Urinary biomarkers of kidney tubule injury, risk of acute kidney injury, and mortality in patients with acute ischaemic stroke treated at a stroke care unit.

BACKGROUND AND PURPOSE: Urinary liver-type fatty-acid binding protein (L-FABP), which is a biomarker of kidney tubule injury, has been studied extensively and established as a risk marker of acute kidney injury (AKI). The aim of this study was to investigate whether kidney tubule injury is associated with the development of AKI and mortality in patients with acute ischaemic stroke. METHODS: Acute ischaemic stroke patients hospitalized in the stroke care unit (SCU) within 24 h after symptom onset were prospectively investigated. AKI was defined on the basis of Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Baseline urinary L-FABP was measured on admission. We evaluated the associations among urinary L-FABP, incidence of AKI, and 90-day mortality adjusted for renal function, albuminuria and other potentially predictive variables, using multivariable analysis. RESULTS: In total, 527 acute ischaemic stroke patients (342 men, median age 74 years) were enrolled in the study. Twenty-seven patients (5.1%) experienced AKI within 7 days of admission. In the univariate analysis, high urinary L-FABP level had positive associations with AKI [53.8 µg/g creatinine (Cr) vs. 3.9 µg/g Cr; P < 0.001] and 90-day mortality (15.5 µg/g Cr vs. 4.0 µg/g Cr; P < 0.001). In the multivariate analysis, elevated urinary L-FABP level (per 10-µg/g Cr increase) was independently associated with AKI (odds ratio 1.225, 95% confidence interval (CI) 1.083-1.454; P = 0.003) and 90-day mortality (hazard ratio 1.091, 95% CI 1.045-1.138; P < 0.001). CONCLUSION: Urinary biomarkers of kidney tubule injury are independently associated with the development of AKI and 90-day mortality in patients with acute ischaemic stroke treated at the SCU.

The relationship between stroke severity and prior direct oral anticoagulant therapy in patients with acute ischaemic stroke and non-valvular atrial fibrillation.

BACKGROUND AND PURPOSE: Anticoagulant treatment with a vitamin K antagonist (VKA) has been reported to reduce stroke severity when patients with atrial fibrillation (AF) suffer acute ischaemic stroke (AIS). Direct oral anticoagulant (DOAC) therapy also has the potential to reduce the initial severity of AIS. However, the effect of DOAC therapy on the severity of AIS is not well known. The aim of the present study was to investigate the effect of DOACs on initial stroke severity in patients with AIS and non-valvular AF. METHODS: From March 2011 to July 2016, consecutive patients with AIS having non-valvular AF were recruited. The effects of prior DOAC treatment on severity were assessed by multivariate logistic regression analyses. RESULTS: A total of 484 patients [208 women; median age 79 (interquartile range, 71-85) years; National Institutes of Health Stroke Scale (NIHSS) score 9 (interquartile range, 3-20)] were enrolled. Of these, 352 (73%) were on no anticoagulant medication, 54 (11%) were undertreated with a VKA, 35 (7%) were sufficiently treated (admission prothrombin time-international normalized ratio: ≥2.0 for patients <70 years old and ≥1.6 for ≥70 years old) with a VKA and 43 (9%) were on a DOAC. The initial NIHSS score (median 10 in patients with no anticoagulation, 13 in undertreated VKA, 7 in sufficient VKA and 6 in DOAC, P = 0.018) was different among the groups. Multivariate analysis showed that DOAC was independently and negatively associated with severe (initial NIHSS score ≥ 10) stroke (odds ratio, 0.39; P = 0.041), compared with no anticoagulant therapy. CONCLUSIONS: Direct oral anticoagulant treatment prior to the event should reduce initial stroke severity in patients with AIS and non-valvular AF.

Regulation of the lysophosphatidylserine and sphingosine 1-phosphate levels in autologous whole blood by the pre-storage leukocyte reduction.

