Switching nanoprecipitates to resist hydrogen embrittlement in high-strength aluminum alloys.

Hydrogen drastically embrittles high-strength aluminum alloys, which impedes efforts to develop ultrastrong components in the aerospace and transportation industries. Understanding and utilizing the interaction of hydrogen with core strengthening elements in aluminum alloys, particularly nanoprecipitates, are critical to break this bottleneck. Herein, we show that hydrogen embrittlement of aluminum alloys can be largely suppressed by switching nanoprecipitates from the η phase to the T phase without changing the overall chemical composition. The T phase strongly traps hydrogen and resists hydrogen-assisted crack growth, with a more than 60% reduction in the areal fractions of cracks. The T phase-induced reduction in the concentration of hydrogen at defects and interfaces, which facilitates crack growth, primarily contributes to the suppressed hydrogen embrittlement. Transforming precipitates into strong hydrogen traps is proven to be a potential mitigation strategy for hydrogen embrittlement in aluminum alloys.

Outcomes of poor peripheral blood stem cell mobilizers with multiple myeloma at the first mobilization: A multicenter retrospective study in Japan.

Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one-third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.

Experience with denosumab (XGEVA®) for prevention of skeletal-related events in the 10 years after approval.

Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor approved for SRE prevention in patients with multiple myeloma and patients with bone metastases from solid tumors. In phase 3 trials, denosumab showed superiority to the bisphosphonate zoledronate in reducing the risk of first on-study SRE by 17% (median time to first on-study SRE delayed by 8.2 months) and the risk of first and subsequent on-study SREs by 18% across multiple solid tumor types, including some patients with multiple myeloma. Denosumab also improved pain outcomes and reduced the need for strong opioids. Additionally, a phase 3 trial showed denosumab was noninferior to zoledronate in delaying time to first SRE in patients with newly diagnosed multiple myeloma. Denosumab has a convenient 120 mg every 4 weeks recommended dosing schedule with subcutaneous administration. Rare but serious toxicities associated with denosumab include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture events, with multiple vertebral fractures reported following treatment discontinuation. After a decade of real-world clinical experience with denosumab, we are still learning about the optimal use and dosing for denosumab. Despite the emergence of novel and effective antitumor therapies, there remains a strong rationale for the clinical utility of antiresorptive therapy for SRE prevention. Ongoing studies aim to optimize clinical management of patients using denosumab for SRE prevention while maintaining safety and efficacy.

Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

BACKGROUND: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. PURPOSE: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. FINDINGS: Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant benefit in overall survival (OS), but it tended to be better in the maintenance group in non-transplanted patients. Regarding the treatment pattern, the substitution or addition of drugs different from the induction therapy and the combination with immunomodulatory drugs and proteasome inhibitors appeared to be more beneficial for PFS but not OS. CONCLUSION: These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM.

Feedback regulation and coordination of the main metabolism for bacterial growth and metabolic engineering for amino acid fermentation.

Living organisms such as bacteria are often exposed to continuous changes in the nutrient availability in nature. Therefore, bacteria must constantly monitor the environmental condition, and adjust the metabolism quickly adapting to the change in the growth condition. For this, bacteria must orchestrate (coordinate and integrate) the complex and dynamically changing information on the environmental condition. In particular, the central carbon metabolism (CCM), monomer synthesis, and macromolecular synthesis must be coordinately regulated for the efficient growth. It is a grand challenge in bioscience, biotechnology, and synthetic biology to understand how living organisms coordinate the metabolic regulation systems. Here, we consider the integrated sensing of carbon sources by the phosphotransferase system (PTS), and the feed-forward/feedback regulation systems incorporated in the CCM in relation to the pool sizes of flux-sensing metabolites and αketoacids. We also consider the metabolic regulation of amino acid biosynthesis (as well as purine and pyrimidine biosyntheses) paying attention to the feedback control systems consisting of (fast) enzyme level regulation with (slow) transcriptional regulation. The metabolic engineering for the efficient amino acid production by bacteria such as Escherichia coli and Corynebacterium glutamicum is also discussed (in relation to the regulation mechanisms). The amino acid synthesis is important for determining the rate of ribosome biosynthesis. Thus, the growth rate control (growth law) is further discussed on the relationship between (p)ppGpp level and the ribosomal protein synthesis.

