Home High-Flow Nasal Cannula Oxygen Therapy for Stable Hypercapnic COPD: A Randomized Clinical Trial.

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

Development of a quantitative prediction model for peripheral blood stem cell collection yield in the plerixafor era.

BACKGROUND AIMS: Predicting autologous peripheral blood stem cell (PBSC) collection yield before leukapheresis is important for optimizing PBSC mobilization and autologous stem cell transplantation (ASCT) for treating hematological malignancies. Although guidelines for plerixafor usage based on peripheral blood CD34+ (PB-CD34+) cell count are available, their predictive performance in the real world remains unclear. METHODS: This study retrospectively analyzed 55 mobilization procedures for patients with non-Hodgkin lymphoma or multiple myeloma and developed a novel quantitative prediction model for CD34+ cell collection yield that incorporated four clinical parameters available the day before leukapheresis; namely, PB-CD34+ cell count the day before apheresis (day -1 PB-CD34+), number of prior chemotherapy regimens, disease status at apheresis and mobilization protocol. RESULTS: The effects of PB-CD34+ cell counts on CD34+ cell collection yield varied widely per patient characteristics, and plerixafor usage was recommended in patients with poorly controlled disease or those with a history of heavy pre-treatments even with abundant day -1 PB-CD34+ cell count. This model suggested a more proactive use of plerixafor than that recommended by the guidelines for patients with poor pre-collection condition or those with a higher target number of CD34+ cells. Further, the authors analyzed the clinical outcomes of ASCT and found that plerixafor use for stem cell mobilization did not affect short- or long-term outcomes after ASCT. CONCLUSIONS: Although external validations are necessary, the results can be beneficial for establishing more effective and safer mobilization strategies.

[Clinical experience of leukapheresis for CD19 CAR-T cell therapy].

To perform chimeric antigen receptor T (CAR-T) cell therapy in heavily pretreated patients with progressive disease and depleted lymphocytes, an optimized leukapheresis protocol must be established. To probe the effects of patient-related parameters on the collection efficiency of CD3+ cells, we retrospectively analyzed patients with relapsed/refractory diffuse large B-cell lymphoma who underwent leukapheresis for tisagenlecleucel at two centers. A total of 51 patients were analyzed, with a median age at apheresis of 59 years, and precollection hemoglobin levels, CD3+ cell counts, and platelet counts of 9.2 g/dl, 574/µl, and 15.8×104/µl, respectively. A median of 3.0×109 (0.7-8.4) CD3+ cells were harvested with 8.7 (4.0-15.7) l apheresis volume. The collection efficiency 2 (CE2) for CD3+ cells was 61.0% (21.0-127.3). One-day apheresis was sufficient to obtain the designated cell numbers in all cases. Lower hemoglobin levels, higher CD3+ cell counts, and higher platelet counts before apheresis were significantly associated with lower CE2 for CD3+ cells. These results suggest a need to increase the apheresis volume in anemic, lymphocyte- or platelet-rich patients due to an expected low CE2. Erythrocyte transfusions before or during apheresis may be a reasonable option for patients with anemia.

Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C-H Bonds Using Ru(II)-Pheox Catalyst.

We have established a method for the highly regio- and enantioselective functionalization of tert-butyl groups via intramolecular amide carbene insertion into C-H bonds, yielding γ-lactams with 91% ee in up to 99% yield. This reaction uses a ruthenium(II) phenyl oxazoline (Ru(II)-Pheox) complex. The catalytic intramolecular carbene transfer reaction to the primary C-H bond proceeds rapidly and selectively compared to that with secondary C-H, benzylic secondary C-H, tert-C-H, or sp2C-H bonds in the presence of 1 mol % Ru(II)-Pheox catalyst. This is the first example of a catalytic carbenoid insertion into an unactivated tert-butyl group with enantiocontrol at the carbenoid carbon.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions was performed using density functional theory (DFT). In this study, cyclopropane ring-fused γ-lactones, which are 5.8 kcal/mol more stable than the corresponding minor enantiomer, are obtained as the major product. The results of the calculations suggest that the enantioselectivity of the Ru(II)-Pheox-catalyzed intramolecular cyclopropanation reaction is affected by the energy differences between the starting structures 5l and 5i. The reaction pathway was found to be a stepwise mechanism that proceeds through the formation of a metallacyclobutane intermediate. This is the first example of a computational chemical analysis of enantioselective control in an intramolecular carbene-transfer reaction using C1 -symmetric catalysts.

Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds.

A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an ammonium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.

Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence: A Post Hoc Analysis of the J-STARS Study (Japan Statin Treatment Against Recurrent Stroke).

BACKGROUND AND PURPOSE: To define desirable target low-density lipoprotein (LDL) cholesterol levels for the prevention of stroke recurrence, a post hoc analysis was performed in the J-STARS study (Japan Statin Treatment Against Recurrent Stroke). METHODS: Subjects (n=1578) were divided into groups based on mean value of postrandomized LDL cholesterol levels until the last observation in 20 mg/dL increments. Adjusted hazard ratios (HRs) and 95% confidence intervals were analyzed for each group, with adjustments for baseline LDL cholesterol, baseline body mass index, hypertension, diabetes mellitus, and statin usage. RESULTS: The postrandomized LDL cholesterol level until the last observation were 104.1±19.3 mg/dL in the pravastatin group and 126.1±20.6 mg/dL in the control group. The adjusted HRs for stroke and transient ischemic attack and all vascular events decreased in the postrandomized LDL cholesterol level of 80 to 100 mg/dL (P=0.23 and 0.25 for the trend, respectively). The adjusted HR for atherothrombotic infarction significantly reduced with the usage of statin after adjusting baseline LDL cholesterol levels (HR, 0.39; 95% confidence intervals, 0.19-0.83). The adjusted HR for atherothrombotic infarction and intracranial hemorrhage were similar among the postrandomized LDL-cholesterol-level subgroups (P=0.50 and 0.37 for the trend, respectively). The adjusted HR for lacunar infarction decreased in the postrandomized LDL cholesterol level of 100 to 120 mg/dL (HR, 0.45; 95% confidence intervals, 0.20-0.99; P=0.41 for the trend). CONCLUSIONS: The composite risk of stroke and transient ischemic attack reduced in the postrandomized LDL cholesterol level of 80 to 100 mg/dL after adjusting for statin usage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00221104.

Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-ß/Smad pathway activation.

The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-ß/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-ß/Smad pathway activation.

Isopentenyl pyrophosphate secreted from Zoledronate-stimulated myeloma cells, activates the chemotaxis of γδT cells.

γδT cell receptor (TCR)-positive T cells, which control the innate immune system, display anti-tumor immunity as well as other non-immune-mediated anti-cancer effects. γδT cells expanded ex vivo by nitrogen-containing bisphosphonate (N-BP) treatment can kill tumor cells. N-BP inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, resulting in the accumulation of isopentenyl pyrophosphate (IPP), which is a stimulatory antigen for γδT cells. We have previously observed that as they get closer, migrating γδT cells increase in speed toward target multiple myeloma (MM) cells. In the present study, we investigated the γδT cell chemotactic factors involving using a micro total analysis system-based microfluidic cellular analysis device. The addition of supernatant from RPMI8226 MM cells treated with the N-BP zoledronic acid (ZOL) or the addition of IPP to the device induced chemotaxis of γδT cells and increased the speed of migration compared to controls. Analysis of the ZOL-treated RPMI8226 cell supernatant revealed that it contained IPP secreted in a ZOL-dose-dependent manner. These observations indicate that IPP activates the chemotaxis of γδT cells toward target MM cells treated with ZOL.

Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907).

PURPOSE: This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. METHODS AND MATERIALS: This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. RESULTS: Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively. CONCLUSIONS: Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

Galectin-9 ameliorates acute GVH disease through the induction of T-cell apoptosis.

Galectins comprise a family of animal lectins that differ in their affinity for ß-galactosides. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that was recently shown to function as a ligand for T-cell immunoglobin domain and mucin domain-3 (Tim-3) expressed on terminally differentiated CD4(+) Th1 cells. Gal-9 modulates immune reactions, including the induction of apoptosis in Th1 cells. In this study, we investigated the effects of Gal-9 in murine models of acute GVH disease (aGVHD). First, we demonstrated that recombinant human Gal-9 inhibit MLR in a dose-dependent manner, involving both Ca(2+) influx and apoptosis in T cells. Next, we revealed that recombinant human Gal-9 significantly inhibit the progression of aGVHD in murine BM transplantation models. In conclusion, Gal-9 ameliorates aGVHD, possibly by inducing T-cell apoptosis, suggesting that gal-9 may be an attractive candidate for the treatment of aGVHD.

