Citations

The discovery of the ubiquitin system was awarded with the Nobel Prize in Chemistry in 2004. Labeling of intracellular proteins for degradation by a multienzymatic complex, called the proteasome, was identified as the main function of this system. Subsequently, it was discovered that the attachment of ubiquitin to proteins can modify their function without degradation. Finally, a number of other molecules were recognized to be conjugated to proteins in a manner similar to ubiquitin and were henceforth called ubiquitin-like proteins. This review provides an overview of this class of molecules and its implication for function, subcellular location, and half-life of proteins.

Abstract The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 × 109/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

Adjuvant chemotherapy has led to improvements in relapse-free and overall survival in patients with breast, colon, and non–small-cell lung cancer, yet many older patients are not offered these potentially life-saving treatments. Moreover, older patients have been either excluded or under-represented in most adjuvant trials, limiting the generalizability of these treatments to older populations. Limited data in elders suggest that older patients derive significant benefits from adjuvant therapies provided they have life expectancies exceeding 5 years. Making treatment decisions in elders is challenging. Many have major comorbidities that may substantially limit life expectancy and minimize or negate the benefits of adjuvant chemotherapy. In this review, we discuss the potential benefits of adjuvant treatment in older patients with solid tumors with a focus on general principles involved in the selection of adjuvant therapy for patients with breast, colon, and non–small-cell lung cancer. In addition, we discuss the role of comorbidity and how it factors in treatment decisions. Finally, we discuss future research directions and funding for elders with cancer.

Purpose Elderly patients often have comorbidities and other characteristics that make the selection of treatment daunting. Methods We have reviewed the available evidence in the literature to gauge the results of therapy for elderly lung cancer patients. Results The beneficial results achieved with adjuvant chemotherapy in the general population with early non–small-cell lung cancer (NSCLC) cannot be automatically extrapolated to the elderly, who are at higher risk of toxicity. Retrospective analyses of combined chemoradiotherapy in locally advanced NSCLC patients suggest equivalent therapeutic benefit for younger and older patients, despite heightened toxicity. There have been no elderly-specific phase III trials for locally advanced NSCLC. For advanced NSCLC, on the basis of evidence-based data, single-agent chemotherapy remains the standard of care for nonselected elderly patients. However, retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. In limited-disease small-cell lung cancer (SCLC), sequential chemoradiotherapy is clearly less toxic compared with a standard concurrent approach, but our assessment of treatment is hindered by the absence of prospective elderly-specific trials. Although prophylactic cranial irradiation has emerged as a standard strategy, it should be omitted in patients with cognitive impairment. In extensive SCLC, etoposide in combination with either cisplatin or carboplatin has emerged as standard treatment; hematopoietic support may be necessary. Conclusion With the exception of advanced NSCLC, prospective elderly-specific studies are lacking. Available data suggest that outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally worse.

We set out to identify predictors for the prophylactic effect of placebo injections in subjects with migraine by post hoc analysis of 81 subjects with episodic migraine receiving single-blind placebo injections in a prospective trial of botulinum toxin. Possible predictors of placebo prophylaxis were compared among placebo responders (PRs) and placebo non-responders (PNRs). There were 34 PRs (42%) and 47 PNRs (58%). Male gender [odds ratio (OR) 5.83, 95% confidence interval (CI) 1.12, 30.14, P = 0.022], a history of opioid use (OR 4.44, 95% CI 1.47, 13.41, P = 0.005) and injections in the neck/shoulders (OR 2.44, 95% CI 0.93, 3.19, P = 0.033) were associated with placebo response. Of subjects with two or more of these signs, 88% were PRs compared with 31% of subjects with one or less. Male gender, opioid use and injections in the neck/shoulders are associated with placebo prophylaxis. These findings may have important implications for the design of future clinical trials and for the clinical management of migraineurs.

Background and Purpose— Intravenous tissue plasminogen activator (tPA) is an economically worthwhile but underused treatment option for acute ischemic stroke. We sought to identify the extent of tPA use in Canadian medical centers and the potential savings associated with increased use nationally and by province. Methods— We determined the nationwide annual incidence of ischemic stroke from the Canadian Institute of Health Information. The proportion of all ischemic stroke patients who received tPA was derived from published data. Economic analyses that report the expected annual cost savings of tPA were consulted. The analysis was conducted from the perspective of a universal health care system during 1 year. We estimated cost-savings with incrementally (eg, 2%, 4%, 6%, 8%, 10%, 15%, and 20%) increased use of tPA for acute ischemic stroke nationally and provincially. Results— The current average national tPA utilization is 1.4%. For every increase of 2 percentage points in utilization, $757 204 (Canadian) could possibly be saved annually (95% CI maximum loss of $3 823 992 to a maximum savings of $2 201 252). With a 20% rate, >$7.5 million (Canadian) could be saved nationwide the first year. Conclusions— We estimate that even small increases in the proportion of all Canadian ischemic stroke patients receiving tPA could result in substantial realized savings for Canada’s health care system.

PurposeThe primary goal of this case study was to describe the speech, prosody, and voice characteristics of a mother and daughter with a breakpoint in a balanced 7;13 chromosomal translocation that disrupted the transcription gene,FOXP2(cf. J. B. Tomblin et al., 2005). As with affected members of the widely cited KE family, whose communicative disorders have been associated with a point mutation in theFOXP2gene, both mother and daughter had cognitive, language, and speech challenges. A 2nd goal of the study was to illustrate in detail, the types of speech, prosody, and voice metrics that can contribute to phenotype sharpening in speech-genetics research.MethodA speech, prosody, and voice assessment protocol was administered twice within a 4-month period. Analyses were aided by comparing profiles from the present speakers (theTBfamily) with those from 2 groups of adult speakers: 7 speakers with acquired (with one exception) spastic or spastic-flaccid dysarthria and 14 speakers with acquired apraxia of speech.ResultsThe descriptive and inferential statistical findings for 13 speech, prosody, and voice variable supported the conclusion that both mother and daughter had spastic dysarthria, an apraxia of speech, and residual developmental distortion errors.ConclusionThese findings are consistent with, but also extend, the reported communicative disorders in affected members of the KE family. A companion article (K. J. Ballard, L. D. Shriberg, J. R. Duffy, & J. B. Tomblin, 2006) reports information from the orofacial and speech motor control measures administered to the same family; reports on neuropsychological and neuroimaging findings are in preparation.

Purpose This report describes the speech characteristics of individuals with a neurodegenerative syndrome called pallido-ponto-nigral degeneration (PPND) and examines the speech samples of at-risk, but asymptomatic, relatives for possible preclinical detection. Method Speech samples of 9 members of a PPND kindred were subjected to perceptual characterization. Speech deterioration patterns were reported for 2 participants followed longitudinally at 6-month intervals. Cross-sectional findings were reported for 3 participants at various stages of disease. Longitudinal and cross-sectional findings were used to guide the examination of 4 at-risk, but asymptomatic, participants. Results Results revealed a progressive mixed dysarthria with hypokinetic, spastic, and flaccid features. It was characterized primarily by vocal tremor and high-frequency vocal flutter, speaking rate abnormalities most often in the direction of slowing, and a tendency toward monopitch. Dysarthria progression was marked by exacerbation and increasing severity of early features, progressive decrease in spontaneous speech output, verbal perseverations, and eventual mutism. Results for at-risk participants revealed preclinical speech abnormalities that preceded other motor signs. Speech results were examined in light of available autopsy findings for site of lesion associations. Conclusion The dysarthria of PPND is an early harbinger of disease onset. It has a mixed presentation, with hypokinetic, spastic, and flaccid features.