BACKGROUND AND OBJECTIVES: The effect of leukoreduction and storage periods on the accumulation of bioactive lysophospholipids and substances in human autologous blood (AB units) has not been fully investigated. MATERIALS AND METHODS: The accumulation of bioactive lysophospholipids such as sphingosine 1-phosphate (S1P) and lysophosphatidylserine (LysoPS) in AB units during the storage was investigated. The time-dependent changes and the effect of the filtration in pre-storage leuckoreduction (LR) and unmodified samples derived from 46 AB units were analysed. Additionally, the changes of lysophospholipids and platelet releasate, namely ß-thromboglobulin (ß-TG), induced by exposure of whole blood (WB) or platelet-rich plasma (PRP) to the filter material were analysed. RESULTS: LysoPS, but not S1P levels, time-dependently and significantly increased in both unmodified and LR samples. LysoPS significantly decreased in LR compared with unmodified samples, whereas S1P increased in LR compared with unmodified samples. In addition, exposure of WB and/or PRP to the filter material in vitro resulted in increased levels of S1P, LysoPS and ß-TG. CONCLUSIONS: LR effectively reduced the accumulation of LysoPS in AB units. On the other hand, it increased concentrations of S1P due to platelet activation by exposure to the filter material. These suggest that increases of S1P levels in LR and LysoPS in the unmodified samples were mainly caused by the leukocytes and/or platelets and that LR was effective in inhibiting the accumulation of LysoPS.

Dysarthria plus dysphagia is associated with severe sleep-disordered breathing in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Sleep-disordered breathing (SDB) is a risk factor for stroke. The frequency of SDB in Japanese patients with acute intracerebral hemorrhage (ICH) was investigated, as well as factors associated with SDB severity. METHODS: Between April 2010 and April 2013, patients with ICH within 24 h of onset were prospectively enrolled to participate in a sleep study within 7 days of admission. SDB was defined as a respiratory disturbance index (RDI: apnea or hypopnea events per hour) of ≥ 5. Patients were assigned to groups based on RDI values of ≥ 30 (severe SDB) and <30 (absent or not severe SDB). The frequency of SDB and factors associated with its severity were investigated using multivariate logistic regression analysis. RESULTS: Of 97 patients (55 males; mean age 68.1 years) enrolled in the study, 91 (94%) had SDB. Severe SDB was evident in 29 (30%) patients. Compared with the RDI< 30 group, the RDI ≥ 30 group had a higher frequency of dysarthria plus dysphagia (76% vs. 47%, P = 0.008), larger waist circumference [86 (84-92) vs. 84 (78-88) cm, P = 0.019] and a greater body mass index [23.8 (21.1-26.8) vs. 21.5 (19.4-25.0) kg/m(2), P = 0.046]. Multivariate logistic regression analysis showed that dysarthria plus dysphagia was independently associated with severe SDB (odds ratio 3.4; 95% confidence interval 1.250-9.252, P = 0.017). CONCLUSION: Most Japanese patients with acute ICH had SDB, and dysarthria plus dysphagia was associated with severe SDB.

Atrial fibrillation is associated with severe sleep-disordered breathing in patients with ischaemic stroke and transient ischaemic attack.

BACKGROUND AND PURPOSE: Sleep-disordered breathing (SDB) is a risk factor for cerebrovascular disease. We investigated the frequency of SDB in Japanese patients with acute ischaemic stroke and transient ischaemic attack (TIA), as well as factors associated with SDB severity. METHODS: Between April 2010 and March 2011, we prospectively enrolled patients with ischaemic stroke and TIA within 24 h of onset to participate in a sleep study within 7 days of admission. We defined SDB as a respiratory disturbance index (RDI) (number of apnoeas or hypopnoeas per hour) of ≥ 5. Patients were assigned to groups based on RDI values of ≥ 30 (severe) and <30 (absent or not severe). The frequency of SDB and factors associated with severity were investigated using multivariate regression analysis. RESULTS: We enrolled 150 patients amongst whom 126 (84%) had SDB. The frequencies of SDB were 21 (75%) patients with TIA, 105 (86%) with ischaemic stroke, 8/10 (80%) with large artery atherosclerosis, 14/14 (100%) with small vessel occlusion, 37/41 (90%) with cardioembolism and 46/57 (81%) with other causes of stroke/undetermined. Severe SDB was evident in 44 (29%) patients. The frequency of males (75% vs. 56%, P = 0.027), atrial fibrillation (AF) (39% vs. 23%, P = 0.045), higher body mass index (23.8 ± 3.8 vs. 22.3 ± 3.8, P = 0.043) and a larger neck circumference (37.8 ± 4.3 vs. 35.8 ± 4.2, P = 0.012) was significantly higher in the group with severe SDB. Multivariate regression analysis found that AF (OR 2.4; 95% CI 1.079-5.836, P = 0.0359) was independently associated with severe SDB. CONCLUSION: Most Japanese patients with acute ischaemic stroke and TIA had SDB, and AF was associated with SDB.

