Our aim was to analyze the joint association of parental characteristics and offspring obesity indicators with metabolic risk in adolescents. A cross-sectional study was carried out with 972 ...adolescents and their parents. We observed that overweight adolescents who have a normal weight mother show lower metabolic risk in comparison with their counterparts with overweight mothers. In conclusion, mother's weight status moderates the relationship between offspring' obesity indicators and metabolic risk in adolescents.
The transepithelial nasal potential difference (NPD) is used to assess cystic fibrosis transmembrane conductance regulator (CFTR) activity. Unreliability, excessive artifacts, and lack of ...standardization of current testing systems can compromise its use as a diagnostic test and outcome measure for clinical trials.
To determine whether a nonperfusing (agar gel) nasal catheter for NPD measurement is more reliable and less susceptible to artifacts than a continuously perfusing nasal catheter, we performed a multicenter, randomized, crossover trial comparing a standardized NPD protocol using an agar nasal catheter with the same protocol using a continuously perfusing catheter. The data capture technique was identical in both protocols. A total of 26 normal adult subjects underwent NPD testing at six different centers.
Artifact frequency was reduced by 75% (P < .001), and duration was less pronounced using the agar catheter. The measurement of sodium conductance was similar between the two catheter methods, but the agar catheter demonstrated significantly greater CFTR-dependent hyperpolarization, because Δ zero Cl- + isoproterenol measurements were significantly more hyperpolarized with the agar catheter (224.2 ± 12.9 mV with agar vs 18.2 ± 9.1 mV with perfusion, P < .05).
The agar nasal catheter approach demonstrates superior reliability compared with the perfusion nasal catheter method for measurement of NPD. This nonperfusion catheter method should be considered for adoption as a standardized protocol to monitor CFTR activity in clinical trials.
Background:
CXCR4 is a chemokine receptor overexpressed in more than 20 tumor types, including malignant plasma cells. The CXCR4/CXCL12 (SDF-1) axis has been known for many years as a critical ...regulator of tumor proliferation, cell, as well as migration into and out of the bone marrow. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 antibody which inhibits the binding of CXCR4 to CXCL12. This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with relapsed/refractory multiple myeloma.
Patients / Methods:
Patients were eligible for this trial if they were 18 years of age or older with relapsed or relapsed/refractory multiple myeloma after having received at least 2 prior lines of treatment. Patients in whom who both lenalidomide and bortezomib had failed were not excluded from re-treatment with the same regimen. Patients were enrolled at four cancer centers in the U.S. from October 2011 to March 2014. Ulocuplumab (1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex or Bor-Dex to identify maximum tolerated dose (MTD). Ulocuplumab was given weekly in combination with either 25mg lenalidomide on days 1-21 and 40mg oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycles on Arm A or 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 and 20mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day cycles on Arm B since cycle 2. The primary endpoints for this study were dose-limiting toxicities. Other key safety endpoints included incidence of adverse events (AE), AEs leading to discontinuation, SAEs, deaths, and laboratory abnormalities. The efficacy endpoints included overall responses, duration of response, and time to response. Responses were assessed using the IMWG criteria.
Results:
Forty-six patients were enrolled (median age, 60 years; range, 53-67). The median number of prior therapies was 3 (range, 1-11), with 70.0% of patients having received ≥ 3 lines of treatment. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events of any grade were neutropenia (13 patients, 43.3%), diarrhea (10 patients, 33.3%), thrombocytopenia (10 patients, 33.3%), and fatigue (7 patients, 23.3%) in Arm A; and thrombocytopenia (6 patients, 37.5%), fatigue (4 patients, 25.0%) and anemia (4 patients, 25.0%) in Arm B. The overall response rate (≥ partial response) for all subjects in escalation and expansion was 44.4% (20/45). The median time to response was 1.5 months (range 0.4-7.8 months) for Arm A and 1.0 month (range 0.5-3.7 months) for Arm B, respectively. Of note, the combination of Ulocuplumab with Len-Dex showed a high response rate of 55.2% and a clinical benefit rate ( ≥ minimal response) of 72.4%, including patients who have been previously treated with lenalidomide.
Conclusion:
This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and has an encouraging response rate of over 50% in the Len-Dex arm of patients with relapsed/refractory myeloma. The distinct mechanisms of action of this antibody, as well as its non- cross resistance with currently approved approaches, make it a new class of anti-myeloma drug that warrants further exploration and evaluation in future clinical trials.
Display omitted
Ghobrial:Takeda: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Consultancy; Takeda Millennium: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; C4 Therapeutics: Equity Ownership. Becker:GlycoMimetics: Research Funding.
Our aim was to analyze the joint association of parental characteristics and offspring obesity indicators with metabolic risk in adolescents. A cross-sectional study was carried out with 972 ...adolescents and their parents. We observed that overweight adolescents who have a normal weight mother show lower metabolic risk in comparison with their counterparts with overweight mothers. In conclusion, mother's weight status moderates the relationship between offspring' obesity indicators and metabolic risk in adolescents.
Background: CXCR4 is a chemokine receptor over-expressed on > 75% of cancers, including malignant plasma cells. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 ...antibody which inhibits the binding of CXCR4 to CXCL12. Ulocuplumab induces apoptosis of CXCR4+ multiple myeloma cell lines and has single agent activity in vivo in MM tumor xenograft models. It is thus hypothesized that Ulocuplumab may improve the overall response rate to standard therapy in relapsed-refractory multiple myeloma (rel/ref MM) by distinct mechanisms of action, i.e., mobilization and apoptosis of malignant plasma cells and immune regulation.
Objective:This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus low-dose dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with rel/ref MM.
