Effects of Arterial Stiffness on Cerebral WM Integrity in Older Adults: A Neurite Orientation Dispersion and Density Imaging and Magnetization Transfer Saturation Imaging Study.

BACKGROUND AND PURPOSE: Arterial stiffness is reported to be able to cause axonal demyelination or degeneration. The present study aimed to use advanced MR imaging techniques to examine the effect of arterial stiffness on the WM microstructure among older adults. MATERIALS AND METHODS: Arterial stiffness was measured using the cardio-ankle vascular elasticity index (CAVI). The high-CAVI (mean CAVI ≥ 9 points) and the low-CAVI groups (mean CAVI < 9 points) were created. The neuronal fiber integrity of the WM was evaluated by neurite orientation dispersion and density imaging and magnetization transfer saturation imaging. Tract-Based Spatial Statistics and the tracts-of-interest analysis were performed. Specific WM regions (corpus callosum, internal capsule, anterior thalamic radiation, corona radiata, superior longitudinal fasciculus, forceps minor, and inferior fronto-occipital fasciculus) were selected in the tracts-of-interest analysis. RESULTS: In Tract-Based Spatial Statistics, the high-CAVI group showed a significantly lower myelin volume fraction value in the broad WM and significantly higher radial diffusivity and isotropic volume fraction values in the corpus callosum, forceps minor, inferior fronto-occipital fasciculus, internal capsule, corona radiata, and anterior thalamic radiation than the low-CAVI group. In tracts-of-interest analysis using multivariate linear regression, significant associations were found between the mean CAVI and radial diffusivity in the anterior thalamic radiation and the corona radiata; isotropic volume fraction in the anterior thalamic radiation and the corona radiata; and myelin volume fraction in the superior longitudinal fasciculus (P < .05). Additionally, partial correlation coefficients were observed for the significant associations of executive function with radial diffusivity and myelin volume fraction (P < .05). CONCLUSIONS: Arterial stiffness could be associated with demyelination rather than axonal degeneration.

Decrescent intensity training concurrently improves maximal anaerobic power, maximal accumulated oxygen deficit, and maximal oxygen uptake.

This study aimed to investigate the effects of a gradually decreasing intensity training from that corresponding to maximal anaerobic power (MAnP) to that of near maximal oxygen uptake ([Formula: see text]) (decrescent intensity training) on MAnP, maximal accumulated oxygen deficit (MAOD), and [Formula: see text] in untrained young men. Seventeen untrained young men were randomly divided into either a training (TR; n = 9) group or a control (CON; n = 8) group. The TR group performed the decrescent intensity training, whereas the CON group did not perform any exercises. The mean training time per session throughout the training period was 275 ± 135 s. There was a Group × Time interaction for both absolute and relative (p < 0.01) values of [Formula: see text], MAOD, and MAnP. The TR group had significantly increased values for all variables after the 8-week training program, and the relative values of all variables were significantly higher in the TR group than in the CON group. Muscle thicknesses in the anterior and posterior aspects of the thigh and maximal isokinetic knee extension and flexion strengths improved only in the TR group (p < 0.05). A single-exercise training with gradually decreasing intensity from that corresponding to the MAnP to that of approximately 100% [Formula: see text] improves MAnP, MAOD, and [Formula: see text] concurrently, despite the short training time per session.

Energy expenditure, recovery oxygen consumption, and substrate oxidation during and after body weight resistance exercise with slow movement compared to treadmill walking.

The benefit of body weight resistance exercise with slow movement (BWRE-slow) for muscle function is well-documented, but not for energy metabolism. We aimed to examine physiological responses [e.g., energy expenditure (EE), respiratory exchange ratio (RER), and blood lactate (La)] during and after BWRE-slow compared to EE-matched treadmill walking (TW). Eight healthy young men (23.4 ± 1.8 years old, 171.2 ± 6.2 cm, 63.0 ± 4.8 kg) performed squat, push-up, lunge, heel-raise, hip-lift, and crunch exercises with BWRE-slow modality. Both the concentric and eccentric phases were set to 3 s. A total of three sets (10 repetitions) with 30 s rest between sets were performed for each exercise (26.5 min). On another day, subjects walked on a treadmill for 26.5 min during which EE during exercise was matched to that of BWRE-slow with the researcher controlling the treadmill speed manually. The time course changes of EE and RER were measured. The EE during exercise for BWRE-slow (92.6 ± 16.0 kcal for 26.5 min) was not significantly different from the EE during exercise for TW (95.5 ± 14.1 kcal, p = 0.36). BWRE-slow elicited greater recovery EE (40.55 ± 3.88 kcal for 30 min) than TW (37.61 ± 3.19 kcal, p = 0.029). RER was significantly higher in BWRE-slow during and 0-5 min after exercise, but became significantly lower during 25-30 min after exercise, suggesting greater lipid oxidation was induced about 30 min after exercise in BWRE-slow compared to TW. We also indicated that BWRE-slow has 3.1 metabolic equivalents in average, which is categorized as moderate-intensity physical activity.

