Regeneration of Bone- and Tendon/Ligament-Like Tissues Induced by Gene Transfer of Bone Morphogenetic Protein-12 in a Rat Bone Defect

Members of the bone morphogenetic protein (BMP) family have diverse physiological roles. For instance, BMP-2 stimulates osteogenesis, while BMP-12 induces the formation of tendon/ligament-like tissues. Here, we designed a study to determine whether BMP-12 has bone and/or cartilage regeneration abilities similar to those of BMP-2. We implanted plasmid vectors encoding either BMP-2 or BMP-12 in rats with femur defects, and monitored the bone healing process for 8-weeks. The BMP-12 transgene induced prominent fibrogenesis by 2 weeks, with bone substitution occurring by 8 weeks. BMP-2, however, was associated predominantly with osteogenesis throughout the 8 week period. Thus, we conclude that BMP-12 does not function similarly to BMP-2 during bone healing. Further work is needed to better understand the mechanisms by which it stimulates bony growths to replace the connective tissues formed during the first stages of bone healing

Case report: Pathological complete response of pregnancy associated pulmonary enteric adenocarcinoma to chemoradiotherapy

Pulmonary enteric adenocarcinoma (PEAC) is a rare lung adenocarcinoma with morphological features similar to those of primary and metastatic colorectal adenocarcinoma. To date, only a few studies have reported the therapeutic effects of chemoradiotherapy on PEAC. This report describes the case of a 28-year-old woman with pregnancy-related PEAC who presented with left shoulder pain. A superior sulcus tumor was identified in the left thoracic cavity, and the biopsy indicated more than 50% intestinal differentiation components. Moreover, immunohistochemical staining revealed positive CDX2 and CK7 expression. Positron emission tomography-computed tomography, upper endoscopy, colonoscopy, and small intestinal capsule endoscopy revealed no gastrointestinal malignancies. The patient was diagnosed with locally advanced PEAC (clinical stage T4N0M0; stage IIIA). Therefore, the patient was treated with preoperative chemoradiotherapy and underwent gross total resection during surgery. Pathological evaluation of the specimen revealed no residual tumor, indicating that the chemoradiotherapy for PEAC was highly effective. One subsequent brain metastasis was also resected, and the patient has not experienced recurrence in 28 months since this resection and continues to be monitored regularly. This is the first pathologically confirmed report of the use of chemoradiotherapy (carboplatin [CBDCA] and paclitaxel [PTX]) for PEAC and its clinical efficacy. Unlike previous reports, the efficacy of this treatment is attributed to the use of PTX in preoperative chemotherapy and the p21− status of the patient, which may have increased sensitivity to chemoradiation therapy. Therefore, chemoradiotherapy (CBDCA + PTX) may be a viable treatment option for advanced intestinal lung adenocarcinoma

Discontinuation of methotrexate in rheumatoid arthritis patients achieving clinical remission by treatment with upadacitinib plus methotrexate (DOPPLER study)

Background: The administration of Janus kinase inhibitors as well as biological disease-modifying anti-rheumatic drugs has dramatically improved the clinical outcomes of patients with rheumatoid arthritis (RA). Previous trials have shown that upadacitinib, a Janus kinase inhibitor, can effectively improve disease activity and prevent progression of joint destruction in RA patients with inadequate responses to methotrexate (MTX). It remains unclear whether reduced disease activity can be maintained after discontinuation of MTX in patients treated with upadacitinib plus MTX. Thus, the aim of this study is to evaluate changes in disease activity after administration of upadacitinib plus MTX in RA patients who failed to achieve an adequate response to MTX and to determine whether clinical relapse can be avoided after discontinuation of MTX in those who achieved clinical remission.Methods/design: The proposed study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. The cohort will include 155 RA patients with at least moderate disease activity during treatment with MTX. Patients will receive upadacitinib and MTX will be discontinued for those who achieve clinical remission. Disease activity will be evaluated longitudinally by measuring clinical disease activity indices and with musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who sustain a disease activity score-28- C reactive protein score of ≤3.2 from week 24 to 48 after a disease activity score-28- C reactive protein score of <2.6 at week 24. Important secondary endpoints are changes from baseline MSUS scores. Serum levels of multiple biomarkers, including cytokines and chemokines, will be comprehensively analyzed.Discussion: The study results are expected to show the clinical benefit of the discontinuation of MTX after achieving clinical remission by treatment with upadacitinib plus MTX combination therapy. The strength of this study is the prospective evaluation of therapeutic efficacy using clinical disease activity indices and standardized MSUS, which can accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers. Furthermore, parameters to predict clinical remission after administration of upadacitinib plus MTX combination therapy and nonclinical relapse after discontinuation of MTX will be screened by integrated multilateral assessments (i.e., clinical disease activity indices, MSUS findings, and serum biomarkers)

Efficacy and safety of selective JAK 1 inhibitor filgotinib in active rheumatoid arthritis patients with inadequate response to methotrexate: comparative study with filgotinib and tocilizumab examined by clinical index as well as musculoskeletal ultrasound assessment (TRANSFORM study): study protocol for a randomized, open-label, parallel-group, multicenter, and non-inferiority clinical trial

Background:Administration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX.Methods:This study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines.Discussion:The study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments—clinical disease activity indices, MSUS findings, and serum biomarkers

Flame-retardant thermoplastics derived from plant cell wall polymers by single ionic liquid substitution

金沢大学理工研究域生命理工学系Three components of plant cell walls—cellulose, hemicellulose and lignin—were converted into flame-retardant thermoplastics by adducting only a single ionic liquid species via covalent bonds. They showed thermoplasticity and formed thin films by hot pressing. They also showed flame retardancy and self-extinguished the fire during burning. The properties of the samples depend on the cation species of ionic liquids adducted and thus are controllable. In the present study, more than 66% of the hydroxyl groups present on the polymers were maintained after derivatisation; they thus have the potential for further functionalisation for moulding, practical use and so on, in addition to flame retardancy and thermoplasticity.Embargo Period 12 monthsThis paper has supplementary information

Regenerative Effects of Mesenchymal Stem Cells: Contribution of Muse Cells, a Novel Pluripotent Stem Cell Type that Resides in Mesenchymal Cells

Mesenchymal stem cells (MSCs) are easily accessible and safe for regenerative medicine. MSCs exert trophic, immunomodulatory, anti-apoptotic, and tissue regeneration effects in a variety of tissues and organs, but their entity remains an enigma. Because MSCs are generally harvested from mesenchymal tissues, such as bone marrow, adipose tissue, or umbilical cord as adherent cells, MSCs comprise crude cell populations and are heterogeneous. The specific cells responsible for each effect have not been clarified. The most interesting property of MSCs is that, despite being adult stem cells that belong to the mesenchymal tissue lineage, they are able to differentiate into a broad spectrum of cells beyond the boundary of mesodermal lineage cells into ectodermal or endodermal lineages, and repair tissues. The broad spectrum of differentiation ability and tissue-repairing effects of MSCs might be mediated in part by the presence of a novel pluripotent stem cell type recently found in adult human mesenchymal tissues, termed multilineage-differentiating stress enduring (Muse) cells. Here we review recently updated studies of the regenerative effects of MSCs and discuss their potential in regenerative medicine