A Clinically Applicable Prediction Model to Improve T Cell Collection in Chimeric Antigen Receptor T Cell Therapy.

As chimeric antigen receptor (CAR) T cell therapy targeting CD19 has shown favorable outcomes in patients with relapsed or refractory (r/r) mature B cell lymphomas and B cell acute lymphoblastic leukemia (B-ALL), an increasing number of patients are waiting to receive these treatments. Optimized protocols for T cell collection by lymphapheresis for chimeric antigen receptor (CAR) T cell therapy are urgently needed to provide CAR T cell therapy for patients with refractory and progressive disease and/or a low number of lymphocytes owing to prior chemotherapy. The predicted efficiency of CD3+ cell collection in apheresis can guide protocols for apheresis, but a clinically applicable model to produce reliable estimates has not yet been established. In this study, we prospectively analyzed 108 lymphapheresis procedures for tisagenlecleucel therapy at 2 centers. The apheresis procedures included 20 procedures in patients with B cell acute lymphoblastic leukemia and 88 procedures in patients with diffuse large B cell lymphoma, with a median age at apheresis of 58 years (range, 1 to 71 years). After lymphapheresis with a median processing blood volume of 10 L (range, 3 to 16 L), a median of 3.2 × 109 CD3+ cells (range, .1 to 15.0 × 109 cells) were harvested. Collection efficiency 2 (CE2) for CD3+ cells was highly variable (median, 59.3%; range, 11.0% to 199.8%). Multivariate analyses revealed that lower hemoglobin levels, higher circulating CD3+ cell counts, and higher platelet counts before apheresis significantly decreased apheresis CE2. Based on multivariate analyses, we developed a novel formula that estimates CE2 from precollection parameters with high accuracy (r = .56; P < .01), which also suggests the necessary processing blood volume. Our strategy for lymphapheresis should help reduce collection failure, as well as achieve efficient utilization of medical resources in clinical practice, thereby allowing delivery of CAR T cell therapy to more patients in a timely manner.

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells.

Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment.

beta-catenin small interfering RNA successfully suppressed progression of multiple myeloma in a mouse model.

PURPOSE: beta-catenin is the downstream effector of the Wnt signaling pathway, and it regulates cell proliferation. beta-catenin overexpression correlates positively with prognosis in several types of malignancies. We herein assessed its effects on growth of multiple myeloma cells using a xenograft model. EXPERIMENTAL DESIGN: We first investigated the expression of beta-catenin in multiple myeloma cell lines and multiple myeloma cells obtained from patients. Next, we investigated the growth inhibitory effects of beta-catenin small interfering RNA on the growth of multiple myeloma cells in vivo. Six-week-old male BALB/c nu/nu mice were inoculated s.c. in the right flank with 5 x 10(6) RPMI8226 cells, followed by s.c. injections of beta-catenin small interfering RNA, scramble small interfering RNA, or PBS/atelocollagen complex twice a week for a total of eight injections. RESULTS: Significantly higher levels of beta-catenin expression were observed in multiple myeloma cell lines and in samples from patients with multiple myeloma than those found in mononuclear cells obtained from healthy volunteers. In in vivo experiments, no inhibitory effects were observed following treatment with scramble small interfering RNA or PBS/atelocollagen complexes, whereas treatment with beta-catenin small interfering RNA/atelocollagen complex significantly inhibited growth of multiple myeloma tumors (P < 0.05). CONCLUSIONS: beta-catenin small interfering RNA treatment inhibited the growth of multiple myeloma tumors in a xenograft model. To our knowledge, this is the first report showing that the treatment with beta-catenin small interfering RNA produces an inhibitory effects on growth of hematologic malignancies in vivo. Because treatment with beta-catenin small interfering RNA inhibited growth of multiple myeloma cells, beta-catenin is the attractive novel target for treating multiple myeloma.

Different Influences of Statin Treatment in Preventing At-Risk Stroke Subtypes: A Post Hoc Analysis of J-STARS.

