Induction of Remission is Difficult due to Frequent Relapse during Tapering Steroids in Korean Patients with Polymyalgia Rheumatica

Polymyalgia rheumatica is an inflammatory disease affecting elderly and involving the shoulder and pelvic girdles. No epidemiological study of polymyalgia rheumatica was conducted in Korea. We retrospectively evaluated patients with polymyalgia rheumatica followed up at the rheumatology clinics of 10 tertiary hospitals. In total 51 patients, 36 patients (70.6%) were female. Age at disease onset was 67.4 yr. Twenty-three patients (45.1%) developed polymyalgia rheumatica in winter. Shoulder girdle ache was observed in 45 patients (90%) and elevated erythrocyte sedimentation rate (> 40 mm/h) in 49 patients (96.1%). Initial steroid dose was 23.3 mg/d prednisolone equivalent. Time to normal erythrocyte sedimentation rate was 4.1 months. Only 8 patients (15.7%) achieved remission. Among 41 patients followed up, 28 patients (68.3%) had flare at least once. Number of flares was 1.5 ± 1.6. The frequency of flare was significantly lower in patients with remission (P = 0.02). In Korea, polymyalgia rheumatica commonly develops during winter. Initial response to steroid is fairly good, but the prognosis is not benign because remission is rare with frequent relapse requiring long-term steroid treatment

CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis. © 2019, Park et al.1

Inorganic-Organic Hybrid Nanomaterials for Therapeutic and Diagnostic Imaging Applications

Nanotechnology offers outstanding potential for future biomedical applications. In particular, due to their unique characteristics, hybrid nanomaterials have recently been investigated as promising platforms for imaging and therapeutic applications. This class of nanoparticles can not only retain valuable features of both inorganic and organic moieties, but also provides the ability to systematically modify the properties of the hybrid material through the combination of functional elements. Moreover, the conjugation of targeting moieties on the surface of these nanomaterials gives them specific targeted imaging and therapeutic properties. In this review, we summarize the recent reports in the synthesis of hybrid nanomaterials and their applications in biomedical areas. Their applications as imaging and therapeutic agents in vivo will be highlighted

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

RUNX Family in Hypoxic Microenvironment and Angiogenesis in Cancers

The tumor microenvironment (TME) is broadly implicated in tumorigenesis, as tumor cells interact with surrounding cells to influence the development and progression of the tumor. Blood vessels are a major component of the TME and are attributed to the creation of a hypoxic microenvironment, which is a common feature of advanced cancers and inflamed premalignant tissues. Runt-related transcription factor (RUNX) proteins, a transcription factor family of developmental master regulators, are involved in vital cellular processes such as differentiation, proliferation, cell lineage specification, and apoptosis. Furthermore, the RUNX family is involved in the regulation of various oncogenic processes and signaling pathways as well as tumor suppressive functions, suggesting that the RUNX family plays a strategic role in tumorigenesis. In this review, we have discussed the relevant findings that describe the crosstalk of the RUNX family with the hypoxic TME and tumor angiogenesis or with their signaling molecules in cancer development and progression

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors