Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has curative potential against hematological malignancies. However, there are concerns about the associated risk of non-relapse mortality (NRM). We performed a retrospective single-center study to assess changes in outcomes after allo-HSCT and causes of NRM over three 5-year periods. The rates of 2-year NRM and overall survival (OS) were 16% and 59%, respectively. We found a significant decrease in NRM (P<0.001), with 2-year NRM of 26, 14 and 9%, and a significant increase in OS (P=0.005), with 2-year OS of 52%, 58% and 65%, over the three periods (1998-2002, 2003-2007 and 2008-2012), respectively. Of note, a steady improvement was observed in NRM, period by period, among patients aged 50 years or older, patients who underwent HSCT from an unrelated bone marrow donor and patients who underwent HSCT with a reduced-intensity conditioning regimen. Our data showed that the improved NRM can mainly be attributed to a decreased mortality related to infection after starting systemic steroid as GVHD treatment, and a decreased mortality related to organ failure.

Nitric oxide confers cisplatin resistance in human lung cancer cells through upregulation of aldo-keto reductase 1B10 and proteasome.

In this study, we show that exposure of human lung cancer A549 cells to cisplatin (cis-diamminedichloroplatinum, CDDP) promotes production of nitric oxide (NO) through generation of reactive oxygen species (ROS) and resulting upregulation of inducible NO synthase (iNOS). The incubation of the cells with a NO donor, diethylenetriamine NONOate, not only reduced the CDDP-induced cell death and apoptotic alterations (induction of CCAAT-enhancer-binding protein homologous protein and caspase-3 activation), but also elevated proteolytic activity of 26S proteasome, suggesting that the activation of proteasome function contributes to the reduction of CDDP sensitivity by NO. Monitoring expression levels of six aldo-keto reductases (AKRs) (1A1, 1B1, 1B10, 1C1, 1C2, and 1C3) during the treatment with the NO donor and subsequent CDDP sensitivity test using the specific inhibitors also proposed that upregulation of AKR1B10 by NO is a key process for acquiring the CDDP resistance in A549 cells. Treatment with CDDP and NO increased amounts of nitrotyrosine protein adducts, indicative of peroxynitrite formation, and promoted the induction of AKR1B10, inferring a relationship between peroxynitrite formation and the enzyme upregulation in the cells. The treatment with CDDP or a ROS-related lipid aldehyde, 4-hydroxy-2-nonenal, facilitated the iNOS upregulation, which was restored by increasing the AKR1B10 expression. In contrast, the facilitation of NO production by CDDP treatment was hardly observed in AKR1B10-overexpressing A549 cells and established CDDP-resistant cancer cells (A549, LoVo, and PC3). Collectively, these results suggest the NO functions as a key regulator controlling AKR1B10 expression and 26S proteasome function leading to gain of the CDDP resistance.

Improved electronic coupling in hybrid organic-inorganic nanocomposites employing thiol-functionalized P3HT and bismuth sulfide nanocrystals.

In this study, we employ a thiol-functionalized polymer (P3HT-SH) as a leverage to tailor the nanomorphology and electronic coupling in polymer-nanocrystal composites for hybrid solar cells. The presence of the thiol functional group allows for a highly crystalline semiconducting polymer film at low thiol content and allows for improved nanomorphologies in hybrid organic-inorganic systems when employing non-toxic bismuth sulfide nanocrystals. The exciton dissociation efficiency and carrier dynamics at this hybrid heterojunction are investigated through photoluminescence quenching and transient absorption spectroscopy measurements, revealing a larger degree of polaron formation when P3HT-SH is employed, suggesting an increased electronic interaction between the metal chalcogenide nanocrystals and the thiol-functionalized P3HT. The fabricated photovoltaic devices show 15% higher power conversion efficiencies as a result of the improved nanomorphology and better charge transfer mechanism together with the higher open circuit voltages arising from the deeper energy levels of P3HT-SH.

