ABSTRACT
Objectives
To investigate the 2 year safety and effectiveness of denosumab 60 mg in patients with rheumatoid arthritis (RA) in clinical practice in Japan.
Methods
This 2 year, prospective, ...observational cohort study included patients who initiated treatment with denosumab 60 mg for the progression of bone erosion associated with RA. Key endpoints were adverse drug reactions (ADRs), progression of bone erosion, and 28-joint Disease Activity Score based on C-reactive protein or erythrocyte sedimentation rate. Univariate and multivariate analyses were conducted to determine the risk factors for ADRs and the progression of bone erosion.
Results
In the safety analysis set (n = 1239), the incidence of ADRs was 3.0%; the most common ADRs were hypocalcaemia (1.2%) and osteonecrosis of jaw-related events (0.6%). A history of any drug allergy was a statistically significant risk factor associated with the occurrence of ADRs. In the effectiveness analysis set (n = 815), the incidence of progression of bone erosion was 8.7%. Steinbrocker stage and initial steroid dose were statistically significant risk factors associated with the progression of bone erosion.
Conclusion
Denosumab demonstrated safety and effectiveness over a 2 year period in RA patients without any new safety concerns.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
This pre-specified exploratory analysis investigated the effect of denosumab on bone mineral density (BMD) and bone microarchitecture in patients with rheumatoid arthritis (RA) treated ...with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).
Materials and methods
In this open-label, parallel-group study, patients were randomly assigned (1:1) to continuous treatment with csDMARDs plus denosumab or continuous treatment with csDMARD therapy alone for 12 months. BMD and bone microarchitecture were measured by dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT).
Results
Of 46 patients enrolled in the primary study, 43 were included in the full analysis set. The mean age was 65.3 years, 88.4% were female, and 60.5% had osteoporosis. Areal BMD of the lumbar spine increased from baseline to 6 and 12 months in both groups, but the increase was higher in the csDMARDs plus denosumab group. Areal BMD of the total hip and femoral neck increased from baseline to 6 and 12 months only in the csDMARDs plus denosumab group. Cortical volumetric BMD and cortical thickness of the distal tibia increased in the csDMARDs plus denosumab group at 6 and 12 months but decreased in the csDMARD therapy alone group. Trabecular bone parameters of the distal tibia improved only in the csDMARDs plus denosumab group at 12 months.
Conclusion
Denosumab may be recommended for patients with RA treated with csDMARDs to increase BMD and improve bone microarchitecture.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hormone therapy with aromatase inhibitors (AIs) for estrogen receptor-dependent breast cancer may expose patients to an increased osteoporosis risk. This study was performed to estimate fracture risk ...in women with breast cancer to whom AIs were prescribed in Japan.
This retrospective study used data from the Japanese Medical Data Vision database. Women with breast cancer prescribed AIs over a 12-month period were identified and matched to women not prescribed AIs using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared using a cause-specific Cox hazard model. The proportion of women undergoing bone density tests was retrieved.
For all fractures sites combined, cumulative fracture incidence at 10 years was 0.19 95%CI: 0.16-0.22 in women prescribed AIs and 0.18 95%CI: 0.15-0.21 without AIs. AI prescription was not associated with any changes in risk (adjusted hazard ratio: 1.08 95%CI: 0.99-1.17
= 0.08). Women prescribed AI more frequently underwent bone density testing (31.9% 95% CI: 31.2%; 32.6% versus 2.2% 95% CI: 2.0%; 2.4%).
The anticipated association between AI exposure and osteoporotic fracture risk in Japanese women with breast cancer was not seen clearly.
INTRODUCTIONThe incidence of the fragility fractures of the pelvis (FFPs) has been increasing in recent years. Operative treatment is effective in patients who are unable to ambulate due to pain. ...Anterior subcutaneous internal fixation (ASIF) is a minimally invasive and stable fixation used to treat the FFPs, with few reported vascular complications. However, we experienced a case in which the rod directly pressed the common femoral artery (CFA). OBJECTIVESThe purpose of this study was to examine the relationship between the rod position as defined by ASIF and the CFA in the FFPs patients, and between BMI and the rod-to-CFA distance. MATERIALS AND METHODSPelvic measurements were performed in 47 patients with FFPs using trauma CT. We identified the anterior inferior iliac spine (AIIS) on both sides in axial CT images. Next, we performed a simulation study using the CT images, in which the virtual fixation rod was bent according to the shape of the patients' abdomen in the supine position. The shortest rod-to-CFA distance when the virtual rod was positioned directly above the AIIS in the CT image was measured. The correlation between body mass index (BMI) and the rod-to-CFA distance was measured. RESULTSThe average shortest rod-to-CFA distance was 18.4 ± 11.1 mm, and the simulated rod compressed the CFA in three of the 47 cases (6.4%). A statistically significant positive correlation between BMI and the rod-to-CFA distance was found (r = 0.47, p = 0.001). CONCLUSIONSThe course of the CFA should be confirmed before ASIF surgery, and if there is danger of compression of the CFA such as in patients with low BMI, the rod-to-AIIS distance should be adjusted to the optimal distance. However, considering the disadvantages, such as decreased stability of the fixation, when adjusting the rod-to-AIIS distance, and skin irritation and abrasion by the rod, ASIF is not recommended in cases in which the rod is close to the CFA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription ...factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.
