HCV Therapy: Treat now or wait?

The combination of first generation protease inhibitors, telaprevir or boceprevir with pegylated interferon and ribavirin has significantly improved response rates when compared to pegylated interferon and ribavirin alone. While safe and effective for many patients, the potential of current DAA based therapy has been limited by tolerability, especially in those with extensive co-morbidities. Newer therapies, likely with improved efficacy and safety profiles are under development, however the timing of availability of these agents remains speculative. The choice to treat with currently available therapy or to wait for newer therapy is complex. These decisions require understanding of unique patient characteristics as well as safety and efficacy of both available therapy and new therapies undergoing investigation.     

31P and 1H MRS of DB‐1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan

In vivo ³¹P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pH_i) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pH_e) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pH_i decreases were sustained for at least 3 h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post‐LND, with no significant change in pH_e and a small transient decrease in bioenergetics (32.9 ± 10.6%, p > 0.05) at 40 min post‐LND. No changes in pH_i or adenosine triphosphate/inorganic phosphate were detected in the brain (pH_i, bioenergetics; p > 0.1) or skeletal muscle (pH_i, pH_e, bioenergetics; p > 0.1) for at least 120 min post‐LND. Steady‐state tumor lactate monitored by ¹H MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three‐fold (p = 0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5 mg/kg intravenously), producing a growth delay of 19.9 ± 2.0 days (tumor doubling time, 6.15 ± 0.31 days; log₁₀ cell kill, 0.975 ± 0.110; cell kill, 89.4 ± 2.2%) compared with LND alone of 1.1 ± 0.1 days and LPAM alone of 4.0 ± 0.0 days. The study demonstrates that the effects of LND on tumor pH_i and bioenergetics may sensitize melanoma to pH‐dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia. Copyright © 2012 John Wiley & Sons, Ltd.     

Does throbbing pain have a brain signature?

Pain sometimes has a throbbing, pulsating quality, particularly when it is severe and disabling. We recently challenged the presumption that this throbbing quality is a sensory experience of arterial pulsations, but were unable to offer an alternative explanation for its rhythmic character. Here we report a case study of a woman with a history of daily headache consistent with the diagnosis of chronic migraine, but whose throbbing quality persisted long after the resolution of the headache. This chronic, daily, and persistent throbbing sensation, in the absence of headache pain, prompted closer examination for its neurophysiological correlate. By simultaneously recording the subjective report of the throbbing rhythm, arterial pulse, and high-density electroencephalogram, we found that the subjective throbbing rate (48 ± 1.7 beats per minute) and heart rate (68 ± 2 beats per minute) were distinct, in accord with our previous observations that the 2 are unrelated. On spectral analysis of the electroencephalogram, we found that the overall amount of activity in the alpha range (8 to 12 Hz), or alpha power, increased in association with greater throbbing intensity. In addition, we also found that the rhythmic oscillations of overall alpha power, the so-called modulations of alpha power, coincided with the timing of the throbbing rhythm, and that this synchrony, or coherence, was proportional to the subjective intensity of the throbbing quality. This index case will motivate further studies whose aim is to determine whether modulations of alpha power could more generally represent a neurophysiological correlate of the throbbing quality of pain.     

The genetics of platelet count and volume in humans

The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet’s role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies—ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)—employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.