Clinical features of adult acute leukemia with 11q23 abnormalities in Japan: a co-operative multicenter study

To clarify the clinical features of adult patients with acute leukemia (AL) with 11q23 abnormalities, we performed a retrospective analysis of data from 58 adult Japanese patients: 51 with acute myeloid leukemia (AML), and 7 with acute lymphoblastic leukemia (ALL). The incidences according to fusion partners in AML were: t(9;11), 31.3%; t(11;19), 27.4%; t(6;11), 21.5%. The incidence of patients with t(11;19) was higher than those in the US and Europe, and the incidence of t(4;11) was lower than that in childhood. The results indicated the poor prognosis of AML with 11q23 abnormalities regardless of the fusion partners. AML patients with 11q23 aged <60 years in the first CR who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed a more favorable outcome than those treated without allo-HSCT, although the differences were not statistically significant (P = 0.322 for DFS, P = 0.138 for OS). This result suggests that treatment strategies including allo-HSCT may be considered in the first CR in cases of AML with 11q23 abnormalities. However, further studies involving a large number of cases are required to assess the effect of allo-HSCT on adult AL with 11q23 abnormalities.     

Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells.

BACKGROUND: There have been a number of recent reports on the use of autologous bone marrow implantation (BMI) in the treatment of peripheral arterial disease, with a clinical response rate of approximately 70%. However, the factors that influence efficacy have not yet been clarified. We have analyzed the relationship between the number of implanted bone marrow cells and the clinical efficacy of BMI. METHODS AND RESULTS: Eight patients with arteriosclerosis obliterans were treated with BMI. Bone marrow was aspirated from the ilium (500-1,000 ml), the mononuclear cells were separated and then were implanted. The clinical effectiveness of BMI was evaluated by assessing changes in the ankle-brachial pressure index (ABI) and the transcutaneous oxygen pressure (TcO2) between the pre-treatment baseline, with follow-up testing at 4 weeks. These changes were defined as DeltaABI and DeltaTcO2. The mean number of CD34-positive cells was 1.04+/-0.60 x10(6) /kg body weight. There was a strong correlation between the number of CD34-positive cells and DeltaABI (r=0.754, p=0.028). CONCLUSIONS: It is likely that the number of implanted CD34-positive cells is one of the primary factors that influence the clinical efficacy of BMI.     

Expression of cutaneous lymphocyte antigen is associated with a poor outcome of nasal-type natural killer-cell lymphoma

Nasal and nasal-type natural killer (NK) lymphoma is a distinct clinicopathological entity mostly associated with Epstein-Barr virus. Cases that have widespread lesions are resistant to ordinary anti-cancer therapy and take a highly aggressive course. To date, there are no available data on the relationships between the localization, clinical outcome and expression of adhesion molecules in such cases. We examined the expression of cutaneous lymphocyte antigen (CLA) in 52 cases of NK-cell lymphoma. CLA was highly expressed in cutaneous cases. Also, the CLA+ group (n=29) had a much worse prognosis than the CLA- group (n=23), regardless of the primary site or clinical staging. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors showed that the expression of CLA was an independent prognostic indicator. In conclusion, the present findings established that CLA is an independent and important prognostic factor in patients with NK-cell lymphomas.     

Gastroesophageal reflux symptoms and nasal symptoms affect the severity of bronchitis symptoms in patients with chronic obstructive pulmonary disease

Background

Cough and sputum production (symptoms of bronchitis) are common in chronic obstructive pulmonary disease (COPD). Extrapulmonary comorbidities, such as gastroesophageal reflux disease (GERD) and post-nasal drip, also cause bronchitis symptoms. The impact of extrapulmonary comorbidities on the severity of bronchitis symptoms in COPD is unknown. The aim of this study was to quantify bronchitis symptoms and assess the impact of GERD and nasal symptoms on the severity of bronchitis symptoms in COPD.

Hidden proteome of synaptic vesicles in the mammalian brain

Current proteomic studies clarified canonical synaptic proteins that are common to many types of synapses. However, proteins of diversified functions in a subset of synapses are largely hidden because of their low abundance or structural similarities to abundant proteins. To overcome this limitation, we have developed an “ultra-definition” (UD) subcellular proteomic workflow. Using purified synaptic vesicle (SV) fraction from rat brain, we identified 1,466 proteins, three times more than reported previously. This refined proteome includes all canonical SV proteins, as well as numerous proteins of low abundance, many of which were hitherto undetected. Comparison of UD quantifications between SV and synaptosomal fractions has enabled us to distinguish SV-resident proteins from potential SV-visitor proteins. We found 134 SV residents, of which 86 are present in an average copy number per SV of less than one, including vesicular transporters of nonubiquitous neurotransmitters in the brain. We provide a fully annotated resource of all categorized SV-resident and potential SV-visitor proteins, which can be utilized to drive novel functional studies, as we characterized here Aak1 as a regulator of synaptic transmission. Moreover, proteins in the SV fraction are associated with more than 200 distinct brain diseases. Remarkably, a majority of these proteins was found in the low-abundance proteome range, highlighting its pathological significance. Our deep SV proteome will provide a fundamental resource for a variety of future investigations on the function of synapses in health and disease.