High-energy x-ray nanotomography introducing an apodization Fresnel zone plate objective lens.

In this study, high-energy x-ray nanotomography (nano-computed tomography, nano-CT) based on full-field x-ray microscopy was developed. Fine two-dimensional and three-dimensional (3D) structures with linewidths of 75 nm-100 nm were successfully resolved in the x-ray energy range of 15 keV-37.7 keV. The effective field of view was ∼60 µm, and the typical measurement time for one tomographic scan was 30 min-60 min. The optical system was established at the 250-m-long beamline 20XU of SPring-8 to realize greater than 100× magnification images. An apodization Fresnel zone plate (A-FZP), specifically developed for high-energy x-ray imaging, was used as the objective lens. The design of the A-FZP for high-energy imaging is discussed, and its diffraction efficiency distribution is evaluated. The spatial resolutions of this system at energies of 15 keV, 20 keV, 30 keV, and 37.7 keV were examined using a test object, and the measured values are shown to be in good agreement with theoretical values. High-energy x-ray nano-CT in combination with x-ray micro-CT is applied for 3D multiscale imaging. The entire bodies of bulky samples, ∼1 mm in diameter, were measured with the micro-CT, and the nano-CT was used for nondestructive observation of regions of interest. Examples of multiscale CT measurements involving carbon steel, mouse bones, and a meteorite are discussed.

Phase II, Multicenter, Single-Arm, Open-Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination with Bortezomib and Dexamethasone in Japanese Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma.

INTRODUCTION: Panobinostat, bortezomib, and dexamethasone combination therapy demonstrated progression-free survival (PFS) benefit over bortezomib and dexamethasone alone in the PANORAMA-1 study in relapsed/refractory multiple myeloma (MM). Here, we present data from a phase II study (NCT02290431) of this combination in Japanese patients with relapsed or relapsed-and-refractory MM. METHODS: Patients received 3-week cycles of 20-mg oral panobinostat (weeks 1 and 2), 1.3-mg/m2 subcutaneous bortezomib (days 1, 4, 8, and 11), and 20-mg oral dexamethasone (day of and the day following bortezomib administration) for a total of 8 cycles (24 weeks; treatment phase 1). Patients with treatment benefit had an option to enter the extension phase to receive 6-week (42-day) cycles of panobinostat (weeks 1, 2, 4, and 5) plus bortezomib (days 1, 8, 22, and 29) and dexamethasone (day of and the day following bortezomib treatment) for 24 weeks. The primary objective was complete response (CR) + near CR (nCR) rate after treatment phase 1 as per the modified European Society for Blood and Marrow Transplantation criteria. RESULTS: Of the 31 patients, 4 (12.9%) completed the treatment and 27 (87.1%) discontinued; 17 (54.8%) entered the extension phase. In total, 24 patients (77.4%) entered the survival follow-up phase and followed until study closure when the last patient was treated for 1 year after treatment phase 1. The CR + nCR rate was 48.4% (90% CI: 33.6-63.2). The overall response rate (CR + nCR + partial response) was 80.6%. The median PFS, duration of response, time to response, and time to progression were 15.3, 22.7, 1.4, and 15.3 months, respectively. All patients experienced adverse events (AEs), with diarrhea (80.6%), decreased appetite (58.1%), and thrombocytopenia (54.8%) being the most frequent, regardless of relationship to the study treatment. Thrombocytopenia (48.4%), fatigue (25.8%), diarrhea (22.6%), neutrophil count decrease (22.6%), platelet count decrease (22.6%), and lymphocyte count decrease (22.6%) were the most frequent grade 3/4 AEs. CONCLUSION: The study met the primary objective with 48.4% CR + nCR rate. The AEs associated with the combination treatment were safely managed using the existing AE management guidelines, including dose interruption/modification and/or supportive medical intervention. This treatment regimen is an effective option with a favorable benefit/risk profile for Japanese patients with relapsed/refractory MM.

Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis.

