The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia

Venetoclax is a promising agent in the treatment of acute myeloid leukemia (AML), though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in AML cell lines and primary AML patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we find that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an AML cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of AML.     

Specificity of Doppler echocardiography for the assessment of changes in valvular regurgitation: comparison of side-by-side versus serial interpretation

OBJECTIVES: We sought to determine the specificity of two different methods for assessing change in aortic (AR), mitral (MR) and tricuspid (TR) valvular regurgitation. BACKGROUND: Echocardiographic imaging with Doppler is the standard noninvasive diagnostic tool for assessing valvular structure and function. Change can be assessed using either independent evaluations (serial) or using a side-by-side comparison. METHODS: Subjects were from the placebo arm of a randomized, double-blind, clinical trial. Three echocardiograms over 10 months were performed. An initial and three-month echocardiogram were read as independent groups, blinded to all parameters except sequence. The initial and 10-month echocardiograms were read side-by-side, blinded to all parameters including sequence. RESULTS: Two hundred nineteen predominantly healthy, obese, white, middle-aged women had initial and three-month echocardiograms (acquisition interval 105 +/- 28 days) evaluated by the serial method (mean 167 +/- 61 days between interpretations). The same subjects had the initial and 10-month studies (acquisition interval 303 +/- 27 days) compared side-by-side. The specificity of the serial versus side-by-side method for determining change in MR grade was 55.8% versus 93.2% (p < 0.001); TR: 63.8% versus 97.6% (p < 0.001) and AR: 93.7% versus 97.6 (p = 0.08). Notably, most of the change occurred in a range (none versus physiologic/mild) that has limited clinical significance. Furthermore, the percentage of echocardiograms interpreted as nonevaluable was lower with the side-by-side method for MR (5.0% vs. 16.0%, p = 0.06), TR (4.6% vs. 15.5%, p < 0.001) and AR (4.1% vs. 12.3%, p = 0.002). CONCLUSIONS: The side-by-side method of assessing change in valvular regurgitation appears to be the more reliable method with a higher specificity and minimal data loss.     

Natural history of patients with unexplained syncope and a nondiagnostic electrophysiologic study

The purpose of this study was to define the natural history of 99 patients with unexplained syncope who underwent an electrophysiologic test that either was entirely normal or demonstrated nonspecific abnormalities that were nondiagnostic (inducible polymorphic ventricular tachycardia or ventricular fibrillation, a mildly prolonged sinus node recovery time of less than 2 s, a His-ventricular interval of 55 to 99 ms or supraventricular tachycardia not associated with hypotension). The mean age (+/- SD) of the patients was 56 +/- 19 years; structural heart disease was present in 47 patients and absent in 52. Complete follow-up was available in 95 patients. During 20 +/- 11 months of follow-up, 2 patients (2%) died suddenly, 19 patients (20%) had recurrent syncope and 74 patients (78%) had no further episodes of syncope. Among the 19 patients who continued to have syncope after the electrophysiologic testing, the cause of syncope was established clinically in 4 and was found to be high degree atrioventricular (AV) block (2 patients) or sinus node dysfunction (2 patients). No clinical or laboratory findings distinguished patients who had sudden death or syncope during follow-up from patients who did not. In conclusion, in patients with unexplained syncope who undergo an electrophysiologic test that is nondiagnostic 1) the incidence of sudden death is low (2%); 2) the remission rate of syncope is high (80%); 3) the electrophysiologic test may be documented to have been falsely negative in greater than or equal to 20% of patients who continue to have syncope, syncope in these patients being caused by AV block or sinus node dysfunction; and 4) patients at risk of sudden death or recurrent syncope, or both, cannot be readily identified prospectively.     

