Naoya Miura

PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

Reduction of Immunocompetent T Cells Followed by Prolonged Lymphopenia in Severe Sepsis in the Elderly.

Objective:To investigate the immunological changes caused by severe sepsis in elderly patients. Design:One-year, prospective observational study. Setting:Emergency department and intensive care unit of a single university hospital. Patients:Seventy-three patients with severe sepsis and 72 healthy donors. Measurements and Main Results:In elderly septic patients (aged 65 yr and over), 3-month survival was significantly reduced compared with that for adult patients (18–64 yr) (60% vs. 89%, p < 0.01). We found that lymphopenia was prolonged for at least 21 days in elderly nonsurvivors of sepsis, while the number of lymphocytes recovered in both adult and elderly survivors of sepsis. In order to examine the immunological status of septic patients, blood samples were collected within 48 hrs of diagnosis of severe sepsis, and peripheral blood mononuclear cells were purified for flow cytometric analysis. T cell levels were significantly reduced in both adult and elderly septic patients, compared with those in healthy donors (56% and 57% reduction, respectively). Interestingly, the immunocompetent CD28+ subset of CD4+ T cells decreased, whereas the immunosuppressive PD-1+ T cells and the percentage of regulatory T cells (CD4+ T cells that are both Foxp3+ and CD25+) increased in elderly patients, especially nonsurvivors, presumably reflecting the initial signs of immunosuppression. Conclusion:Reduction of immunocompetent T cells followed by prolonged lymphopenia may be associated with poor prognosis in elderly septic patients.

PI3K/p110 is a novel therapeutic target in multiple myeloma

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

Risk factors for QT prolongation associated with acute psychotropic drug overdose

BACKGROUND Antipsychotic/Antidepressant use is a risk factor for QT interval (QT) prolongation and sudden cardiac death. However, it is unclear which drugs are risk factors for QT prolongation and torsades de pointes in cases of psychotropic drug overdose. METHODS After correction of QT data by Bazett formula (QTc), QTc was classified into 3 categories (QTc<440 milliseconds, 440 milliseconds≤QTc<500 milliseconds, and QTc≥500 milliseconds), and the blood concentration of each drug was classified as not detected, therapeutic range, or toxic range. The association of the blood concentration of each drug with QTc was analyzed using the ordinal logistic regression model. Drugs that induced QT-heart rate pairs higher than the at-risk line of Isbisters QT-heart rate nomogram (QT nomogram) were further analyzed using the binomial logistic regression model. RESULTS A total of 649 patients were enrolled in the study. The independent risk factors for QTc prolongation were therapeutic and toxic range of phenotiazine antipsychotic drug (therapeutic range: odds ratio [OR], 1.56 [P=.039]; toxic range: OR, 3.85 [P<.001]), and toxic range of cyclic antidepressants (OR, 2.39; P=.018). In addition, toxic range of phenotiazine antipsychotic drug (OR, 3.87; P=.012) and tricyclic antidepressants (OR, 4.94; P<.001) were risk factors for QT higher than the at-risk line of the QT nomogram. CONCLUSIONS The possibility of QT prolongation and torsades de pointes due to overdose of phenotiazine antipsychotic drug or tricyclic antidepressants requires particular consideration.

Serum concentration of eperisone hydrochloride correlates with QT interval

BACKGROUND Eperisone hydrochloride is a centrally acting muscle relaxant prescribed for muscle stiffness that acts by depressing the activities of α and γ efferent neurons in the spinal cord and supraspinal structures. Although a case of eperisone-induced severe QT prolongation had been reported, the relationship between serum eperisone concentration and QT interval remains obscure. OBJECTIVE The aim of this study was to investigate the relationship between serum eperisone concentration and QT interval. METHODS Four patients who overdosed on eperisone were admitted to our hospital between January 2010 and December 2011. We took simultaneous serial measurements of serum eperisone concentration and QT interval in the intensive care unit. In total, 22 measurement points were plotted for these patients. We analyzed the correlation between the serum eperisone concentration and corrected QT (QTc) interval. RESULTS Three men and one woman (mean age, 50 years) overdosed on eperisone with an average dose of 3087.5 mg (therapeutic dose, 150 mg/day). The mean QTc interval at arrival was 592 ms (range, 444-825 ms), and the mean serum eperisone concentration at arrival was 1257.5 ng/mL (range, 14.5-4120.0 ng/mL). The correlation coefficient was 0.833 between serum eperisone concentration and QTc interval (P < .001). CONCLUSION Serum eperisone concentration correlates with QTc interval in patients who overdose on eperisone.

Risk factors for ground-level falls differ by sex

BACKGROUND The populations of many developed countries have been aging in recent years, resulting in increasing numbers of elderly-related injuries. Conventionally regarded as minor, injuries from ground-level falls are now associated with a higher risk of death for elderly people. METHODS The subjects of this study were 15662 adult patients with injuries from ground-level falls who were registered in the Japan Trauma Data Bank between 2007 and 2013. Logistic regression analysis was used to evaluate the effects of age, sex, Injury Severity Score, and Revised Trauma Score (RTS) on inhospital mortality. Patients aged 60 years or older were further categorized into 4 subgroups by age and sex, and the effect of the presence of injuries of Abbreviated Injury Scale greater than or equal to 3 in each region on inhospital mortality was analyzed. RESULTS Logistic regression analysis for inhospital mortality showed significant interactions between sex and age and between sex and RTS, and subgroup analysis by sex was, therefore, performed. The odds ratio (95% confidence interval) for inhospital mortality compared with patients older than 60 years was 2.75 (1.90-3.96) for men aged 60 to 79 years and 5.44 (3.77-7.85) for men 80 years or older and 1.46 (0.83-2.58) for women aged 60 to 79 years and 2.32 (1.35-4.01) for women 80 years or older. The odds ratios (95% confidence interval) for RTS less than 7.840 was 6.89 (5.56-8.55) for men and 9.97 (7.59-13.10) for women. CONCLUSIONS The effects of age and RTS on inhospital mortality of patients after ground-level falls differed by sex.