Time to achieve target mean arterial pressure during resuscitation from experimental anaphylactic shock in an animal model. A comparison of adrenaline alone or in combination with different volume expanders.

Anaphylactic shock is a rare, but potentially lethal complication, combining life-threatening circulatory failure and massive fluid shifts. Treatment guidelines rely on adrenaline and volume expansion by intravenous fluids, but there is no solid evidence for the choice of one specific type of fluid over another. Our purpose was to compare the time to achieve target mean arterial pressure upon resuscitation using adrenaline alone versus adrenaline with different resuscitation fluids in an animal model and to compare the tissue oxygen pressures (PtiO2) with the various strategies. Twenty-five ovalbumin-sensitised Brown Norway rats were allocated to five groups after anaphylactic shock induction: vehicle (CON), adrenaline alone (AD), or adrenaline with isotonic saline (AD+IS), hydroxyethyl starch (AD+HES) or hypertonic saline (AD+HS). Time to reach a target mean arterial pressure value of 75 mmHg, cardiac output, skeletal muscle PtiO2, lactate/pyruvate ratio and cumulative doses of adrenaline were recorded. Non-treated rats died within 15 minutes. The target mean arterial pressure value was reached faster with AD+HES (median: 10 minutes, range: 7.5 to 12.5 minutes) and AD+IS (median: 17.5 minutes, range: 5 to 25 minutes) versus adrenaline alone (median: 25 minutes, range: 20-30 minutes). There were also reduced adrenaline requirements in these groups. The skeletal muscle PtiO2 was restored only in the AD+HES group. Although direct extrapolation to humans should be made with caution, our results support the combined use of adrenaline and volume expansion for resuscitation from anaphylactic shock. When used with adrenaline the most effective fluid was hydroxyethyl starch, whereas hypertonic saline was the least effective.

Time to first cigarette and lung cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. PATIENTS AND METHODS: This case-control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. RESULTS: TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min and 1.86 (1.28-2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). CONCLUSIONS: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking.

Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice.

The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.

Region-specific diversity of striosomes in the mouse striatum revealed by the differential immunoreactivities for mu-opioid receptor, substance P, and enkephalin.

The complexity of the internal structure of the striatum is not completely understood, and the striosomes/matrix compartmentalization in particular has been one of the intriguing substructures of the striatum. Although various neurochemical markers have been used to visualize striosomes with sufficient clarity, it still remains obscure whether striosomes that are detectable by a single marker represent all of the striosomal compartments and to what extent the compartments are uniform across different intrastriatal positions. Triple immunohistochemical labeling for the three representative striosomes/matrix markers, µ-opioid receptor (MOR), substance P (SP), and enkephalin (Enk), was applied to serial sections covering the whole striatum of the mouse (n=8). The majority of MOR-positive striosomes were confined to the rostral quarter of the striatum. In contrast, SP-positive striosomes were distributed more broadly in the rostral two-thirds of the striatum. No striosomes were observable in the caudal third by the present method. In the rostral striatum, the majority of striosomes were labeled for both MOR and SP, but some at the most rostral positions were detectable only by MOR, while caudally located striosomes were identifiable only by SP. Thus MOR- and SP-immunoreactivities in striosomes exhibited contrasting patterns along the rostrocaudal axis. The Enk immunohistochemistry produced complicated profiles and was unsuitable for the detection of striosomes in mice. However, Enk immunoreactivity in MOR and/or SP-positive striosomes was higher in the ventral portion than in the dorsal portion in the rostral striatum. The present study revealed the region-specific diversity of striosomes, suggesting site-dependent differential regulation of striosomal neurons by MOR ligands and SP that are contained in indirect- and direct-pathway neurons, respectively. The results further suggest the necessity of viewing the striosomes as non-uniform compartments in addition to the traditional dichotomous view, which focuses on discrimination between the striosomes and the matrix.

Comparative study of sitagliptin with pioglitazone in Japanese type 2 diabetic patients: the COMPASS randomized controlled trial.