Heat stress-induced phosphorylation of FoxO3a signalling in rat skeletal muscle.

AIM: A recent study demonstrated that FoxO3a was directly induced by the overexpression of Hsp72 in rat soleus muscle. However, whether heat stress treatment induces FoxO3a phosphorylation in rat skeletal muscle remains unclear. This study examined the effects of heat stress on the regulation of the FoxO3a signalling pathway in rat skeletal muscle. METHODS: Thirty-two male Wistar rats (15 weeks old) were randomly assigned into two groups; sedentary control group (Sed, n = 8) and experimental group (n = 24). After an overnight fast, one leg of each rat (HS leg) in the experimental group was immersed in hot water (43 °C) for 30 min, and the soleus and plantaris muscles in both legs were removed immediately (0 min), 30 min, 60 min, or 24 h after the heat stress (n = 6 each group). The contralateral, non-heated leg in the experimental group served as an internal control (CT leg). RESULTS: Heat stress treatment resulted in a significant increase in FoxO3a phosphorylation (Ser253) in the soleus and plantaris muscles of heat-stressed legs after 24 h. Hsp72 expression in heat-stressed legs was significantly higher at 60 min and 24 h in these muscles. Activation of the PTEN/Akt and MEK/ERK pathways was also observed in these muscles immediately after stress, but not at 24 h. There were no differences in FoxO1 and AMPKα phosphorylation in either muscle. CONCLUSION: Heat stress in rat skeletal muscle induces phosphorylation of FoxO3a signalling, and it may be related to Hsp72 upregulation, and the activation of the PTEN/Akt and MEK/ERK pathways.

Evaluation of PSF1 as a prognostic biomarker for prostate cancer.

BACKGROUND: Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer. METHODS: We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry. We divided patients into PSF1-positive or -negative groups and analyzed the relationships between the expression of PSF1, the Gleason score, PSA level, TNM classification and prognosis. RESULTS: Our results showed that the PSF1 expression correlated significantly with PSA values at diagnosis (P=0.0028), with tumor grade (P<0.0001), and with clinical stage (P=0.0005). Moreover, the PSF1 expression correlated significantly with overall survival (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.17-15.8; P=0.003) and progression-free survival in 99 consecutive patients with prostate cancer. Noteworthy, the prognosis of PSF1-positive cases was also worse in patients with a Gleason score of 8-10 (HR 3.7; 95% CI 1.28-13.43; P=0.0143). Limitations include that this study had a retrospective design, that patients in the study were heterogeneous and included those with early and advanced cancer, and that small tumor fragments may not be representative of the entire carcinoma. CONCLUSIONS: PSF1 is expressed in high-grade prostate cancer and may be a useful biomarker to identify patients with a poor prognosis at the time of diagnosis.

Traditional and ankle-specific vertical jumps as strength-power indicators for maximal sprint acceleration.

AIM: This study aimed to determine the demand of strength-power capabilities represented by traditional and ankle-specific vertical jump modalities ­ squat jump (SJ), counter-movement jump (CMJ), rebound-continuous jump (RJ), rebound-continuous ankle jump (AJ) ­ relative to sprint acceleration ability during the entire acceleration phase of maximal sprint. METHODS: Nineteen male sprinters performed a 60-m maximal sprint and various vertical jumps. Correlation coefficients among the vertical jump performances and between those and the 60-m sprint time and sprint acceleration at each step were calculated. RESULTS: There were significant relationships between the 60-m sprint time and SJ height, CMJ height, AJ height, and AJ index. AJ height and index had no correlation with any other jump variables. Acceleration was significantly correlated with SJ height from the 6th to the 10th steps (r=0.48-0.51) and with CMJ height from the 5th to the 11th steps (r=0.46-0.54). Acceleration was also correlated with the AJ index from the 14th to the 19th steps (r=0.48-0.54). Acceleration had no correlation with the RJ index at any step. CONCLUSION: The results suggest that the AJ allows assessment of different reactive strengths compared with traditional jump modalities. To accelerate effectively, the explosive strengths of the SJ and CMJ are important during the early stage of acceleration (from 6.6±0.4 to 17.5±0.8 m), and the reactive strength represented by the AJ is necessary during the later stage of acceleration (from 23.4±1.0 to 33.7±1.4 m). Sprinters and coaches should be aware of the different demands of strength-power capability for effective acceleration.

