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Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome β5 subunit ( PSMB5 ), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene.

Purpose The phase III COLUMBA study evaluated daratumumab (DARA) intravenous (IV) and subcutaneous (SC) in patients with relapsed or refractory multiple myeloma. Here, we report patient-reported satisfaction with therapy (SWT) in COLUMBA. Methods DARA IV or DARA SC was administered weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks (cycles 7 +). Patients completed a modified version of the Cancer Therapy Satisfaction Questionnaire (CTSQ) at weekly (cycles 1–2) and monthly (cycles 3 +) intervals and at the end of treatment. Results for each item and the SWT domain score were summarized using descriptive statistics. The distribution of responses for individual items was calculated for each assessment. The proportion of patients for whom SWT domain score change from first assessment met or exceeded the minimally important difference (MID) of 5.9 points was calculated at each assessment time point. Results Two-hundred fifty-nine patients were randomized to DARA IV and 263 to DARA SC. Mean scores for SWT domain questions were high and largely positive during treatment. Responses indicating positive perceptions of therapy were given by a numerically greater proportion of patients in the DARA SC group than the DARA IV group for most questions. Changes from the first assessment in SWT domain scores met or exceeded the MID for an average of ~ 40% of patients. Conclusion In COLUMBA, modified CTSQ results suggest patients in the DARA SC group were more satisfied with their cancer therapy than those in the DARA IV group. Trial registration ClinicalTrials.gov identifier NCT03277105. Registered September 8, 2107.

Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 ( FLT3 ) and rat sarcoma viral oncogene homolog ( RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3- ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain ( FLT3 -TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-α (40%) mutations. However, epigenetics-modifying gene ( DNMT3a , TET2 and IDH1/2 ) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3 -ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them ( P =0.001). Moreover, the high frequency of FLT3 -ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations ( P <0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3 -ITD, leading to resistance to therapy and relapse.

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro . Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

BackgroundIt has reported that Iguratimod (IGU), one of methanesulfonanilide of anti-inflamamatory agents, can inhibit anti-arthritic activity of rheumatoid arthritis (RA). IGU was approved for rheumatoid arthritis patients with inappropriate response to conventional treatments in Japan in September 2012.ObjectivesWe aimed to assess the efficacy of IGU alone or in combination with Methotrxate (MTX) in patients with rheumatoid ArthritisMethodsPatients who had an inadequqte response to MTX were enrolled. From December 2012, forty nine patients treated with IGU were analyzes retrospectively; 17 of 49 patients were treated with only IGU, 32 of 49 patients were treated with add-on IGU in combination with MTX. Disease activity and clinical response were assessed by disease activity score 28/ESR (DAS28-ESR) and EULAR response criteria, respectively. The DAS28-ESR, CRP, SDAI, CDAI at 1, 2, 3, 6, 12, 24 months from administration of IGU were examined.ResultsThe average amount of IGU is 40.7mg in MTX group and 41.3mg in non- MTX group. The average amount of MTX was 7mg. After follow up 24 months, escape cases was six cases. The DAS28-ESR. After 12 months of treatment, The DAS28-ESR was decreased from4.32 to 2.37 significantly in MTX group (P<0.01), and also decreased from4.23 to 2.37 significantly in non-MTX group (P<0.01). According to EULAR response criteria at 12 months, The DAS28-ESR remission was observed in 46.9% of patients in MTX group and 52.9% in non- MTX group. CRP decreased from1.9 to 0.7 significantly in MTX group (P<0.01), and also decreased from 2.1 to 0.8 significantly in non-MTX group (P<0.05).There was no significant difference between the two groups.ConclusionsBased on these results, we can conclude that the treatment of IGU is effective and well tolerated, and represents a new option for RA patients, including patient with inadequqte response to MTX.ReferencesLiang-jing Lu,et al. Multicenter,dandomized,double-blind,controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate. Arthritis. Rheumatol 61, No. 7 July 2009:979–987Y Aikawa, et al.An anti-rheumatic agent T-614 inhibits NF-kB activation in LPS- and TNF-α-stimulated THP-1 cells without interfering with IkBα degration. Inflammation Research April 2002,Vol51 4:188–194Xu Y, et al Regulatory Effect of Iguratimod on the Balance of Th Subsets and Inhibition of Inflammatory Cytokines in Patients with Rheumatoid.Medators Inflamm 2015 Dec 2.:1155Okamura K, et al. Efficacy of the clinical use of iguratimod therapy in patients with rheumatoid arthritis. Mod Rheumatol2015 Mar;25(2):235–40Disclosure of InterestNone declared

Synopsis Generation of neutral atomic beam is under development for the ion-neutral merged-beam experiment at the RIKEN Cryogenic Electrostatic ion storage ring (RICE). The beam is produced by a photodetachment of a negative ion beam using a high power laser diode array with a wavelength of 808 nm. In order to increase the detachment efficiency, we have developed an optical cavity built with a planar mirror. In this presentation we will present the current status of the neutral atom beam source.

Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months ( n =33) and a second group with PFS⩾6 months ( n =23). Of the 15 genes analyzed, the expression of activating transcription factor 3 ( ATF3 ) and ATF4 was significantly lower in patients with shorter PFS ( P =0.0157 and P =0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa , which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03–185.00%) and 148.02% (90% CI, 113.32–193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105

Recent studies have demonstrated that one-third of known microRNAs (miRNAs) are stably detectable in plasma. Therefore, we assessed plasma miRNAs to investigate the dynamics of oncomir 17-92a, which is highly expressed in multiple myeloma (MM) patients. The plasma miR-92a level in symptomatic MM patients was significantly downregulated compared with normal subjects ( P <0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. In contrast, miR-92a levels in peripheral blood CD8 + or CD4 + cells from MM patients were lower than those of normal subjects, and the miR-92a levels of the cells tended to correlate with plasma miR-92a levels. The plasma miR-92a level in the complete remission group became normalized, whereas the partial response (PR) and very good PR groups did not reach the normal range. In smoldering MM, the plasma miR-92a level did not show a significant difference compared with normal subjects. Our findings suggest that measurement of the plasma miR-92a level in MM patients could be useful for initiation of chemotherapy and monitoring disease status, and the level may represent, in part, the T-cell immunity status of these patients.