Plasma brain natriuretic peptide predicts death during hospitalization in acute ischaemic stroke and transient ischaemic attack patients with atrial fibrillation.

BACKGROUND AND PURPOSE: atrial fibrillation (AF) is the most powerful predictor of early death in patients with acute ischaemic stroke. We investigated whether the plasma brain natriuretic peptide (BNP) level on admission can serve as a biological marker of in-hospital death in acute ischaemic stroke and transient ischaemic attack (TIA) patients with AF. METHODS: we prospectively enrolled ischaemic stroke and TIA patients with AF within 24 h of onset and measured plasma BNP on admission. Patients were divided into two groups: the deceased group, who died during hospitalization, and the survival group. The factors associated with in-hospital death were investigated by multivariate logistic regression analysis. RESULTS: a total of 221 patients with AF were enrolled. Death occurred in 24 (10.9%) patients. The mean ± SD of the plasma BNP level of the deceased group was significantly higher than that of the survival group (714.1 ± 716.3 vs. 320.0 ± 380.7 pg/ml, P < 0.0001). The optimal cutoff level, sensitivity, and specificity of BNP levels to distinguish the deceased group from the survival group were 320 pg/ml, 79.2, and 69.0%, respectively. Multivariate logistic regression analysis demonstrated that age per 10 years increase (OR, 3.56; 95% CI, 1.728-7.346, P = 0.0006), internal carotid artery occlusion (OR, 10.20; 95% CI, 2.525-41.177, P = 0.0011), NIHSS score of >17 (OR, 4.68; 95% CI, 1.137-19.286, P = 0.0325), and plasma BNP level of > 320 pg/ml (OR, 4.74; 95% CI, 1.260-17.800, P = 0.0213) were independent factors associated with in-hospital death. CONCLUSION: the plasma BNP level on admission can predict in-hospital death in acute ischaemic stroke and TIA patients with AF.

Development of novel projection-type imaging mass spectrometer.

We developed a novel imaging mass spectrometer based on our accumulating technology for projection-type imaging mass spectrometry, the simulation of an accurate ion trajectory, and the theory for ion optics. The newly developed apparatus yields high spatial resolution with a substantially shorter image-acquisition time compared with conventional scanning-type imaging mass spectrometers. In order to maintain a high mass resolution, a multi-turn time-of-flight mass spectrometer is combined with post-extraction differential acceleration methods. Consequently, a mass resolution of m/Δm ∼ 10 000 and a spatial resolution of 1 µm were achieved simultaneously in this study. Application of our newly established apparatus to biological samples accomplished successful imaging mass spectrometry by exhibiting an organ-specific distribution of endogenous ions as well as a localized distribution of exogenously applied ions with an ultra-high spatial resolution image in the size of 18.5 megapixels.

Comparison of interdevice measurement difference of pedometers in younger and older adults.

OBJECTIVES: In this study, the relationship between inter-instrument differences in regard to the daily number of steps with the intensity distribution of daily physical activity in younger and older adults was examined. METHODS: 17 younger individuals and 28 older individuals wore two pedometers (Lifecorder (LC) and EC-200 (YM)) simultaneously for 7 days, in order to determine the number of steps each took. Furthermore, LC determined the time spent in light, moderate and vigorous physical activity, corresponding to <3 metabolic equivalent (METs), 3 to 6 METs and >6 METs, respectively. RESULTS: The LC detected a significantly larger number of steps than YM (p<0.001), yet there was a strong relationship between the two measurements (r = 0.962, p<0.001). The interdevice difference with the number of steps significantly decreased in inactive older individuals compared with the active older and younger individuals, and it was also significantly negatively correlated with the time spent in light-intensity physical activity (LPA) (r = 0.523, p<0.01). CONCLUSION: This study showed that the interdevice difference with the number of steps significantly increased in older participants due to the greater length of time spent in LPAs.