AIMS: To understand the different influences of statins on the incidence rate of each stroke subtype in association with low-density lipoprotein (LDL) cholesterol levels, we performed a post hoc analysis on the data from the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study. METHODS: Subjects (n=1,578) were divided into three groups according to their mean postrandomized LDL cholesterol level (＜100, 100-120, and ≥ 120 mg/dL) until the last observation before the event or the end of follow-up. A Cox proportional hazard model for time to events was used for calculating adjusted hazard ratios, 95% confidence intervals, and the trend tests. RESULTS: The event rates for atherothrombotic stroke did not decrease in accordance with the postrandomized LDL cholesterol level subgroups of either the control or the pravastatin group (p=0.15 and 0.33 for the trend, respectively). In the control group, however, no atherothrombotic stroke event was observed in the subgroup of the low postrandomized LDL cholesterol level (less than 100 mg/dL). The event rates for atherothrombotic stroke were lower in the middle postrandomized LDL cholesterol level subgroup (100-120 mg/dL) of the pravastatin group than that of the control group. The event rates for lacunar stroke decreased in the lower postrandomized LDL cholesterol level subgroup of the control group but not of the pravastatin group (p=0.004 and 0.06 for the trend, respectively). CONCLUSIONS: Statins showed different influences on the risks of atherothromobotic and lacunar stroke according to postrandomized LDL cholesterol levels.

Effect of Statin on Stroke Recurrence Prevention at Different Infarction Locations: A Post Hoc Analysis of The J-STARS Study.

AIM: Posterior circulation stroke (PCS) has different clinical features and prognosis compared with anterior circulation stroke (ACS), and whether the effect of statin therapy on stroke prevention differs according to infarction location remains unclear. This post hoc analysis of the J-STARS study aimed to compare the usefulness of statin at different infarction locations (i.e., ACS and PCS). METHODS: In the J-STARS study, 1578 patients were randomly assigned to the pravastatin or control group. The subjects were divided into two subgroups (ACS and PCS groups) based on the arteries responsible for the infarction. Cox proportional hazards models were used to investigate whether the all stroke recurrence rate was different between the ACS and PCS groups. RESULTS: The PCS group (n=499) had a significantly higher prevalence of diabetes than the ACS group (n=1022) (30.7% vs. 19.8%, P＜0.001). During the follow-up (4.9±1.4 years), the incidence of all stroke was significantly lower in the pravastatin group than in the control group among patients with PCS (adjusted hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.009); however, the stroke recurrence rates were not significantly different between both groups among patients with ACS (adjusted HR 1.32, 95% CI 0.93-1.88,P=0.123). A significant interaction between the ACS and PCS groups in terms of pravastatin effects was noted (P=0.003 for interaction). CONCLUSIONS: Pravastatin significantly reduced the recurrence rate of all stroke among patients with PCS. Thus, the effect of statin on the recurrence of stroke may differ according to infarction location.

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin.

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.

Ligand Exchange Reaction on a Ru(II)-Pheox Complex as a Mechanistic Study of Catalytic Reactions.

A ligand exchange of one of the acetonitrile ligands of the (acetonitrile)4Ru(II)-phenyloxazoline complex (Ru(II)-Pheox) by pyridine was demonstrated, and the location of the exchange reaction was examined by density functional theory (DFT) calculations to study the mechanism of its catalytic asymmetric reactions. The acetonitrile was smoothly exchanged with a pyridine to afford the corresponding (pyridine)(acetonitrile)3Ru(II)-Pheox complex with a trans orientation (C-Ru-N(pyridine)) in a quantitative yield, and the complex was analyzed by single-crystal X-ray analysis. DFT calculations indicated that the most eliminable acetonitrile is the trans group, which is consistent with the X-ray analysis. The direction of the ligand exchange is thus determined on the basis of the energy gap of the ligand elimination instead of the stability of the metal complex. These results suggested that a reactant in a Ru-Pheox-catalyzed reaction should approach trans to the C-Ru bond to generate chirality on the Ru center.

Highly stereoselective spirocyclopropanation of various diazooxindoles with olefins catalyzed using Ru(ii)-complex.

Optically active spirocyclopropyloxindole derivatives were efficiently synthesized from diazooxindoles and olefins in the presence of a Ru(ii)-Pheox catalyst. Among a series of Ru(ii)-Pheox catalysts, Ru(ii)-Pheox 6e was determined to be the best catalyst for spirocyclopropanation reactions of diazooxindoles with various olefins in high yields (up to 98%) with high diastereoselectivities (up to trans:cis = >99:1<) and enantioselectivities (up to 99% ee). Furthermore, as the first catalytic asymmetric synthesis, anti-HIV active candidate 4a and a bioactive compound of AMPK modulator 4c were easily synthesized from the corresponding diazooxindoles 1i and 1b, respectively, in high yields with high enantioselectivities (4a: 82% yield, 95% ee, 4b: 99% yield, 93% ee).