The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 10/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy.

No abstract

No abstract

No abstract

Study Design. Retrospective cross-sectional analysis. Summary of Background Data. Degenerative changes are a major contributor to chronic neck pain. According to the vascular hypothesis of disk disease, atherosclerosis of the segmental arteries contributes to ischemia of the lumbar disks and resulting degenerative changes. Prior studies have demonstrated an association between atherosclerotic risk factors and lumbar degenerative disease. Similarly, atherosclerosis may contribute to cervical disk degeneration. Cardiovascular disease is associated with the development of atherosclerosis, particularly in small vessels to the cervical spine. Hypercholesterolemia is a major contributor to the morbidity associated with cardiovascular disease. This study aims to examine the relationship between hypercholesterolemia and neck pain. Materials and Methods. Analysis was focused on the respondents to neck pain items of the standardized questionnaire. Odds ratios were calculated, and logistic regression analyses adjusted for demographic, education, and mental health conditions. Results. There were 30,461 participants in the 2018 Medicare Expenditure Panel Survey (MEPS) survey. Of those, 1049 (3.4%) subjects responded to presence of a diagnosis of cervical disorders with neck pain. Mean age of respondents was 62.6±16.1. Overall prevalence of neck pain was 21.1%. Prevalence of neck pain was similar by age, sex, education level, and occupation (P>0.05 for each). Neck pain was more prevalent in white race and lower total family income (P<0.05). Current everyday smokers also had higher prevalence of neck pain (P<0.05). Logistic regression analysis revealed a higher prevalence of neck pain in those with hypercholesterolemia after controlling for relevant covariates (adjusted odds ratio=1.54, 95% CI: 1.08–2.22, P=0.018). Conclusions. Subjects with hypercholesterolemia were 54% more likely to have neck pain after controlling for confounders. This suggests that hypercholesterolemia has a role to play in degeneration of the cervical spine. Therefore, prevention and proper management of high cholesterol may curtail the development and progression of degenerative cervical disk disease and thus, neck pain.

Acute myeloid leukemia (AML) therapy is associated with pancytopenia and with a high failure rate due to resistant leukemia stem cells that home to marrow niches. We present here updated results of this study that combined the low anticoagulant heparin CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7+3) along with CX-01. Patients younger than 60 received consolidation therapy with high dose cytarabine along with CX-01. Twelve patients were enrolled (median age 56; range 22 - 74; 3 women). Three, 5, and 4 patients had good, intermediate, and poor risk disease, respectively. Two patients did not finish induction due to events unrelated to CX-01. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had a morphologic complete remission after one induction (CR1), including all patients with de novo AML (11/11). No patient required re-induction at Day 14. Eight patients are alive at a median follow-up of 24 months (range 13 - 29). Four patients remain in CR1. Four patients received an allogeneic stem cell transplant in CR1. All patients who received a full induction were evaluable for platelet recovery and had a median day to an untransfused platelet count ≥ 20,000/μl of 21. Five patients who received a full induction without myelopoietic growth factor support were evaluable for neutrophil recovery and had a median time to a neutrophil count ≥ 500/mL of 22 days (mean 22.6 ± 2.4, range 21 - 27). Median disease free survival was 14.8 months. Median overall survival was not attained at the maximum follow up time of 29.4 months. No CX-01-associated serious adverse events occurred. In a supplemental surface plasmon resonance study, CX-01 inhibited binding of CXCL12 to surface conjugated heparin with a 50% inhibitory concentration (IC50) of 4.7 nM, suggesting the possibility that CX-01 may enhance CR by disrupting the CXCL12-mediated leukemic stem cell marrow niche. We conclude that CX-01 is well tolerated when combined with intensive therapy for AML. It appears to be associated with enhanced count recovery and treatment efficacy. Thus, CX-01 warrants further study in this setting. Disclosures Kovacsovics: Seattle Genetics: Research Funding. Deininger:CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kennedy:Cantex Pharmaceuticals: Equity Ownership. Marcus:Cantex Pharmaceuticals: Employment, Equity Ownership. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

No abstract