Neural cell adhesion molecule mediates contact-dependent inhibition of growth of near-diploid mouse fibroblast cell line m5S/1M.

A near-diploid mouse fibroblast cell line m5S/1M used in this study shows a high sensitivity to contact-dependent inhibition of growth, and the addition of EGF causes both morphological change and loss of contact-dependent inhibition of growth. The m5S/1M cell and its transformants obtained by x-ray irradiation have been used to search for the cell surface glycoproteins that are responsible for the growth regulation via cell-cell interactions. Lectin blotting analyses showed that the expression of the cell surface glycoprotein of 140 kD (140KGP) is highly sensitive to the transformation induced either by x-ray irradiation or by the EGF stimulation. We purified the 140KGP and found that it was composed of two glycoproteins. The major component of 140KGP was identified as neural cell adhesion molecule (NCAM) by amino acid sequence analyses of the peptide fragments and by the cross-reactivity with anti-NCAM mAb, clone H28.1.2.3. Monoclonal antibody against 140KGP (clone LN-10) recognizes all three isoforms of NCAM expressed on m5S/1M cell and showed that the expression of NCAM was highly sensitive to the transformation. Furthermore, the immobilized LN-10 strongly inhibited the growth of actively proliferating m5S/1M cells and the LN-10 in a soluble form showed a significant growth-stimulating effect on the confluent quiescent cultures of m5S/1M cells. The results show that NCAM plays a major role in the contact-dependent inhibition of growth of m5S/1M, and that NCAM might be involved in the regulation of cell growth during embryogenesis and formation of nervous systems.

Nectin/PRR: an immunoglobulin-like cell adhesion molecule recruited to cadherin-based adherens junctions through interaction with Afadin, a PDZ domain-containing protein.

We have isolated a novel actin filament-binding protein, named afadin, localized at cadherin-based cell-cell adherens junctions (AJs) in various tissues and cell lines. Afadin has one PDZ domain, three proline-rich regions, and one actin filament-binding domain. We found here that afadin directly interacted with a family of the immunoglobulin superfamily, which was isolated originally as the poliovirus receptor-related protein (PRR) family consisting of PRR1 and -2, and has been identified recently to be the alphaherpes virus receptor. PRR has a COOH-terminal consensus motif to which the PDZ domain of afadin binds. PRR and afadin were colocalized at cadherin-based cell-cell AJs in various tissues and cell lines. In E-cadherin-expressing EL cells, PRR was recruited to cadherin-based cell-cell AJs through interaction with afadin. PRR showed Ca2+-independent cell-cell adhesion activity. These results indicate that PRR is a cell-cell adhesion molecule of the immunoglobulin superfamily which is recruited to cadherin-based cell-cell AJs through interaction with afadin. We rename PRR as nectin (taken from the Latin word "necto" meaning "to connect").

Lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid.

Lysophosphatidic acid receptor (LPA(1)) signaling initiates neuropathic pain and several pathological events in a partial sciatic nerve injury model. Recently, we reported that lysophosphatidic acid (LPA) induces neuropathic pain as well as demyelination and pain-related protein expression changes via LPA(1) receptor signaling. Lysophosphatidylcholine (LPC), also known as lysolecithin, which is hydrolyzed by autotaxin/ATX into LPA, induces similar plastic changes. Here, we attempted to clarify whether ATX and LPA(1) receptor signaling is involved in the LPC-induced neuropathic pain. In wild-type mice, a single intrathecal (i.t.) injection of LPC induced mechanical allodynia and thermal hyperalgesia 2 days after injection; this persisted for 7 days at least. On the other hand, LPC-induced mechanical allodynia and thermal hyperalgesia were completely abolished in mice lacking an LPA(1) receptor gene. Furthermore, the LPC-induced response was also significantly, but partially reduced in heterozygous mutant mice for the ATX gene. These findings suggest that intrathecally-injected LPC is converted to LPA by ATX, and this LPA activates the LPA(1) receptor to initiate neuropathic pain.

Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving beta-oxidation of long-chain fatty acids. CPT II deficiency is a wide-spectrum disorder that includes a lethal neonatal form, an infantile form, and an adult-onset form. However, the ethnic characteristics and the relationship between genotype and clinical manifestation are not well understood. We investigated three non-consanguineous Japanese patients with CPT II deficiency and examined cell lines from 4 unrelated patients and 50 healthy donors. The CPT 2 gene was typed by direct DNA sequencing of polymerase chain reaction-amplified gene products. Case 1 (infantile form) was heterozygous for a phenylalanine to tyrosine substitution at position 383 (p.F383Y) and a novel valine to leucine substitution at 605 (p.V605L). Cases 2, 4, and 5 (infantile form) and case 3 (adult-onset form) were heterozygous for a single mutation at F383Y. Case 6 (adult-onset form) was compound heterozygous at the CPT 2 locus, with deletion of cytosine and thymine at residue 408, resulting in a stop signal at 420 (p.Y408fsX420), and an arginine to cysteine substitution at position 631 (p.R631C). Case 7 (adult-onset form) was homozygous for the p.F383Y mutation. In conclusion, we identified p.F383Y mutations in six of seven patients with CPT II deficiency and two novel variants of the coding gene: p.Y408fsX420 and p.V605L. These mutations differ from those in Caucasian patients, who commonly harbor p.S113L, p.P50H, and p.Q413fsX449 mutations; therefore, our data and those of other Japanese groups suggest that the p.F383Y mutation is significant in Japanese patients with CPT II deficiency.

Future stent drug delivery systems.

Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface have reduced in-stent restenosis and repeat revascularization compared with bare metal stent (BMS) across nearly all lesion and patient subsets. However, the small number of patients with in-stent restenosis after DES treatment still exists. Furthermore, concerns about long-term safety of DES are raised, particularly regarding the higher-than-expected late-event thrombosis. There is no doubt that the DES will continue to play a pivotal role in the treatment of coronary artery disease, yet future designs need to incorporate features that reduce thrombosis and promote endothelialization along with maintaining the efficacy. This review focuses on novel generation of DES, discussing new programs, including new antiproliferative agents, novel polymeric and non polymeric stents.

Small GTPase RhoG is a key regulator for neurite outgrowth in PC12 cells.

The Rho family of small GTPases has been implicated in cytoskeletal reorganization and subsequent morphological changes in various cell types. Among them, Rac and Cdc42 have been shown to be involved in neurite outgrowth in neuronal cells. In this study, we examined the role of RhoG, another member of Rho family GTPases, in nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Expression of wild-type RhoG in PC12 cells induced neurite outgrowth in the absence of NGF, and the morphology of wild-type RhoG-expressing cells was similar to that of NGF-differentiated cells. Constitutively active RhoG-transfected cells extended short neurites but developed large lamellipodial or filopodial structures at the tips of neurites. RhoG-induced neurite outgrowth was inhibited by coexpression with dominant-negative Rac1 or Cdc42. In addition, expression of constitutively active RhoG elevated endogenous Rac1 and Cdc42 activities. We also found that the NGF-induced neurite outgrowth was enhanced by expression of wild-type RhoG whereas expression of dominant-negative RhoG suppressed the neurite outgrowth. Furthermore, constitutively active Ras-induced neurite outgrowth was also suppressed by dominant-negative RhoG. Taken together, these results suggest that RhoG is a key regulator in NGF-induced neurite outgrowth, acting downstream of Ras and upstream of Rac1 and Cdc42 in PC12 cells.

Turbulent cascade in vortex dynamics of magnetized pure electron plasmas.