Association of acceleration with spatiotemporal variables in maximal sprinting.

This study clarified the association between acceleration and the rates of changes in spatiotemporal variables on a step-to-step basis during the entire acceleration phase of maximal sprinting. 21 male sprinters performed a 60-m sprint, during which step-to-step acceleration and rates of changes in step length (RSL) and step frequency (RSF) were calculated. The coefficients of correlation between acceleration and other variables were tested at each step. There were positive correlations between acceleration and the RSF up to the second step. Acceleration was positively correlated with the RSL from the 5(th) to the 19(th) step. At the third and from the 16(th) to the 22(nd) step and from the 20(th) to the 21(st) step, there was no significant correlation, but weak relationships were found between acceleration and the RSF and RSL. The results suggest that the acceleration phase can be divided into 3 sections, and for sprinting to be effective, it is important to accelerate by increasing the step frequency to the third step, increasing the step length from the 5(th) to the 15(th) step, and increasing the step length or frequency (no systematic relative importance of step length or frequency) from the 16(th) step in the entire acceleration phase.

Effects of walking combined with restricted leg blood flow on mTOR and MAPK signalling in young men.

UNLABELLED: Walking combined with blood flow reduction (BFR-walk) elicits muscle hypertrophy. However, the skeletal muscle intracellular signalling behind this response is currently unknown. AIM: To investigate the effects of BFR-walk on mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signalling pathways in young men. METHODS: Six young men performed 20 min of treadmill walking at 55% of their predetermined maximum oxygen uptake. A pressure cuff belt was applied to the most proximal thigh of only one leg (BFR-Leg, external compression was 240 mmHg), whereas the other leg (CON-Leg) was without BFR during walking. Muscle biopsies were taken from the vastus lateralis of the CON-Leg before exercise and in both legs 3 h after exercise. RESULTS: Erk1/2 phosphorylation levels were significantly (P < 0.05) increased after exercise in both legs; however, only the BFR-Leg saw an increased phosphorylation of p38. For mTOR signalling, there were no changes in Akt, mTOR or S6K1 phosphorylation levels before or after walking. However, eEF2 phosphorylation level was significantly (P < 0.05) lower for the BFR-Leg 3 h after walking compared with CON-Leg. CONCLUSION: BFR-walk exercise may activate some intracellular signalling cascades that are associated with muscle hypertrophy in young men.

Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis.

A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.

Evaluation of automated 2D-3D image overlay system utilizing subtraction of bone marrow image for EVAR: feasibility study.

OBJECTIVE: To evaluate the automated 2D-3D image overlay system ("3D Roadmap") for use during endovascular aneurysm repair (EVAR) in the hybrid operating theater. METHODS: Datasets of preoperative CT images were modified to subtract dense bone marrow to improve the visualization of vasculature on the overlaid image, and allow for accurate navigation of the endovascular devices. The 3D-CT overlay image was registered on the 2D fluoroscopy image to mark the iliac crest and lumbar vertebrae on both images as landmarks. RESULTS: Arteriography was performed only twice to confirm the precision of the position of renal artery and the final evaluation. Twenty patients underwent EVAR with Medtronic Endurant, Gore Excluder, or COOK Zenith using "3D Roadmap". The origin of the renal artery and iliac bifurcation were registered with complete accuracy in 10 patients (50%). The lower renal artery deviated toward the cranial side less than 3 mm in six patients. In all cases, EVAR was successful, and completed with the volume of contrast material limited to 43.8 ± 3.1 mL. CONCLUSION: "3D Roadmap" was confirmed to be valuable for visualization of vessel origin in a fused image and for reduction of contrast material during EVAR.

Effect of lidocaine on dynamic changes in cortical reduced nicotinamide adenine dinucleotide fluorescence during transient focal cerebral ischemia in rats.