AIMS: To compare the efficacy and safety of these two agents and the impact on surrogate markers related to diabetic complications in Japanese type 2 diabetic patients. METHODS: In a multicenter, open-label trial, 130 patients whose diabetes had been inadequately controlled (HbA1c, 6.9-9.5%) with metformin and/or sulphonylurea were randomly assigned to a sitagliptin group (50 mg/day) or a pioglitazone group (15 mg/day) and were followed up for 24 weeks. At 16 weeks, if the patient's HbA1c level was ≥6.5%, the dose of sitagliptin or pioglitazone was increased up to 100 or 30 mg/day, respectively. Main outcome measure was the difference in the mean changes in the HbA1c level from baseline at 24 weeks between these two groups. RESULTS: Of the 130 patients who were enrolled, 115 subjects (sitagliptin group: 58 patients, pioglitazone group: 57 patients) completed this trial. At 0 weeks, the mean HbA1c level was 7.47 ± 0.66% in the sitagliptin group and 7.40 ± 0.61% in the pioglitazone group. At 24 weeks, the mean changes in the HbA1c level from baseline were -0.86 ± 0.63% versus -0.58 ± 0.68% (p = 0.024). Hypoglycaemia (2 patients, 3.4% vs. 2 patients, 3.5%), gastrointestinal symptoms (3 patients, 5.2% vs. 1 patient, 1.8%) and pretibial oedema (0 patients, 0% vs. 39 patients, 68.4%, p < 0.001) were observed for 24 weeks. CONCLUSIONS: Sitagliptin was not only more tolerable, but also more effective than pioglitazone in Japanese type 2 diabetic patients who had been treated with metformin and/or sulphonylurea.

Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance.

AIMS/HYPOTHESIS: Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 ( -/- ) mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions. METHODS: Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 ( -/- ) mice were also subjected to an HF diet for 60 weeks. RESULTS: Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 ( -/- ) mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia. CONCLUSIONS/INTERPRETATION: IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.

Reproductive and hormonal risk factors for luminal, HER2-overexpressing, and triple-negative breast cancer in Japanese women.

BACKGROUND: Although the clinical relevance of the molecular subtypes of breast cancer is evident, etiological differences among subtypes have not been well established, especially among Asian. Here, we evaluated the hypothesis that the etiologic impact of reproductive and hormonal features differs among molecular subtypes. MATERIALS AND METHODS: We conducted a case-control study in pre- and postmenopausal Japanese. We examined 706 breast cancer patients and 1412 age- and menopausal status-matched noncancer controls. Immunohistochemical stains for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were used to classify the cases into 554 luminal (hormone receptor positive), 84 HER2-overexpressing (hormone receptor negative, HER2 positive), and 68 triple-negative cases (hormone receptor negative, HER2 negative). Associations were evaluated using multivariate polytomous logistic regression models. RESULTS: A significant association was observed between early age at menarche and risk of luminal disease (odds ratios = 1.67, 95% confidence interval: 1.22-2.29; P trend = 0.001). No significant differences in association with parity, age at first live birth, breastfeeding history, age at menopause, or synthetic hormonal use were seen across molecular subtypes of breast cancer. CONCLUSIONS: These findings indicate that reproductive events in adolescence have differential impact on the risk of breast cancer molecular subtypes in Japanese.

Genetic polymorphism of IGF-I predicts recurrence in patients with gastric cancer who have undergone curative gastrectomy.

