Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th International Post-ASH Symposium

Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.     

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human γδ T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of γδ T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of γδ T cell-based strategies in the current landscape of cancer immunotherapies.     

Vascular effects of nonsteroidal antiinflammatory drugs

The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on the risk of cardiovascular events remains controversial. Among NSAIDs, only low-dose aspirin exerts protective vascular effects. Low-dose aspirin has been proven effective for secondary prevention. For primary prevention, the usefulness of low-dose aspirin is debated, as illustrated by the differences in recommendations across countries. NSAIDs other than aspirin, whether COX-2 selective or nonselective, increase the risk of cardiovascular events. Among them, naproxen is associated with the smallest risk increase. In patients with a history of coronary artery disease, diclofenac seems to carry the greatest risk, but all NSAIDs should be avoided. Uncertainties persist about aspirin interactions with other NSAIDs and with proton pump inhibitors. An adverse effect of acetaminophen on the risk of cardiovascular disease cannot be completely ruled out.     

Genetic characterization of tick-borne flaviviruses: new insights into evolution, pathogenetic determinants and taxonomy

Here, we analyze the complete coding sequences of all recognized tick-borne flavivirus species, including Gadgets Gully, Royal Farm and Karshi virus, seabird-associated flaviviruses, Kadam virus and previously uncharacterized isolates of Kyasanur Forest disease virus and Omsk hemorrhagic fever virus. Significant taxonomic improvements are proposed, e.g. the identification of three major groups (mammalian, seabird and Kadam tick-borne flavivirus groups), the creation of a new species (Karshi virus) and the assignment of Tick-borne encephalitis and Louping ill viruses to a unique species (Tick-borne encephalitis virus) including four viral types (i.e. Western Tick-borne encephalitis virus, Eastern Tick-borne encephalitis virus, Turkish sheep Tick-borne encephalitis virus and Louping ill Tick-borne encephalitis virus). The analyses also suggest a complex relationship between viruses infecting birds and those infecting mammals. Ticks that feed on both categories of vertebrates may constitute the evolutionary bridge between the three distinct identified lineages.     

Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.     

Breath sound distribution images of patients with pneumonia and pleural effusion

OBJECTIVE: To determine whether breath sound distribution maps can differentiate between patients with pneumonia or pleural effusion versus healthy controls. METHODS: We recorded breath sounds from 20 patients conventionally diagnosed as having pleural effusion, 20 patients conventionally diagnosed as having pneumonia, and 60 healthy controls, of whom 20 served as a learning sample. All subjects were examined with a computer-based multi-sensor breath sound mapping device that records, analyzes, and displays a dynamic map of breath sound distribution. The physicians who interpreted the breath sound images were first trained in identifying common characteristics of the images from the learning sample of normals. Then the images from the 40 patients and the 40 controls were interpreted as either normal or abnormal. RESULTS: In the normal images, the left and right lung images developed synchronously and had similar size, shape, and intensity. The sensitivity and specificity of blinded differentiation between normal and abnormal images when the physician interpreter did not know the patient's workup were 82.5% and 80%, respectively. The sensitivity and specificity of blinded detection of normal and abnormal images when the interpreter did know the patient' workup were 90% and 88%, respectively. CONCLUSIONS: Computerized dynamic imaging of breath sounds is a sensitive and specific tool for distinguishing pneumonia or pleural effusion from normal lungs. The role of computerized breath sound analysis for diagnosis and monitoring of lung diseases needs further evaluation.