INTRODUCTION: The primary analysis of a global phase 3 study that evaluated the efficacy and safety of denosumab versus zoledronic acid for preventing skeletal-related events (SREs) in adults with newly diagnosed multiple myeloma (MM) indicated that denosumab was noninferior to zoledronic acid for time to first on-study SREs. Here we present a subgroup analysis to evaluate efficacy and safety in Asian patients. METHODS: Patients were randomized 1:1 to receive denosumab 120 mg subcutaneously or zoledronic acid intravenously 4 mg every 4 weeks in a double-blind, double-dummy fashion. All patients received standard-of-care first-line antimyeloma treatment. Each patient received either study drug until an estimated 676 patients experienced at least one on-study SRE and the primary efficacy and safety analyses were completed. RESULTS: Of 1718 total enrolled patients, 196 Asian patients (denosumab, n = 103; zoledronic acid, n = 93) were included in this subgroup analysis. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% and 50.5%, respectively (HR [95% CI], 0.77 [0.48-1.26]). All 194 patients receiving at least one dose of study drug experienced at least one treatment-emergent AE. The most common AEs reported in either group (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), and pyrexia (38.2%, 41.3%). Treatment-emergent renal toxicity occurred in 9/102 (8.8%) and 20/92 (21.7%) patients, respectively. Similar rates of positively adjudicated osteonecrosis of the jaw (7 [6.9%] vs 5 [5.4%]) and treatment-emergent hypocalcemia (19 [18.6%] vs 17 [18.5%]) were reported in the denosumab and zoledronic acid groups, respectively. CONCLUSION: Efficacy and safety outcomes from this Asian subgroup were comparable to those of the full study population. Overall, this analysis supports denosumab as an additional treatment option for standard of care for Asian patients with newly diagnosed MM with lytic bone lesions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01345019.

Microbial Bioremediation of Feather Waste for Keratinase Production: An Outstanding Solution for Leather Dehairing in Tanneries.

In leather industries and tanneries, large amount of wastes has been disposed; which polluting water, soil, and atmosphere and causing serious human health problems. In particular, chemical dehairing process of leather industries produces fair amount of toxic wastes. It is, thus, urgently needed to use alternative processes free from pollution. As more than 90% of keratin is contained in feather, it is desirable to develop bioremediation process using keratinolytic microorganisms. In the present investigation, therefore, we first identified Bacillus cereus and Pseudomonas sp. to be able to produce keratinase. Then, the optimization was performed to maximize the keratinase activity with respect to cultivation temperature, pH, and incubation time. Moreover, the effects of metal ions and various substrates on keratinase activity were also investigated. The result indicates that keratinase activity became maximum at 50°C for both strains, whereas the optimal pH was 10.0 for B. cereus and 7.0 for Pseudomonas sp. The highest keratinase activity of 74.66 ± 1.52 U/mL was attained by B. cereus, whereas 57.66 ± 2.52 U/mL was attained by Pseudomonas sp. Enzymatic dehairing efficiency of leathers was also compared with chemical dehairing (Na2S and CaO), where complete dehairing was achieved by treating them with crude keratinase. Partial enzyme purification was performed by acetone precipitation. Batch cultivation of B. cereus using 1 L fermentor indicates a potential candidate for large-scale keratinase production. Thus, keratinase enzyme by degrading poultry wastes (feather) can be an alternative approach to chemical dehairing in leather industries, thus preventing environmental pollution through bioremediation.

Hydrogen-accelerated spontaneous microcracking in high-strength aluminium alloys.

Aluminium alloys are re-evaluated as most feasible way to satisfy the industrial needs of light-weight structural materials. However, unlike conventional structural metals such as iron and titanium, aluminium does not have easily accessible secondary phases, which means that aluminium-based alloys cannot be strengthened by harnessing multiple phases. This leaves age hardening as the only feasible strengthening approach. Highly concentrated precipitates generated by age hardening generally play a dominant role in shaping the mechanical properties of aluminium alloys. In such precipitates, it is commonly believed that the coherent interface between the matrix and precipitate does not contribute to crack initiation and embrittlement. Here, we show that this is not the case. We report an unexpected spontaneous fracture process associated with hydrogen embrittlement. The origin of this quasi-cleavage fracture involves hydrogen partitioning, which we comprehensively investigate through experiment, theory and first-principles calculations. Despite completely coherent interface, we show that the aluminium-precipitate interface is a more preferable trap site than void, dislocation and grain boundary. The cohesivity of the interface deteriorates significantly with increasing occupancy, while hydrogen atoms are stably trapped up to an extremely high occupancy over the possible trap site. Our insights indicate that controlling the hydrogen distribution plays a key role to design further high-strength and high-toughness aluminium alloys.

Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.

Redox rebalance against genetic perturbations and modulation of central carbon metabolism by the oxidative stress regulation.

The micro-aerophilic organisms and aerobes as well as yeast and higher organisms have evolved to gain energy through respiration (via oxidative phosphorylation), thereby enabling them to grow much faster than anaerobes. However, during respiration, reactive oxygen species (ROSs) are inherently (inevitably) generated, and threaten the cell's survival. Therefore, living organisms (or cells) must furnish the potent defense systems to keep such ROSs at harmless level, where the cofactor balance plays crucial roles. Namely, NADH is the source of energy generation (catabolism) in the respiratory chain reactions, through which ROSs are generated, while NADPH plays important roles not only for the cell synthesis (anabolism) but also for detoxifying ROSs. Therefore, the cell must rebalance the redox ratio by modulating the fluxes of the central carbon metabolism (CCM) by regulating the multi-level regulation machinery upon genetic perturbations and the change in the growth conditions. Here, we discuss about how aerobes accomplish such cofactor homeostasis against redox perturbations. In particular, we consider how single-gene mutants (including pgi, pfk, zwf, gnd and pyk mutants) modulate their metabolisms in relation to cofactor rebalance (and also by adaptive laboratory evolution). We also discuss about how the overproduction of NADPH (by the pathway gene mutation) can be utilized for the efficient production of useful value-added chemicals such as medicinal compounds, polyhydroxyalkanoates, and amino acids, all of which require NADPH in their synthetic pathways. We then discuss about the metabolic responses against oxidative stress, where αketoacids play important roles not only for the coordination between catabolism and anabolism, but also for detoxifying ROSs by non-enzymatic reactions, as well as for reducing the production of ROSs by repressing the activities of the TCA cycle and respiration (via carbon catabolite repression). Thus, we discuss about the mechanisms (basic strategies) that modulate the metabolism from respiration to respiro-fermentative metabolism causing overflow, based on the role of Pyk activity, affecting the NADPH production at the oxidative pentose phosphate (PP) pathway, and the roles of αketoacids for the change in the source of energy generation from the oxidative phosphorylation to the substrate level phosphorylation.

Report of phase I and II trials of melphalan, prednisolone, and thalidomide triplet combination therapy versus melphalan and prednisolone doublet combination therapy in Japanese patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplantation.

We conducted a phase I study to determine the recommended dose of thalidomide combined with melphalan plus prednisolone (MPT) and a phase II study evaluating the efficacy and safety of this MPT regimen in transplant-ineligible Japanese patients with untreated multiple myeloma. The recommended dose was determined to be 100 mg/day in the phase I study. In the phase II, randomized, double-blind, parallel-group study, patients were allocated to either MPT (n = 52) or MP (n = 51), with 21 and 29 patients completing the study, respectively. Overall response rate, the primary endpoint, was significantly higher in the MPT [40.4% (21/52 patients), 95% confidence interval (CI) 27.0-54.9%] than in the MP [19.6% (10/51 patients), 95% CI 9.8-33.1%] group (P = 0.022). Time to response was also significantly shorter in the MPT group. Incidences of hematological toxicities were similar in the two groups, suggesting that addition of thalidomide did not increase hematological toxicity. Although incidences of some non-hematological toxicities tended to be higher in the MPT group, the low incidence of ≥ Grade 3 toxicities suggests that MPT therapy was well tolerated. These results support the safety and efficacy of MPT therapy in untreated Japanese multiple myeloma patients.

Correction to: Thalidomide maintenance therapy in Japanese myeloma patients: a multicenter, phase II clinical trial (COMET study).

The authors would like to correct the errors in the publication of the original article. The correction details are given below.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Survival differences in multiple myeloma in Latin America and Asia: a comparison involving 3664 patients from regional registries.