Rats were subjected to 90min of focal ischemia by occluding the left middle cerebral and both common carotid arteries. The dynamic changes in the formation of brain ischemic areas were analyzed by measuring the direct current (DC) potential and reduced nicotinamide adenine dinucleotide (NADH) fluorescence with ultraviolet irradiation. In the lidocaine group (n=10), 30min before ischemia, an intravenous bolus (1.5mg/kg) of lidocaine was administered, followed by a continuous infusion (2mg/kg/h) for 150min. In the control group (n=10), an equivalent amount of saline was administered. Following the initiation of ischemia, an area of high-intensity NADH fluorescence rapidly developed in the middle cerebral artery territory in both groups and the DC potential in this area showed ischemic depolarization. An increase in NADH fluorescence closely correlated with the DC depolarization. The blood flow in the marginal zone of both groups showed a similar decrease. Five minutes after the onset of ischemia, the area of high-intensity NADH fluorescence was significantly smaller in the lidocaine group (67% of the control; P=0.01). This was likely due to the suppression of ischemic depolarization by blockage of voltage-dependent sodium channels with lidocaine. Although lidocaine administration did not attenuate the number of peri-infarct depolarizations during ischemia, the high-intensity area and infarct volume were significantly smaller in the lidocaine group both at the end of ischemia (78% of the control; P=0.046) and 24h later (P=0.02). A logistic regression analysis demonstrated a relationship between the duration of ischemic depolarization and histologic damage and revealed that lidocaine administration did not attenuate neuronal damage when the duration of depolarization was identical. These findings indicate that the mechanism by which lidocaine decreases infarct volume is primarily through a reduction of the brain area undergoing NADH fluorescence increases which closely correlates with depolarization.

microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin.

Angiogenesis is controlled positively or negatively by extrinsic and intrinsic molecular cues in endothelial cells (ECs); in the tumor microenvironment, the action of positive regulators exceeds that of negative regulators. Thus, overinduction of negative regulators may inhibit tumor angiogenesis. MicroRNAs (miRNAs or miRs) are endogenous short noncoding RNAs regulating gene expression either through translational inhibition or destabilization of target mRNA. Here, we show that miR-125b expression is transiently induced in ECs on stimulation with vascular endothelial growth factor or by ischemia. miR-125b inhibits translation of vascular endothelial (VE)-cadherin mRNA and in vitro tube formation by ECs. Injection of miR-125b into the tumor inhibited VE-cadherin expression by ECs and induced nonfunctional blood vessel formation, resulting in inhibition of tumor growth. It has been suggested that pro-angiogenic signals in ECs also upregulate anti-angiogenic molecules simultaneously via negative feedback. Because miR-125b induction in ECs is transient after pro-angiogenic stimulation, prolonged overexpression of miR-125b could result in blood vessel regression. Thus, miR-125b may be useful in cancer therapy by causing the collapse of the lumen of ECs.

Heat stress activates the Akt/mTOR signalling pathway in rat skeletal muscle.

AIM: It is well known that various stimuli, such as mechanical stress and nutrients, induce muscle hypertrophy thorough the Akt/mTOR signalling pathway, which is a key mediator of protein synthesis and hypertrophy in skeletal muscle. It was recently reported that heat stress also induces an increase in muscle weight and muscle protein content. In addition, heat stress enhances Akt/mTOR signalling after one bout of resistance exercise. However, it remains unclear whether increased temperature itself stimulates the Akt/mTOR signalling pathway. METHODS: Forty-two male Wistar rats (279.5 ± 1.2 g) were divided into a control group (CON) or one of five thermal stress groups at 37, 38, 39, 40 or 41 °C (n = 7 each group). After overnight fasting, both legs were immersed in different temperatures of hot water for 30 min under sodium pentobarbital anaesthesia. The soleus and plantaris muscles were immediately removed from both legs after the thermal stress. RESULTS: The phosphorylation of mTOR or 4E-BP1 and heat shock protein (HSP) expression levels were similar among groups in both the soleus and plantaris muscles. However, Akt and p70S6K phosphorylation significantly increased at 41 °C in the soleus and plantaris muscles. Moreover, we observed a temperature-dependent increase in Akt and p70S6K phosphorylation in both muscles. CONCLUSION: Our data indicate that the altered temperature increased phosphorylation in a temperature-dependent manner in rat skeletal muscle and may itself be a key stimulator of Akt/mTOR signalling.

Interaction between Lactococcus lactis and Lactococcus raffinolactis during growth in milk: development of a new starter culture.

Many milk fermentations use mixed cultures of lactic acid bacteria. To select a new mixed starter culture, 100 acid-producing bacterial strains were isolated from raw cow milk. Of these, 13 strains identified as belonging to the genera Lactococcus, Lactobacillus, Leuconostoc, or Weissella (based on phenotypic and genotypic tests) were assessed for a symbiotic effect between pairs of isolated strains during growth in milk. Among the strains tested, a mixed culture of Lactococcus lactis ssp. lactis strain 54 and Lactococcus raffinolactis strain 37 stimulated greater acid production during fermentation than occurred with pure fermentation. This stimulatory effect was not observed in milk supplemented with yeast extract or glucose or in constituted medium. Addition of a cell-free filtrate from milk fermented by strain 54 increased acid production by strain 37; however, the converse effect was not observed. The increased acid production by this mixed culture was, therefore, due to stimulation of strain 37 by metabolic products of strain 54, suggesting that the interaction between strains 54 and 37 is commensal. Analysis with a taste-sensing system indicated that fermented milk containing the mixed culture was more acidic, had more anionic bitterness, had greater aftertastes of anionic bitterness and astringency, and was less salty and umami than milk containing the individual cultures. This study identifies a new commensal relationship between 2 lactococcal strains that are commonly used for making dairy products.