BACKGROUND: To our knowledge, no reports have evaluated the effects of genetic polymorphisms of insulin-like growth factor-I (IGF-I) on clinical outcomes of gastric cancer patients. METHODS: We retrospectively analyzed the impact of IGF-I polymorphisms on recurrence-free survival (RFS) in 430 patients with gastric cancer who underwent curative gastrectomy between 2001 and 2005 in our institution. RESULTS: Among the 430 gastric cancer patients, 345 were pathological stage I or II, while 85 were stage III or IV. The median 5-year RFS rate was 85.3% (95% confidence interval [CI] 81.4-88.5). In a multivariate Cox model (adjusted for age, gender, histology, pathological stage, adjuvant chemotherapy, and history of diabetes), two IGF-I polymorphisms, rs1520220 and rs2195239, were significantly associated with RFS (hazard ratio [HR] 0.60, 95% CI 0.40-0.91; and HR 0.60, 95% CI 0.41-0.89, respectively, in a per-allele model). When stratified by stage (I-II versus III-IV), rs1520220 in particular was associated with RFS in patients with stage III-IV disease, with a P-value for interaction of 0.01. CONCLUSIONS: Our findings indicate that genetic polymorphisms of IGF-I may have a substantial effect on recurrence for gastric cancer patients who have undergone curative gastrectomy. This information may help identify population subgroups that could benefit from IGF-I-targeting agents.

Inverse association between soy intake and non-Hodgkin lymphoma risk among women: a case-control study in Japan.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is one of the common malignant tumors worldwide. Environmental factors, such as diet have an important association with the risk of cancer. Although soy intake has been associated with a reduced risk of several cancers, its association with NHL is not known. PATIENTS AND METHODS: We evaluated the association between soy consumption and risk of NHL by conducting a hospital-based case-control study in 302 patients with NHL and 1510 age- and sex-matched control subjects. Odds ratio (OR) and 95% confidence intervals (CIs) for groups with moderate (27-51 g/day) to high (>51 g/day) relative to low (<27 g/day) intake were calculated using multivariate conditional logistic regression model. RESULTS: Soy intake was significantly associated with a reduced risk of NHL in women but not in men (OR [95% CI] for moderate and high intake: women, 0.64 [0.42-1.00] and 0.66 [0.42-1.02], respectively; men, 1.40 [0.87-2.24] and 1.33 [0.82-2.15], respectively; P-interaction = 0.02). This finding appeared consistent across NHL subtypes. CONCLUSION: These results indicate the potential importance of certain ingredients in soy for lymphomagenesis. Further studies to evaluate the mechanism behind the association between soy intake and lymphomagenesis are warranted.

Association between dietary folate intake and clinical outcome in head and neck squamous cell carcinoma.

BACKGROUND: The association between dietary folate intake, two polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS), and survival in head and neck squamous cell carcinoma (HNSCC) patients is not clarified. PATIENTS AND METHODS: We conducted a retrospective cohort study of 437 HNSCC patients treated at Aichi Cancer Center. We evaluated the survival impact of pretreatment dietary folate intake, which was estimated using a food-frequency questionnaire, and two polymorphisms, MTHFR C677T and a 6-bp insertion/deletion in the 3'-untranslated region of TYMS, using multivariate proportional hazard models. RESULTS: Patients with high folate intake (≥320 µg/day; n=144) had significantly higher survival than patients with low or medium folate intake (<320 µg/day; n=278; 79.1% versus 68.2%, respectively, P=0.020). This association was consistent with multivariate analyses adjusted for established prognostic factors (hazard ratio 0.56; 95% confidence interval 0.37-0.84). MTHFR and TYMS polymorphisms did not show significant association with survival, although the TYMS 6-bp insertion allele showed potential association with a reduced risk of death. Notably, no significant interaction was observed between folate intake and the two examined polymorphisms. CONCLUSIONS: High pretreatment dietary folate intake was identified as an independent prognostic factor associated with improved clinical outcomes in HNSCC patients. Further study is warranted.

The effect of bisphosphonate and intermittent human parathyroid hormone 1-34 treatments on cortical bone allografts in rabbits.

