The authors describe a region of human chromosome 8q24 involved in variant Burkitt's lymphoma translocations, and where an interstitial deletion occurs in an HTLV-I super(+) ATL and three myc) ...amplicons terminate.
To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite ...treatment with MTX.
This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (</=20 mg/week, median dosage 15 mg/week, range 5-20 mg/week) were enrolled and received 3 mg/day tacrolimus as a single oral dose once per day for 6 months while continuing to receive MTX at the existing stable dosage. All other disease-modifying antirheumatic drugs were discontinued; stable dosage of nonsteroidal antiinflammatory drugs and oral corticosteroids (</=10 mg/day prednisone or its equivalent) were allowed. All 80 patients received at least one dose of the study drug and were included in the primary safety and efficacy analyses. Seventy-five patients had at least one postbaseline efficacy assessment, and 63 patients (78.8%) completed the study. The primary clinical response criterion was the American College of Rheumatology definition of 20% improvement (ACR20) at the end of treatment.
Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (+/-SD) creatinine (Cr) level increased from 0.74 +/- 0.16 mg/dl at baseline to 0.81 +/- 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty-three patients (28.8%) had a >/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%).
In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.
Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular ...dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups.
To investigate outcomes after 30 months of open-label vamorolone treatment.
This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021.
Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d.
Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone.
Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean SD age, 5.33 0.96 years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 0.070 rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time.
This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD.
ClinicalTrials.gov Identifier: NCT03038399.
Ia antigens, encoded within the I region of the mouse major histocompatibility complex, control the ability of the organism to mount effective antigen-specific immune responses. The authors have ...isolated and determined the nucleotide sequences of cDNA and genomic clones for the I-E sub( beta ) super(s) gene and present the predicted protein sequence for most of the E sub( beta ) super(s) polypeptide chain. The E sub( beta ) super(s) polypeptide shows 95% protein homology to the other cloned E sub( beta ) alleles.
The Ia antigens, encoded within the I region of the major histocompatibility complex, are a group of cell surface glycoproteins that are involved in the control of immune responsiveness. The authors ...isolated and determined the sequence of a 1,045-base-pair cDNA clone for one of the murine immune response genes, E super(k)d beta . Comparison of the predicted amino acid sequence of the product of E super(k)d beta with that of E super(d)d beta shows that most of the amino acid differences are clustered in short stretches of peptide sequence in the first external protein domain. This clustering of allelic variation suggests that observed haplotype-specific immune responsiveness to certain antigens may be controlled, at least in part, by differences in configuration defined by these regions of allelic variability in the NH sub(2)-terminal domain of the E beta chain.
H-2u haplotype mice are unique among all E alpha+ strains because they do not provide in heterozygotes an E alpha chain that interacts with E betak,s,etc. sufficiently well to allow certain ...E-restricted immune responses. As a first step in understanding this peculiarity, we have sequenced E alpha u and E beta u cDNA and compared the derived amino acid sequences with those of previously analyzed alleles. Although no glaring structural abnormalities were found, we have identified some u-specific residues and suggest which are the most likely to provoke a pairing anomaly.
Cytogenetic abnormalities involving chromosome 14 band q32 are consistently observed in human T-cell tumors. Patients with ataxia-telangiectasia (AT) are especially prone to development of these ...tumors, which frequently carry either inversion inv(14)(q11;q32) or translocation t(14;14) (q11;q32) chromosomes. We have previously shown that the cytogenetic breakpoints of one t(14;14)(q11;q32) chromosome and two inv(14)(q11;q32) chromosomes in T-cell tumors from AT and non-AT patients join the T-cell receptor alpha chain locus, at chromosome band 14q11, with a region(s) at 14q32 centromeric of the immunoglobulin heavy chain variable region (VH) gene IGHV. We now show that these two inv(14) breakpoints are linked by 2.1 kb of germ-line 14q32 DNA and that the three breakpoints define, by in situ hybridization analysis, a single locus at chromosome band 14q32.1 located about 15-20 million base pairs on the centromeric side of the IGH locus. Sequence analysis of the 14q32.1 breakpoint regions indicates that abnormal recombination does not universally result from mistaken V-D-J joining (D = diversity region; J = joining region). Therefore, we invoke a tumor selection model to describe the role of the 14q32.1 locus in tumor development.
Objective
To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active ...despite treatment with MTX.
Methods
This was a multicenter open‐label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for ≥1 month with a stable, maximally tolerated dosage of oral MTX (≤20 mg/week, median dosage 15 mg/week, range 5–20 mg/week) were enrolled and received 3 mg/day tacrolimus as a single oral dose once per day for 6 months while continuing to receive MTX at the existing stable dosage. All other disease‐modifying antirheumatic drugs were discontinued; stable dosage of nonsteroidal antiinflammatory drugs and oral corticosteroids (≤10 mg/day prednisone or its equivalent) were allowed. All 80 patients received at least one dose of the study drug and were included in the primary safety and efficacy analyses. Seventy‐five patients had at least one postbaseline efficacy assessment, and 63 patients (78.8%) completed the study. The primary clinical response criterion was the American College of Rheumatology definition of 20% improvement (ACR20) at the end of treatment.
Results
Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (±SD) creatinine (Cr) level increased from 0.74 ± 0.16 mg/dl at baseline to 0.81 ± 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty‐three patients (28.8%) had a ≥30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6–63.4%).
Conclusion
In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well‐tolerated and provides clinical benefit.
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