Citations

Background— Na V 1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a Na V 1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results— Mechanosensitivity of Na V 1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing Na V 1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and Na V 1.5-expressing human embryonic kidney 293 cells, negative pressure increased Na V peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by −11 mV and −10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC 50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of Na V 1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of Na V 1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions— Ranolazine effectively inhibits mechanosensitivity of Na V 1.5. The block of Na V 1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of Na V 1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Abstract Background: Colorectal cancer (CRC) is the third most common incident cancer among women in the United States. Alcohol use has been proposed as a CRC risk factor, but existing observational data remain inconsistent. To date, relatively few studies have examined associations between alcohol use and CRC risk based on molecularly-defined subtypes. Aim: To evaluate associations between alcohol use and incident CRC overall, as well as by molecularly-defined subtypes including microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF mutation status in the prospective, population-based, Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55–69 years at enrollment, in 1986. Women with prevalent cancers or no follow-up were excluded, leaving 38,001 eligible for this study. Alcohol use was obtained from a self-administered food frequency questionnaire at study baseline. Incident CRCs were identified through annual linkage with the State Health Registry of Iowa. Archived, paraffin-embedded tissue specimens were recently requested for incident CRC cases diagnosed through December 31, 2002. In the present study, useable tissue specimens were obtained and molecularly characterized for 563/1,255 cases (45%), whose baseline age, body mass index, physical activity level, total energy intake and alcohol use were similar to non-retrieved cases (p > 0.05 for each comparison). Alcohol use was categorized as never (n=21,464), < 3.4 g/day (n=8,313) and > 3.4 g/day (n=8,224), based on the median split among users. Molecularly-defined CRC subtypes were categorized as MSI-high (MSIH; n=148), MSI-low or microsatellite stable (MSI-L/MSS; n=400); CIMP-positive (n=167) or CIMP-negative (n=368); and BRAF-mutation (n=154) or BRAF-wildtype (n=391). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated for alcohol use compared to never drinkers, using multivariable Cox regression models adjusted for body mass index, waist-to-hip ratio, smoking status, physical activity level, exogenous estrogen use, and daily intakes of total energy, total fat, red meat, sucrose, calcium, folate, methionine and vitamin E. Results: There was no statistically significant association between alcohol use and overall CRC risk (RR=1.00; 95% CI = 0.86–1.15 for < 3.4 g/day versus none; RR=1.06; 95% CI=0.91–1.24 for >3.4 g/day versus none). Further, there were no associations with alcohol use for specific, molecularly-defined CRC subtypes (RRs shown for > 3.4 g/day versus none): MSI-H (RR=1.07; 95% CI=0.70–1.64); MSI-L or MSS (RR=1.12; 95% CI=0.85–1.47); CIMP-positive (RR=0.97; 95% CI=0.64–1.47); CIMP-negative (RR=1.13; 95% CI=0.85–1.50); BRAF-mutation (RR=0.94; 95% CI=0.61–1.45); and BRAF-wildtype (RR=1.20; 95% CI=0.91–1.57). Conclusion: In this cohort of older women, alcohol use did not appear to be a risk factor for incident CRC, overall or by the defined molecular subtypes. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A115.

A 60-year-old male presented with hoarseness. His past medical history was remarkable for a plasmacytoma of the left maxillary sinus having been resected without systemic evidence of plasma cell myeloma (PCM), also known as multiple myeloma (MM), at the time. This maxillary sinus disease recurred and was treated with radiation. Workup for PCM was conducted. Treatment included melphalan and autologous stem cell transplant. Because of the therapeutic and prognostic implications, a Plasma cell neoplasm (PCN) in a neck mass must be carefully evaluated by clinical and pathological criteria in order to distinguish plasmacytoma from PCM. PCN involvement of the thyroid cartilage is very rare, with only 5 previously reported cases.