AIM: This study compares the effect of bisphosphonate and intermittent PTH administration on haversian remodeling in cortical bone allografts in rabbits. MATERIALS AND METHODS: An intercalary heat-treated cortical bone allograft was applied to a segment skeletal defect in the left femur of Japanese white rabbits. The rabbits were randomly assigned to one of three groups: the vehicle control group (CNT); the bisphosphonate group (B group); and the intermittent PTH treatment group (P group). Periodic radiographic evaluation was performed and peripheral quantitative computerized tomography (pQCT) was used to evaluate the total bone area (Area), bone mineral density (BMD), and bone mineral content (BMC). The allografts also underwent histological examination. RESULTS: The P group was radiographically superior in the latter stage, compared with the other groups. pQCT analysis of the allografts showed that the B group had a significantly higher Area and BMC. These parameters in the latter stage were significantly lower in the P group than in the other groups. The allograft of the B group was histologically mostly necrotic bone, whereas allograft of the P group showed abundant newly formed bone. CONCLUSION: In rabbits, bisphosphonate prevents resorption, but suppresses remodeling and incorporation; by contrast, PTH increases resorption and accelerates allograft remodeling and incorporation. Based on our preliminary data, we suggest that further research on the manner of administration of bisphosphonate and PTH - which have contrasting effects - can be beneficial in maintaining bone strength and in regulating remodeling and allograft incorporation.

Depressive-type emotional response pattern in impulsive-aggressive patients with borderline personality disorder.

INTRODUCTION: Borderline personality disorder (BPD) is typically characterized by severe affective dysregulation leading to impulsive behaviors. Accordingly, preliminary data suggest the hypothesis that BPD patients could have a specific and altered pattern of subjective emotional response to stimuli. The nature of the emotional response in BPD can be compared with other affective disorders and provide further insight on the nosological proximity with other psychiatric disorders. METHODS: Subjective emotional response was investigated in 19 patients with DSM-IV BPD with no current depressive episode and in 19 healthy control subjects by using the International Affective Picture System (IAPS). The intensity of arousal, valence and dominance was rated in response to 60 images categorized as pleasant, unpleasant and neutral by using a self-assessment instrument. ANOVA of multiple factors was used for between-groups comparisons. RESULTS: The obtained pattern showed that BPD patients considered the unpleasant and neutral images as less aversive than controls, but the activation that these images induced was higher. Patients showed significantly greater arousal than controls for unpleasant and neutral images (p<0.05) but presented greater valence (more positive emotion) for these images (p<0.05). In addition, BPD patients showed lower dominance (greater insecurity and dyscomfort) for positive images (p<0.05). CONCLUSIONS: The subjective emotional response pattern of BPD patients suggests a trait of vulnerability to pleasant stimuli and is similar to the pattern found in depressive patients in previous studies. This supports the evidence that BPD could in part be related with the spectrum of the affective temperament and affective disorders.

Isolation of a thermotolerant bacterium producing medium-chain-length polyhydroxyalkanoate.

AIMS: The aim of this study was to isolate a thermotolerant micro-organism that produces polyhydroxyalkanoates (PHAs) composed of medium-chain-length (mcl) HA units from a biodiesel fuel (BDF) by-product as a carbon source. METHODS AND RESULTS: We successfully isolated a thermotolerant micro-organism, strain SG4502, capable to accumulate mcl-PHA from a BDF by-product as a carbon source at a cultivation temperature of 45°C. The strain could also produce mcl-PHA from acetate, octanoate and dodecanoate as sole carbon sources at cultivation temperatures up to 55°C. Taxonomic studies and 16S rRNA gene sequence analysis revealed that strain SG4502 was phylogenetically affiliated with species of the genus Pseudomonas. This study is the first report of PHA synthesis by a thermotolerant Pseudomonas. CONCLUSIONS: A novel thermotolerant bacterium capable to accumulate mcl-PHA from a BDF by-product was successfully isolated. SIGNIFICANCE AND IMPACT OF THE STUDY: A major issue regarding industrial production of microbial PHAs is their much higher production cost compared with conventional petrochemical-based plastic materials. Especially significant are the cost of a fermentative substrate and the running cost to maintain a temperature suitable for microbial growth. Thus, strain SG4502, isolated in this study, which assimilates BDF by-product and produces PHA at high temperature, would be very useful for practical application in industry.