We constructed a reporter cell line with FoxO1 promoter sequences and performed high-throughput screening (HTS) of the Repurposing, Focused Rescue and Accelerated Medchem (ReFRAME) library . Hits from the HTS were validated and function was assessed in human chondrocytes, meniscus cells and synoviocytes and following administration to mice. The most promising hit, the histone deacetylase inhibitor (HDACI) panobinostat was tested in a murine OA model.
Among the top hits were HDACI and testing in human chondrocytes, meniscus cells and synoviocytes showed that panobinostat was the most promising compound as it increased the expression of autophagy genes and PRG4 while suppressing the basal and IL-1β induced expression of inflammatory mediators and extracellular matrix degrading enzymes. Intraperitoneal administration of panobinostat also suppressed the expression of mediators of OA pathogenesis induced by intra-articular injection of IL-1β. In a murine OA model, panobinostat reduced the severity of histological changes in cartilage, synovium and subchondral bone and improved pain behaviours.
Panobinostat has a clinically relevant activity profile and is a candidate for OA symptom and structure modification.
Abstract Background: Not all exosomes in the blood of cancer patients originate from cancer cells. This study evaluated the relationships between mRNAs and miRNAs in pancreatic cancer (PC) cell lines ...and those in exosomes secreted into the supernatant. We aimed to identify candidates for PC biomarkers from cancer-specific exosomal mRNAs and miRNAs. Materials and Methods: Three PC cell lines were utilized. Exosomes were isolated from the supernatant, and cellular and exosomal mRNAs and miRNAs were extracted. Subsequently, RNA sequencing (RNA-seq) was performed, and the data were analyzed using R software. Results: In the MIAPaCa-2 cell line, the expression of cellular mRNAs and corresponding exosomal mRNAs showed a strong correlation. In the other two cell lines, a moderate correlation was observed. Across all three cell lines, cellular miRNAs and corresponding exosomal miRNAs exhibited moderate correlation. We focused on RNAs that were lowly expressed in cells but highly expressed in exosomes and conducted differential expression analysis using R. Compared with healthy volunteers in the GEO database, some RNAs showed high expression in the supernatant and low expression in the plasma of healthy volunteers. Conclusion: We identified three mRNAs and three miRNAs that may serve as promising biomarker candidates for PC. Citation Format: Yuhan Rong, Naoki Okubo, Noritoshi Kobayashi, Eriko Katsuta, Yasushi Ichikawa. Identification of highly expressed exosomal RNAs derived from pancreatic cancer cell lines and exploration of their potential as biomarkers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2431.
The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBα and REV-ERBβ are involved in the cell-autonomous circadian ...transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erbα/Rev-erbβ double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout of both Rev-erbα and Rev-erbβ does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBα/β deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abnormal chondrocyte gene expression promotes osteoarthritis (OA) pathogenesis. A previous RNA-sequencing study revealed that circadian rhythm pathway and expression of core clock gene cryptochrome 2 ...(CRY2) are dysregulated in human OA cartilage. Here we determined expression patterns and function CRY1 and CRY2.
CRY mRNA and protein expression was analyzed in normal and OA human and mouse cartilage. Mice with deletion of Cry1 or Cry2 were analyzed for severity of experimental OA and to determine genes and pathways that are regulated by Cry.
In human OA cartilage, CRY2 but not CRY1 staining and mRNA expression was significantly decreased. Cry2 was also suppressed in mice with aging-related OA. Cry2 knock out (KO) but not Cry1 KO mice with experimental OA showed significantly increased severity of histopathological changes in cartilage, subchondral bone and synovium. In OA chondrocytes, the levels of CRY1 and CRY2 and the amplitude of circadian fluctuation were significantly lower. RNA-seq on knee articular cartilage of wild-type and Cry2 KO mice identified 53 differentially expressed genes, including known Cry2 target circadian genes Nr1d1, Nr1d2, Dbp and Tef. Pathway analysis that circadian rhythm and extracellular matrix remodeling were dysregulated in Cry2 KO mice.
These results show an active role of the circadian clock in general, and of CRY2 in particular, in maintaining extracellular matrix (ECM) homeostasis in cartilage. This cell autonomous network of circadian rhythm genes is disrupted in OA chondrocytes. Targeting CRY2 has potential to correct abnormal gene expression patterns and reduce the severity of OA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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