The functions of eukaryotic cells, in all their complexity, depend upon highly specific compartmentalization into subcellular domains, including organelles. These compartments represent functional units characterized by specific supramolecular protein complexes. A major goal of modern biology is to establish an exhaustive, quantitative inventory of the protein components of each intracellular compartment. Such inventories are points of departure, not only for functional understanding and reconstruction of biological systems, but also for a multitude of investigations, such as evolutionary diversification and derivation of general principles of biological regulation and homeostasis.Essential to communication within the nervous system, chemical synapses constitute highly specific compartments that are connected by axons to frequently distant neuronal cell bodies. Common to all chemical synapses are protein machineries that orchestrate exocytosis of synaptic vesicles (SVs) filled with neurotransmitters in response to presynaptic action potentials (APs), resulting in activation of postsynaptic receptors. Moreover, synapses are composed of structurally and functionally distinct subcompartments, such as free and docked SVs, endosomes, active zones (AZs) at the presynaptic side, and receptor-containing membranes with associated scaffold proteins on the postsynaptic side. Thus, it is not surprising that mass spectrometry (MS)-based proteomics, combined with subcellular fractionation, yields protein inventories of high complexity. For instance, >2,000 protein species were identified in synaptosomes (1), ∼400 in the SV fraction (2), ∼1,500 in postsynaptic densities (3), and ∼100 in an AZ-enriched preparation (4).While these studies provide insights into the protein composition of synaptic structures, they are still inherently limited for two reasons. First, synapses are functionally diverse with respect to the chemical nature of their neurotransmitters, as well as their synaptic strength, kinetics, and plasticity properties (5). Therefore, analyzed subcellular fractions represent “averages” of a great diversity of synapses (6) or SVs (2). The second limitation is that proteins known to be present in specific subsets were not found in these studies, despite the unprecedented sensitivity of modern mass spectrometers. In fact, many functionally critical synaptic proteins have remained undetected. For example, the synaptotagmin (Syt) family, major Ca²⁺ sensors of SV exocytosis, comprises >15 members, of which only 5 had been identified in previous SV proteomics (2, 4, 7). Missing isoforms included Syt7, involved in asynchronous transmitter release (8), synaptic plasticity (9), and SV recycling (10). Likewise, the vesicular transporters for monoamines (VMATs) and acetylcholine (VAChT) neurotransmitters were missing in these studies. Clearly, known components of the diversified synaptic proteome have been missing, and it is not possible to predict how many more such proteins remain hidden.What are the reasons for the continuing incompleteness of the synaptic protein inventory? Proteome identification and quantification rely heavily on MS detectability of peptides generated by digestion of extracted proteins with sequence-specific enzymes, such as trypsin. However, in MS analysis of complex biological samples, peptide signals from a few abundant proteins often mask those that are less abundant. Additionally, the probability of obtaining peptides with similar masses, but different amino acid sequences, increases with increasing sample complexity (11, 12). To overcome these limitations, we have elaborated a workflow with dual-enzymatic protein digestion in sequence combined with an extensive peptide separation prior to MS analysis. As proof of concept, we have utilized purified SV fractions from rat whole brain, which serve as a benchmark for quantitative organellar proteomics (2). As a result, we detected ∼1,500 proteins in the SV fraction, three times more than reported previously. This proteome not only covers all known canonical SV proteins but also contains proteins previously overlooked, such as the low-abundance Syts and SV transporters. Moreover, peptide quantification allowed for differentiating “SV-resident” from “SV-visitor” proteins. In fact, most “SV-resident” proteins revealed in our SV proteomics are of low abundance, with an average copy number of less than 1 per SV, suggesting a larger molecular and functional diversity of SVs than previously thought. Remarkably, more than 200 proteins detected in the SV fraction are genetically associated with brain disorders, 76% of which were previously hidden.     

Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes

Grb2-associated binder-1 (Gab1) is a scaffolding/docking protein and contains a Pleckstrin homology domain and potential binding sites for Src homology (SH) 2 and SH3 domains. Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including interleukin-6. We previously demonstrated that interleukin-6-related cytokine, leukemia inhibitory factor (LIF), induced cardiac hypertrophy through gp130. In this study, we report the role of Gab1 in gp130-mediated cardiac hypertrophy. Stimulation with LIF induced tyrosine phosphorylation of Gab1, and phosphorylated Gab1 interacted with SHP2 and p85 in cultured cardiomyocytes. We constructed three kinds of adenovirus vectors, those carrying wild-type Gab1 (AdGab1WT), mutated Gab1 lacking SHP2 binding site (AdGab1F627/659), and beta-galactosidase (Adbeta-gal). Compared with cardiomyocytes infected with Adbeta-gal, longitudinal elongation of cardiomyocytes induced by LIF was enhanced in cardiomyocytes infected with AdGab1WT but inhibited in cardiomyocytes infected with AdGab1F627/659. Upregulation of BNP mRNA expression by LIF was evoked in cardiomyocytes infected with Adbeta-gal and AdGab1WT but not in cardiomyocytes infected with AdGab1F627/659. In contrast, Gab1 repressed skeletal alpha-actin mRNA expression through interaction with SHP2. Furthermore, activation of extracellular signal-regulated kinase 5 (ERK5) was enhanced in cardiomyocytes infected with AdGab1WT compared with cardiomyocytes infected with Adbeta-gal but repressed in cardiomyocytes infected with AdGab1F627/659. Coinfection of AdGab1WT with adenovirus vector carrying dominant-negative ERK5 abrogated longitudinal elongation of cardiomyocytes induced by LIF. Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5.     

Improvement of cardiac function after treatment with octreotide followed by trans-sphenoidal surgery in an acromegalic patient who presented with congestive heart failure

Cardiovascular disease is a major cause of mortality and morbidity in patients with acromegaly. We describe the case of a 43-year-old man with acromegaly who presented with severe congestive heart failure. Treatment with the somatostatin analog octreotide improved cardiac function with an increase in left ventricular ejection fraction (LVEF) from 11% to 27%. LVEF further increased to 43% after trans-sphenoidal surgery. Recovery was uneventful. We emphasize the need for early diagnosis and effective treatment of acromegaly to prevent cardiovascular complications. Octreotide therapy or trans-sphenoidal surgery, if possible, should be considered to control cardiac function even in acromegalic patients with severe congestive heart failure.     

Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid, and recidiva cutis due to Leishmania (V.) panamensis

In recent times, there has been an increase in the number of reports for new and rare variants of cutaneous leishmaniasis (CL). Here, we describe three unusual clinical forms of CL identified in Ecuadorian children. A total of 131 patients with CL were diagnosed over a 2-year period of active search. In 3 (2.29%), the lesions were very unusual; these included erysipeloid, recidiva cutis (LRC), and disseminated leishmaniasis (DL). The erysipeloid case is characterized by erythematous and indurated plaque seen on the face of a 5-year-old boy; the LRC one is differentiated by slowly progressing red-brown papules around large scars of healed sores in a 6-year-old girl, and the DL case is characterized by dozens of cutaneous ulcers distributed in the whole body of a 1-year-old girl. Leishmania parasites were isolated by lesion aspirate and analyzed by the technique multilocus enzyme electrophoresis (MLEE). All three isolates were identified as Leishmania (Viannia) panamensis. These distinct clinical variants rarely have been reported previously in the American cutaneous leishmaniasis, and for the first time L. (V.) panamensis was identified as the etiologic agent. Our cases extend the spectrum of clinical presentations in New World leishmaniasis.     

Early myoelectrical activity changes during gastric or duodenal ulceration in dogs

Antroduodenal myoelectric activity and gastric transmural potential difference were recorded before and during fundic, antral, or duodenal ulceration in dogs. Gastric injury was obtained by electrocoagulation of the fundic or antral mucosa. Duodenal ulceration was induced by cysteamine injection which was accompanied by nausea or vomiting. Both antral electrocoagulation and cysteamine injection were also accompanied by antral dysrhythmia and a transient decrease of the gastric transmural potential difference. Effects of antral electrocoagulation were prevented by selective vagotomy. Since antral dysrhythmia disappeared as soon as the antral or duodenal ulcers became active, ie, within three days and 24 hr respectively, it is suggested that antral dysrhythmia is the result of antroduodenal stimulation and could thus not be assessed as a criterion of active ulceration.     

Cyclin D1 Expression Is Useful as a Prognostic Indicator for Advanced Esophageal Carcinomas, but Not for Superficial Tumors

The purpose of the present study was to define the overexpression of cyclin D1 in superficial and advanced esophageal carcinomas and to investigate whether the expression of this molecule indicates a poor prognosis. This study included 41 patients with superficial esophageal carcinomas (Tis and T1) and 48 patients with advanced esophageal carcinomas (T2, T3, and T4). The expression of cyclin D1 in surgically resected specimens was evaluated immunohistochemically with a monoclonal antibody. Positive immunoreactivity was found in 31 of 89 cases (35%). Overexpression of cyclin D1 did not correlate with TNM classification or histologic type. Of the 48 patients with advanced esophageal carcinomas, 32 patients with cyclin D1-negative tumors survived longer than did 16 patients with cyclin D1-positive tumors (P = 0.0017). In contrast, we observed no survival difference between patients with cyclin D1-positive and -negative superficial esophageal carcinoma. These results suggest that cyclin D1 indicates a poor prognosis in cases of advanced esophageal carcinoma but not in cases of superficial esophageal carcinoma.