Citations

AbstractCyclin-dependent kinase (CDK) inhibitors have the potential to induce cell-cycle arrest and apoptosis in cancer cells. Seliciclib (CYC202 or R-roscovitine) is a potent CDK inhibitor currently undergoing phase-2 clinical testing in lung and B-cell malignancies. Here we studied the in vitro cytotoxic activity of seliciclib against multiple myeloma (MM) cells. Our data demonstrate that seliciclib has potent cytotoxicity against MM cells that are both sensitive and resistant to conventional therapy as well as primary MM cells from patients. Cell-cycle and Western blot analysis confirmed apoptosis. Importantly, seliciclib triggered a rapid down-regulation of Mcl-1 transcription and protein expression independent of caspase cleavage. Adherence of MM cells to bone marrow stromal cells (BMSCs) induced increased Mcl-1 expression associated with signal transducer and activator of transcription 3 (STAT3) phosphorylation, which was inhibited in a time- and dose-dependent manner by seliciclib. Furthermore, seliciclib inhibited interleukin 6 (IL-6) transcription and secretion triggered by tumor cell binding to BMSCs. Up-regulation of Mcl-1 expression in cocultures was only partially blocked by neutralizing antibody to IL-6, suggesting alternative mechanisms of Mcl-1 modulation by seliciclib. Finally, combination studies of seliciclib with doxorubicin and bortezomib show in vitro synergism, providing the rationale for testing these drug combinations to improve patient outcome in MM.

ABSTRACTSignaling lymphocytic activation molecule (SLAM, CD150) is the universal morbillivirus receptor. Based on the identification of measles virus (MV) hemagglutinin (H) amino acids supporting human SLAM-dependent cell entry, we mutated canine distemper virus (CDV) H and identified residues necessary for efficient canine SLAM-dependent membrane fusion. These residues are located in two nearby clusters in a new CDV H structural model. To completely abolish SLAM-dependent fusion, combinations of mutations were necessary. We rescued a SLAM-blind recombinant CDV with six mutations that did not infect ferret peripheral blood mononuclear cells while retaining full infectivity in epithelial cells.

ABSTRACT DNA from 101 specimens containing herpes simplex virus (HSV) produced atypical intermediate melting curves compared with those expected for HSV type 1 or HSV type 2 subsequent to real-time PCR. Nucleic acid sequence analysis of amplified target DNA revealed 1- or 3-bp polymorphisms in the probe region which allowed designation of these viruses as HSV genotype 1 or HSV genotype 2. These two subpopulations of HSV were also identified as HSV genotype 1 or HSV genotype 2 using another commercially available PCR method. Amplified HSV target DNA producing intermediate melting curves could be designated as HSV genotype 1 or HSV genotype 2 without performing sequencing or another PCR method with 96/101 (95%) specimens by adding known intermediate HSV DNA characteristic for the two subpopulations as controls.

Abstract The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Background— In a recent study, we reported that the Duke treadmill score was unable to effectively stratify elderly patients according to risk. The purpose of this study was to evaluate the prognostic value of exercise single-photon emission computed tomography (SPECT) in this same population and to examine results by gender. Methods and Results— A cohort of 247 elderly (age ≥75 years) patients (108 women, 139 men, age 77±3 years) who underwent exercise thallium-201 SPECT were followed up for a median duration of 6.4 years. SPECT variables were significantly associated with cardiac death: summed stress score (SSS) χ 2 =19.5, P <0.001; summed difference score χ 2 =12.3, P <0.001; increased lung uptake χ 2 =9.6, P =0.002; and left ventricular enlargement χ 2 =8.3, P =0.004. The Duke score was not significantly associated with cardiac death (χ 2 <1, P =NS). The SSS classified most patients as low risk (49%) or high risk (35%); the Duke score classified the majority (68%) as intermediate risk. Annual cardiac mortality rates for patients categorized by SSS as low risk and high risk were 0.8% and 5.8%, respectively. Cardiac survival rates according to SSS risk categories were significantly different for both women ( P =0.012) and men ( P =0.003). Conclusions— SPECT classified most elderly patients into clinically useful low- and high-risk categories and accurately predicted outcomes in both genders. If these results can be validated in future studies, exercise SPECT rather than standard treadmill testing may emerge as the initial noninvasive testing strategy in elderly patients who are able to exercise.

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.

OBJECTIVE:To assess the magnetic resonance imaging (MRI) safety of titanium middle ear prostheses at 3.0 tesla (T).STUDY DESIGN AND SETTING:Titanium middle ear prostheses from 3 commercial vendors were examined for magnetic field interactions at 3 T. Initially, ex vivo studies were performed to test for rotational motion and forward displacement (translational motion) of the prostheses in a static magnetic field. If movement was observed during this screening study, then the prosthesis was tested to determine the translational or rotational force acting upon the prosthesis. In addition to testing for prosthesis displacement, temperature changes of the prostheses were measured to assess for radiofrequency heating during imaging.RESULTS:Twenty‐one of the 24 titanium prostheses tested revealed no movement when tested in the 3 T static magnetic field. Three prostheses revealed minimal movement during the screening study. A translational force test (string test) was performed upon these 3 prostheses, and the measured angle of displacement was used to determine the force. This calculated force acting upon each prosthesis was essentially zero. Therefore, we conclude that the magnetic field interaction is negligible. A positive control with a ferromagnetic stainless steel prosthesis demonstrated obvious displacement during the screening study, as well as deflection of the prosthesis by 90° in the translational force test. Last, heating of the titanium prostheses did not occur in the 7 models tested.CONCLUSIONS:Middle ear prostheses made from titanium are safe, neither deflecting nor heating during magnetic resonance examinations conducted at 3 T. EBM rating: C‐1.