a 32% decrease in metastases (p < 0.05). Additionally, combinations of Ta1 and an anti-PD-1 antibody led to significantly fewer metastases than vehicle. In the tumor growth model, significant decreases in tumor growth were seen: 34% (p = 0.015) to 46% (p = 0.001) depending on the Ta1 dose. In the CLP sepsis model, Ta1 treatment showed a positive trend towards increased survival and decreased bacterial load. In this CLP model, Ta1 also appeared to have an effect on the levels of some biomarkers. CONCLUSIONS: All three models demonstrated a benefit after treatment with Ta1, with no evidence of toxicity. These initial pilot studies support the hypothesis that immune-suppressive indications, including sepsis and melanoma, may be treated with Ta1 alone or by Ta1 in combination with other immunotherapies.

Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8⁺ T cells in type 1 diabetes.

In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the ß cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve ß cell function in T1D patients through reduction of insulin-specific CD8⁺ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⁺ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⁺ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⁺ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.

Hemophagocytic lymphohistiocytosis: a rare cause of pancytopenia.

A 36-year-old man with fever and pancytopenia due to Hemophagocytic Lymphohistiocytosis is reported. The patient was started on the HLH-94 based treatment. Two weeks after the initiation of therapy the patient's pancytopenia had resolved and he was discharged to complete treatment as an outpatient. The initial clinical presentation, diagnostic criteria, pathophysiology and treatment will be discussed.