The bone is a metabolically active organ which undergoes repeated remodeling cycles of bone resorption and formation. In this study, we revealed a robust and extremely long-lasting circadian rhythm ...in ex vivo culture maintained for over six months from the femoral bone of a PERIOD2(Luciferase) mouse. Furthermore, we also identified robust circadian clocks in flat bones. High- or low-magnification real-time bioluminescence microscopic imaging revealed that the robust circadian rhythms emanated from the articular cartilage and the epiphyseal cartilage within the growth plate of juvenile animals. Stimulation by forskolin or dexamethasone treatment caused type 0 phase resetting, indicating canonical entraining properties of the bone clock. Together, our findings from long-term ex vivo culture revealed that "tissue-autonomous" circadian rhythm in the articular cartilage and the growth plate of femoral bone functions for several months even in an organ culture condition, and provided a useful in vitro assay system investigating the role of the biological clock in bone formation or development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuroendocrine carcinoma (NEC) is a rare subtype of malignant gallbladder tumor. Although surgical resection is the only potentially curative therapy for gallbladder NEC, most cases are surgically ...unresectable because of advanced stage disease and/or biologically aggressive behavior. The standard palliative treatment for malignant gallbladder tumors is chemotherapy; however, the efficacy of chemoradiotherapy in the treatment of gallbladder tumors is controversial. Here, we report a case of gallbladder NEC that showed a durable response to chemoradiotherapy. A 68-year-old Japanese man presented with a huge gallbladder tumor with liver and duodenal invasion. Pathological findings revealed poorly differentiated NEC of the gallbladder. After seven cycles of chemotherapy comprising cisplatin and irinotecan, computed tomography (CT) revealed remarkable tumor shrinkage, but an enlarged portal lymph node. The patient was treated with 50.4 Gy in 28 fractions with two cycles of cisplatin and etoposide. After chemoradiotherapy, the enlarged lymph node also decreased in size. Maximum standardized uptake value of fluorodeoxyglucose-positron emission tomography/CT(FDG-PET/CT) changed from 8.2 to physiological accumulation. We defined this condition as a complete response on both enhanced CT and FDG-PET/CT; therefore, we did not perform systemic treatment and only observed his condition. This patient remained healthy with no recurrence at 3 years after chemoradiotherapy.
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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
Introduction: In diffuse idiopathic skeletal hyperostosis (DISH), fracture of the continuous ankylosing vertebral body might cause severe stress on the damaged vertebral body. In addition, screws ...placed in traditional trajectories might become loose or back out to severe vertebral bone fragility caused by stress shielding. Therefore, introduction of a penetrating endplate screw (PES), which improves the insertion torque by penetrating the cranial vertebral endplate of the screw-inserted vertebra, is increasingly being performed instead of the traditional trajectory screw (TTS) for spinal injury in DISH. The aim of this study was to evaluate surgical outcomes using the PES method for thoracolumbar injury in DISH.Method: From April 2014 to March 2018, we treated patients with DISH thoracolumbar injury with either percutaneous pedicle screw insertion using the PES method (PES method group, including PES alone or PES combined with TTS) or the TTS alone method (TTS group). We investigated the characteristics of patients, cases of reoperation due to implant failure and screw loosening in both groups. The results were expressed as mean±standard deviation and were statistically analyzed using Wilcoxon's rank sum test, chi-square test and Fisher's exact test.Results: The study included 21 patients, 9 in the PES group (1 male and 8 females) and 12 in the TTS group (3 males and 9 females). Mean patient age in the two groups was 80±7 years and 79±7 years (p = 0.72), respectively, and mean body weight was 51±10 kg and 63±19 kg (p = 0.19), respectively. YAM values in the PES and TTS groups were 72±11% and 71±14% (p = 0.97), respectively. The number of ankylosing vertebral bodies extending cranially and caudally from the fractured vertebrae was 11±3 vertebral bodies and 11±2 vertebral bodies (p = 0.97), respectively. One patient in the TTS group underwent reoperation due to implant failure, with no such cases in the PES group (p = 0.57). Loosening of screws occurred in 22% (2/9 cases) of patients in the PES group, and 50% (6/12 cases) of patients in the TTS group (p = 0.20). The number of loosened screws was 5/85 (6%) in the PES group, 2/13 (15%) of the TTS in PES group patients who also received TTS, and 20/140 (14%) in the TTS group (p = 0.12).Conclusion: Compared to the TTS method, the PES method showed less tendency for screw loosening and no reoperations due to implant failure. The PES method with penetration of cortical bone might be useful in the management of thoracolumbar spine injury in elderly DISH patients with severe bone fragility.
Background and purpose - The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a ...transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur.
Patients and methods - Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression.
Results - Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage.
Interpretation - In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair.
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DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background:
Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change ...their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events.
Case presentation:
A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration.
Conclusion:
The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.
Cartilage tissues possess intrinsic circadian oscillators, which influence chondrocyte function and chondrocyte specific gene expression. However, it is not fully understood how chondrogenesis ...influences the circadian clock, and vice versa. Thus, we established ATDC5 cells which were stably transfected with the Bmal1:luc reporter and revealed robust circadian rhythms in ATDC5 cells during differentiation. Moreover, the circadian clock in ATDC5 cells was strongly reset by PTH in a circadian time-dependent manner. This assay system is expected to be useful for investigating the role of the circadian clock in chondrogenic differentiation and the precise molecular mechanisms underlying PTH action on the chondrocyte circadian clock.
To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese ...patients with rheumatoid arthritis (RA).
In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months.
Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo.
Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction.
JapicCTI-101263.
Denosumab, a human monoclonal antibody against RANK ligand, is shown to have strong anti-fracture effects in Japanese osteoporosis patients. However, there have been no data showing actions on ...Japanese bone architecture. Here we show that denosumab continuously improves several geometrical parameters calculated by hip structural analysis for 3 years. Compared to placebo, denosumab significantly increased bone mineral density, cortical thickness and cross sectional area in all of the three analyzed areas: the narrow neck, intertrochanter and femoral shaft. The subsequent derived mechanical parameters, cross-sectional moment of inertia, section modulus and buckling ratio, were also improved by denosumab. In addition, the improvement of these parameters was also observed in the patients that had switched from placebo to denosumab treatment. The present study suggests the structural evidence explaining the strong anti-fracture efficacy of denosumab and its significant effects on cortical bone in Japanese.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid ...arthritis (RA).
This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.
In total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.
Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.
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