The association of RBC sodium-lithium countertransport (Vmax) with left ventricular mass in African American women

In Caucasian hypertensives and diabetics, increased RBC sodium-lithium countertransporter activity (SLC) is a marker for end-organ complications of vascular disease. A subgroup of African Americans with high Vmax for SLC show strong correlations with dyslipidaemia, insulin resistance, microalbuminuria and higher blood pressure. The purpose of our study was to determine if Vmax in premenopausal African American women correlates with left ventricular mass (LVM) before the onset of clinically diagnosed hypertension. Non-diabetic African American women (n = 35, mean age 31 years) were evaluated for cardiovascular disease risk factors, including anthropometric and blood pressure measurements, oral glucose tolerance test (OGTT), and euglycaemic hyperinsulinaemic clamp for insulin sensitivity. Fasting blood specimens were assayed for SLC activity (Vmax) and lipids. Cardiac structure was determined by 2-D echocardiography. LVM was calculated by the cube root formula and adjusted for height (LVM index). Vmax correlated significantly with average systolic blood pressure (r = 0.45, P = 0.007), diastolic blood pressure (r = 0.48, P = 0.004), mean blood pressure (r = 0.48, P = 0.003) and LVM index (r = 0.40, P = 0.02). Vmax was also associated with fasting insulin (r = 0.39, P = 0.01), the sum of insulin (r = 0.52, P = 0.002), and insulin sensitivity adjusted for fat-free mass (r = -0.55, P = 0.001). There was no statistically significant relationship between Vmax and body mass or lipids. Vmax for SLC correlates with cardiac structure in premenopausal African American women. Vmax is also associated with insulin sensitivity and insulin resistance in this non-diabetic sample. SLC activity may be useful in identifying a subgroup of young African American women with left ventricular hypertrophy and insulin resistance before the onset of clinically diagnosed hypertension and diabetes. Journal of Human Hypertension (2000) 14, 213-219.     

Anemia of the Belgrade rat: evidence for defective membrane transport of iron

The mechanisms underlying the impaired utilization of transferrin-bound iron by erythroid cells in the anemia of the Belgrade laboratory rat were investigated using reticulocytes from homozygous anemic animals and transferrin labeled with 59Fe and 125I. The results were compared with those obtained using reticulocytes from phenylhydrazine-treated rats and iron-deficient rats. Each step in the iron uptake mechanism was investigated, ie, transferrin-receptor interaction, transferrin endocytosis, iron release from transferrin, and transferrin exocytosis. Although there were quantitative differences, no fundamental difference was found in any of the abovementioned aspects of cellular function when the reticulocytes from Belgrade rats were compared with those from iron-deficient animals. The basic defect in the Belgrade reticulocytes must therefore reside in subsequent steps in iron uptake, after it is released from transferrin within endocytotic vesicles, ie, in the mechanism by which it is transferred across the lining membrane of the vesicles into the cell cytosol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reticulocyte ghosts extracts demonstrated a prominent protein band of mol wt 69,000 that was absent or present only in low concentration extracts from the other two types of reticulocytes. This may be a result of the genetic defect.     

GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma

3F8 is a murine monoclonal IgG3 antibody specific for the tumor-associated antigen ganglioside GD2. Previous in vitro studies suggest that tumor regressions observed in a phase I clinical trial of 3F8 may be attributable to complement activation by 3F8 and to 3F8-dependent cellular cytotoxicity (ADCC) with lymphocytes. We now describe 3F8-mediated ADCC of GD2-positive tumor targets (melanoma and neuroblastoma) with human granulocytes and report that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced this phenomenon. Cytotoxicity required binding of 3F8 to the low-affinity Fc receptor type III (CD16) on the granulocytes and was poor with tumor-binding monoclonal antibodies of other immunoglobulin (ie, non-IgG3) subclasses. GM-CSF (2 to 20 ng/mL) increased ADCC by 93% to 267% at limiting dilutions of 3F8 (1 microgram/mL). With most GD2-positive cell lines tested, this effect translated into a tenfold or greater augmentation in 3F8 efficiency at mediating ADCC. Comparable enhancement occurred whether GM-CSF was present in the ADCC assay or granulocytes were incubated with GM-CSF and washed before the assay. Nonoxidative mechanisms may be important for ADCC since 3F8 mediated ADCC with granulocytes from two children with chronic granulomatous disease; this cytotoxicity was also enhanced by GM-CSF. Since GM-CSF induces a neutrophilia in patients, our data suggest that this cytokine may have the potential of amplifying 3F8 antitumor activity in patients by increasing effector cell numbers and by priming granulocytes for greater cytotoxicity.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.