Elementary processes in free-decaying two-dimensional (2D) turbulence are examined by extensive analyses of fine structures in the density distribution of a magnetized pure electron plasma that is linearly unstable with the initial ring-shaped profile, deforms nonlinearly into patches of vortices, and relaxes into a single-peaked stable distribution via successive mergers among the patches. The stochastic dynamics of the decreasing number of vortices in the real space correspond to the time evolution of energy spectra E(k) in the wave number (k) space that the energy transfers down to lower k while the upward-spreading tails of the spectra fit to the power-law (proportional k(-alpha)) with alpha > 3. The transfer rates, epsilon(k) and eta(k) in energy and enstrophy spaces, evaluated from the time-resolved k -spectra demonstrate characteristic features of the 2D turbulence, i.e., epsilon(k) is negative and deepest below the k(inj) corresponding to the size of the first-generated patches, and eta(k) increases from zero to a constant value at k > k(inj). By averaging the time-dependent spectra of E(k), epsilon(k), and eta(k), constructions are carried out for the spectra in a stationary turbulence that is sustained by the continuous generation of vortices due to the instability and dissipation at high k. The spectra are qualitatively consistent with the 2D turbulence theory with discrepancies including that alpha approximately 4.4 and that the enstrophy transfer rate is almost zero around k = k(inj) reflecting the contribution from the coherent vortices.

Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids.

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for these SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors to the induction of VSMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced VSMC dedifferentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, this report demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.

Structure of a microbial homologue of mammalian platelet-activating factor acetylhydrolases: Streptomyces exfoliatus lipase at 1.9 A resolution.

BACKGROUND: Neutral lipases are ubiquitous and diverse enzymes. The molecular architecture of the structurally characterized lipases is similar, often despite a lack of detectable homology at the sequence level. Some of the microbial lipases are evolutionarily related to physiologically important mammalian enzymes. For example, limited sequence similarities were recently noted for the Streptomyces exfoliatus lipase (SeL) and two mammalian platelet-activating factor acetylhydrolases (PAF-AHs). The determination of the crystal structure of SeL allowed us to explore the structure-function relationships in this novel family of homologous hydrolases. RESULTS: The crystal structure of SeL was determined by multiple isomorphous replacement and refined using data to 1.9 A resolution. The molecule exhibits the canonical tertiary fold of an alpha/beta hydrolase. The putative nucleophilic residue, Ser131, is located within a nucleophilic elbow and is hydrogen bonded to His209, which in turn interacts with Asp177. These three residues create a triad that closely resembles the catalytic triads found in the active sites of other neutral lipases. The mainchain amides of Met132 and Phe63 are perfectly positioned to create an oxyanion hole. Unexpectedly, there are no secondary structure elements that could render the active site inaccessible to solvent, like the lids that are commonly found in neutral lipases. CONCLUSIONS: The crystal structure of SeL reinforces the notion that it is a homologue of the mammalian PAF-AHs. We have used the catalytic triad in SeL to model the active site of the PAF-AHs. Our model is consistent with the site-directed mutagenesis studies of plasma PAF-AH, which implicate Ser273, His351 and Asp296 in the active site. Our study therefore provides direct support for the hypothesis that the plasma and isoform II PAF-AHs are triad-containing alpha/beta hydrolases.

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR.

Although allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for adults with acute myeloid leukemia (AML) in their first CR, transplant-related morbidity and mortality remains a major drawback. We retrospectively compared the outcomes of patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT; n=375) with those who underwent allogeneic bone marrow transplantation (allo-BMT; n=521) and allo-PBSCT (n=380) from MSDs for adults with AML/CR1, in which propensity score models were used to adjust selection biases among patients, primary physicians and institutions to overcome ambiguity in the patients' background information. Both the multivariate analysis and propensity score models indicated that the leukemia-free survival rate of auto-PBSCT was not significantly different from that of allo-BMT (hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.92 to 1.66; P=0.16) and allo-PBSCT (HR, 1.13; 95% CI, 0.85-1.51; P=0.40). The current results suggest that auto-PBSCT remains a promising alternative treatment for patients with AML/CR1 in the absence of an available MSD.

Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells.

G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.