Methods: Ulocuplumab (i.e., 1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex orBor-Dex to identify MTD. For Cycle 1, Ulocuplumab was administered as monotherapy on Days 1 and 8. Starting on Day 15, Ulocuplumab was administered in combination with lenalidomide 25 mg/d/21 days of a 28 day cycle plus low dose dexamethasone 40 mg/week and monitored for incidence of DLT(s) within Cycle 1 (42 Days) of study treatment. For the Bor-Dex group, also starting on Day 15, Ulocuplumab was administered in combination with bortezomib (1.3 mg/m2Days 1, 4, 8, 11 of a 21 day cycle plus dexamethasone days 1,2,4,5,8,9,11,12 and monitored for incidence of DLT(s) within Cycle 1 (35 Days) of study treatment. For the expansion phase, subjects received 10mg/kg Ulocuplumab monotherapy on Days 1 and 8 followed by weekly doses in combination with Len-Dex (28-day cycles). Subjects were assessed at day 14 and after every cycle by IMWG criteria.
Results: Forty four subjects were evaluated (median age, 59.5 yrs; range, 44-77). The median number of prior therapies was 4, (range, 1-9), with 76% of subjects having received ≥ 3. Subjects had received bortezomib in 93% of the cases, lenalidomide in 86% , thalidomide in 30%, carfilzomib in 20% and pomalidomide in 11%. Thirty subjects in escalation received Ulocuplumab alone and in combination with Len-Dex : One subject in the U-Bor-Dex group experienced a DLT in which there was delayed platelet recovery to ≤ Grade 1 or baseline which resulted in a delay of dosing of ≥ 21 days. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD in monotherapy or in combination therapy. Twenty one subjects were treated in expansion phase. There were no grade 4 toxicities with Ulocuplumab monotherapy and Grade 3 toxicities with monotherapy included thrombocytopenia (6.5%), anemia (4.3%), respiratory infections (4.3%), femur fracture (4.3%), lymphopenia (2.2%), neutrophil count decreased (2.2%), platelet count decreased (2.2%) and cerebrovascular accident (2.2%). The safety profile of Ulocuplumab with Len-Dex or Bor-Dex was similar to either combination alone. Two subjects (4.5%) presented reversible G2 infusion reactions. The overall response rate (≥ PR) for all subjects in escalation and expansion was 50% (22/44), including 1 CR, 6 VGPR and 15 PR. The ORR by group was 55.1 % (16/29) and 40% (6/15) for U-Len-Dex and U-Bor-Dex, respectively. Furthermore, the ORR in expansion with 10 mg/kg U-Len-Dex was 57% (12/21) with 4 VGPRs and 8 PRs. Eight subjects in this expansion group had at least SD with a mean duration of 159 days (range, 46-437 days), resulting in 95% of subjects with clinical benefit. A median 2-fold mobilization of leukocytes into the peripheral circulation was reported after each infusion of Ulocuplumab at 3 and 10 mg/kg. Samples showed rapid mobilization of leukocytes at 2 hours post-Ulocuplumab with a partial decrease at 3-4 days post-administration without reaching baseline. Mobilization of plasma cells was also documented in some subjects.
Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and shows a high response rate of over 50% in the Len-dex arm of patients with relapsed/refractory myeloma who have been previously treated with lenalidomide and bortezomib. The distinct mechanisms of action of this antibody make it a new class of anti-myeloma drug that deserves further exploration in clinical trials.
Ghobrial:Onyx: Advisory board Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Plerixafor is not FDA approved for relapsed myeloma. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy. Sabbatini:Bristol-Myers Squibb: Employment. Dilea:Bristol-Myers Squibb: Employment. Cardarelli:BMS: Employment. Wade:Bristol-Myers Squibb: Employment. Xing:Bristol-Myers Squibb: Employment. Gutierrez:Bristol-Myers Squibb: Employment. Cohen:BMS: Employment.
Novel 2-phenyl-oxazole-4-carboxamide-containing apoptosis inducers were discovered from a cell-based assay for caspase-3 activation. Synthesis, in vitro, and in vivo activity profiles are reported.
...As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure–activity relationships of this class of molecules were explored. Compound
1k, with EC
50 of 270
nM and GI
50 of 229
nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound
1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50
mpk, bid.
Denaturation of rabbit skeletal-muscle AMP deaminase in acidic medium followed by chromatography on DEAE-cellulose in 8 M urea atpH 8.0 allows separation of two main peptide components of similar ...apparent molecular mass (75-80 kDa) that we tentatively assume correspond to two different enzyme subunits. Whereas the amino acid composition of one of the two peptides is in good agreement with that derived from the nucleotide sequence of the known rat and human AMPD1 cDNAs, the second component shows much higher contents of proline, glycine and histidine. N-Terminal sequence analysis of the fragments liberated by limited proteolysis with trypsin of the novel peptide reveals a striking similarity to the fragments produced by plasmin cleavage of the rabbit plasma protein called histidine-proline-rich glycoprotein (HPRG). However, some divergence is observed between the sequence of one of the fragments liberated from AMP deaminase by a more extensive trypsinization and rabbit plasma HPRG in the region containing residues 472-477. A fragment with a blocked N-terminus, which was found among those liberated by proteolysis with pepsin of either whole AMP deaminase or the novel component of the enzyme, shows an amino acid composition quite different from that of the N-terminus of the known subunit of AMP deaminase. By coupling this observation with the detection in freshly prepared AMP deaminase of a low yield of the sequence (LTPTDX) corresponding to that of HPRG N-terminus, it can be deduced that in comparison with HPRG, the putative HPRG-like component of AMP deaminase contains an additional fragment with a blocked N-terminus, which is liberated by a proteolytic process during purification of the enzyme. The implications of the association to rabbit skeletal-muscle AMP deaminase of a HPRG-like protein species are discussed.
PDF