In previous observational studies, we have separately characterized patients with multiple myeloma (MM) both from Latin America (LA) and from Asia. Here, we analyze these two datasets jointly, in order to assess the overall survival (OS) in these two world regions. Data were available from 3664 patients (1968 from LA and 1696 from Asia); all of whom diagnosed between 1998 and 2007. Approximately, 26% of patients in both world regions underwent transplantation. OS (from diagnosis of MM) was explored with Kaplan-Meier analyses and Cox proportional hazards models. Patients from LA were significantly younger and had hypercalcemia more often than Asian patients, who in turn had higher proportions of anemia and International Staging System (ISS) stage III disease. The median OS was 56 months in LA, and 47 months in Asia (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.76 to 0.91; P < 0.001). In multivariable analysis, age, ISS stage III, anemia, hypercalcemia, and world region remained significantly associated with OS (P < 0.001 for all covariates). These results were largely driven by patients not undergoing transplantation, as no difference in OS emerged between the two world regions in univariable or multivariable analysis for transplanted patients. Despite adverse prognostic features differentially favoring each region, and adjusting for such differences, we found an OS advantage for patients from LA, in comparison with contemporaneous patients from Asia. Whether this is due to different biological features, differences in access to novel agents (especially thalidomide in earlier periods of the study), unmeasured confounders, or the play of chance, remain unknown.

Thalidomide maintenance therapy in Japanese myeloma patients: a multicenter, phase II clinical trial (COMET study).

A prospective, multicenter, phase II study was performed to assess the efficacy and safety of thalidomide maintenance therapy at different doses in Japanese multiple myeloma (MM) patients. This study included 34 patients (median age, 74 years) who were previously treated with not more than three prior therapies and whose response status was evaluated as at least stable disease. They were randomized into Group A (no maintenance; 12 patients), Group B (50 mg thalidomide maintenance; 12 patients), and Group C (100 mg thalidomide maintenance; 10 patients), respectively. Thalidomide maintenance therapy resulted in improved depth of response in three cases (13.6%) and sustained response after induction therapy in eight cases (36.4%). Two-year progression-free survival (PFS) was 25.0%, 33.3%, and 77.8% in Groups A, B, and C, respectively, and was significantly higher in Group C than in Group A (p = 0.005). There was no difference in the incidence of hematological or non-hematological adverse events between Groups B and C. The current study demonstrates that maintenance with daily thalidomide at 100 mg, but not 50 mg, improved depth of response and prolonged PFS, and that this treatment was feasible for use in Japanese MM patients.

Regulation of glycolytic flux and overflow metabolism depending on the source of energy generation for energy demand.

Overflow metabolism is a common phenomenon observed at higher glycolytic flux in many bacteria, yeast (known as Crabtree effect), and mammalian cells including cancer cells (known as Warburg effect). This phenomenon has recently been characterized as the trade-offs between protein costs and enzyme efficiencies based on coarse-graining approaches. Moreover, it has been recognized that the glycolytic flux increases as the source of energy generation changes from energetically efficient respiration to inefficient respiro-fermentative or fermentative metabolism causing overflow metabolism. It is highly desired to clarify the metabolic regulation mechanisms behind such phenomena. Metabolic fluxes are located on top of the hierarchical regulation systems, and represent the outcome of the integrated response of all levels of cellular regulation systems. In the present article, we discuss about the different levels of regulation systems for the modulation of fluxes depending on the growth rate, growth condition such as oxygen limitation that alters the metabolism towards fermentation, and genetic perturbation affecting the source of energy generation from respiration to respiro-fermentative metabolism in relation to overflow metabolism. The intracellular metabolite of the upper glycolysis such as fructose 1,6-bisphosphate (FBP) plays an important role not only for flux sensing, but also for the regulation of the respiratory activity either directly or indirectly (via transcription factors) at higher growth rate. The glycolytic flux regulation is backed up (enhanced) by unphosphorylated EIIA and HPr of the phosphotransferase system (PTS) components, together with the sugar-phosphate stress regulation, where the transcriptional regulation is further modulated by post-transcriptional regulation via the degradation of mRNA (stability of mRNA) in Escherichia coli. Moreover, the channeling may also play some role in modulating the glycolytic cascade reactions.

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and ß2-microglobulin levels. In the two determinants, ß2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.