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy.

Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported to improve the effect of immuno-, chemo- and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.

Satellite cell pool enhancement in rat plantaris muscle by endurance training depends on intensity rather than duration.

AIM: Increases in the number of satellite cells are necessary for the maintenance of normal muscle function. Endurance training enhances the satellite cell pool. However, it remains unclear whether exercise intensity or exercise duration is more important to enhance the satellite cell pool. This study examined the effects of different intensity and duration of endurance training on the satellite cell pool in rat skeletal muscle. METHODS: Forty-one 17-week-old female Sprague-Dawley rats were assigned to control (n = 8), high intensity and high duration (n = 7), high intensity and low duration (n = 8), low intensity and high duration (n = 9) and low intensity and low duration (n = 9) groups. Training groups exercised 5 days per week on a motor driven treadmill for 10 weeks. After the training period, animals were anaesthetized and the plantaris muscles were removed, weighed and analysed for immunohistochemical and histochemical properties. RESULTS: Although no significant differences were found in muscle mass, mean fibre area and myonuclei per muscle fibre between all groups, the percentage of satellite cells was significantly higher in the high-intensity groups than in the other groups (P < 0.05). CONCLUSION: Increases in the satellite cell pool of skeletal muscle following endurance training depend on the intensity rather than duration of exercise.

Effects of ageing and endurance exercise training on alpha-actinin isoforms in rat plantaris muscle.

AIM: We recently reported that α-actinin adaptation occurs at the isoform level. This study was undertaken to clarify the effects of: (1) ageing-induced shift of myosin heavy chain (MyHC) composition and (2) endurance exercise training on α-actinin isoforms in rat plantaris muscle. METHODS: Adult (18 mo) and old (28 mo) male Fischer 344 rats were assigned to either sedentary control or endurance exercise training groups. Animals in the training groups ran on a treadmill for 8 week with training intensity adjusted to be equal for adult and old groups. After the training was completed, the plantaris muscles were taken for analyses of α-actinin-2, α-actinin-3, and MyHC composition and metabolic enzyme activities. RESULTS: The proportion of type IIb MyHC was lower, and that of type I MyHC was higher in old animals than in adult animals. α-actinin-3 was significantly lower in old animals than in adult animals. No significant difference was found in α-actinin-2 and citrate synthase (CS) activity between adult and old animals. Citrate synthase activity was higher in trained animals than in sedentary animals. Endurance training produced a fast-to-slow shift within type II MyHC isoforms in both adult and old animals. α-actinin-2 was significantly higher in trained animals than in sedentary animals. No significant difference was found in α-actinin-3 between trained and sedentary animals. CONCLUSION: These results support the α-actinin adaptation at the isoform level and show that the α-actinin-3 expression depends on the amount of type II MyHC, whereas α-actinin-2 expression is associated with improvement of muscular aerobic capacity.

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms.

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1 n, and had 30-50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene; IC(50)=11-120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.

High susceptibility to severe infectious complications at reinduction chemotherapy in patients who relapse after stem cell transplantation.

Patients who relapse after stem cell transplantation (SCT) usually appear to be liable to severe infectious complications at reinduction chemotherapy compared to patients at the first induction therapy, though this is not statistically substantiated. The aim of this study was to analyze episodes of infectious complications during reinduction chemotherapy among patients who relapsed after SCT compared with those at the first induction chemotherapy. Between February 1988 and March 2004, 145 children received SCT, and 17 (12 with hematologic malignancies and 5 with solid tumors) were enrolled as eligible subjects for this study. Positive blood cultures (sepsis) were present in six patients exclusively at the reinduction therapy but none at the first induction (P = .009). Three of the six patients progressed to septic shock. Moreover, all patients positive for blood cultures were those with hematologic malignancy (P = .007), and every patient with septic shock had received allogenic transplantation. Our results showed that reinduction chemotherapy needs attention for severe infectious complications, particularly among patients with hematologic malignancies receiving allogenic transplantations. Possible immaturity of the reconstructed systemic immune system and/or insufficient recovery of mucosal protective functions in the patients after SCT are discussed in view of their high susceptibility to severe infectious complications.