Lung cancer represents the leading cause of cancer-associated mortality, and non-small-cell lung cancer (NSCLC) is the most frequent histologic sub-type. It is therefore urgent to develop novel agents for the treatment of NSCLC. Fraxetin (FXT) is a potent plant-derived product and has been recognized as a promising anticancer agent for breast cancer and osteosarcoma. However, the anti-cancer potential of FXT for NSCLC remains to be elucidated. Accordingly, in the present study, we evaluated the inhibitory effect of FXT on the proliferation and growth of NSCLC cells using six human NSCLC cell lines: A549, H460, HCC827, H1650, PC-9 and H1975. FXT exhibited significant inhibitory effects on the proliferation of these cancer cell lines. By contrast, no inhibitory effect was observed on the viability of non-cancer lung cell lines even at the highest concentration of FXT (100 μM). Among the NSCLC cell lines, HCC827 and H1650 cells showed the most sensitive to FXT. Accordingly, HCC827 and H1650 cells were used for the subsequent experiments. Flow cytometric analysis revealed that FXT caused a significant cell cycle arrest and pro-apoptotic effects. Mechanistically, FXT suppressed the IL-6-induced phosphorylation of tyrosine residue (Tyr705) of signal transducer and activator of transcription 3 (STAT3) probably by binding to STAT3. Molecular docking and molecular dynamic simulations studies indicated that FXT interacts with STAT3 through hydrogen bond and hydrophobic interaction. In conclusion, these findings suggest that FXT could be a promising lead compound to be used as a novel STAT3 inhibitor and potential antitumor agent for the treatment of NSCLC.

Synovial fat deposition, also known as lipoma arborescens, is a rare articular disorder with villous synovial proliferation, commonly seen in the knee. We explored the relationship between the degree of synovial fat deposition on the magnetic resonance imaging (MRI) and the severity of degenerative joint disorder, also called osteoarthritis, on plain radiography. The enrolled patients underwent MRI with a 0.4T permanent magnetic unit in a single institution over a 9-month period. The indications of MRI were chronic knee disorder of non-specific cause. Patients with minor trauma were also included. Consecutive 1,091 knees of 1,075 patients were assessed for the degree of synovial fat deposition on MRI and the severity of degenerative joint disorder on plain radiography. The degenerative joint disorder was graded by radiographic features obtained within one month from MRI using Kellgrene-Lawrence (K-L) scores. MRI features of synovial fat deposition were classified as none, mild and severe. Synovial fat deposition was identified in 30 knees of 29 patients (2.7%) (11 men and 18 women; aged from 25 to 86 years, one patient with bilateral lesions): one female patient with osteoarthritis secondary to rheumatoid arthritis and 28 patients with degenerative joint disorder. The K-L grade was 4 in the case of rheumatoid arthritis. There was a moderate positive correlation between the K-L grade and fat deposition grade (correlation coefficient: 0.59, p < 0.001). Thus, synovial fat deposition was noted in the advanced degenerative joint disorder. We propose that fat deposition represents a nonspecific secondary phenomenon of degenerative joint disorder.

On March 11, 2011, the Great East Japan Earthquake and ensuing tsunami that hit the northeastern coastal region of Japan caused about 18,000 casualties and destroyed numerous buildings. Additionally, many medical facilities were damaged and patient medical records lost. In order to maintain patient clinical information, a prefectural medical network system, the Miyagi Medical and Welfare Information Network (MMWIN), began providing backup data storage services in 2013 for hospitals, clinics, pharmacies, and other care facilities as a precaution for upcoming disasters. This system also facilitates the sharing of clinical information trans-institutionally as long as patients provide consent for this. In the present study, we examined the development of the MMWIN and its efficiency during the 5 years from its launch, and identified general problems to maintain such a backup system. At the end of 2018, the system contained backup data from more than 11 million patients with more than 420 million data items; more than 900 facilities were MMWIN users, and the number of patients consenting to sharing their clinical information reached 90,000. The use of the system has become widespread and the accumulating data should be utilized for research in the future. Maintaining a balance between income and cost is critical to make this project independent from local government subsidies.

Medication-related osteonecrosis of the jaw (MRONJ) is a condition of exposed bone in the maxillofacial region, which occurs among subjects treated with antiresorptive agents or anti-angiogenesis drugs, despite the lack of a history of head or neck radiation treatment. Although there are still many points to be clarified about the mechanism of MRONJ, it is possible to hypothesize a common pathogenetic mechanism for two different classes of drugs: antiresorptive and anti-angiogenetic drugs. These drugs can inhibit angiogenesis by interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis. This hypothesis could be of immediate translational interest. Targeting the anti-angiogenetic effect of the antiresorptive agents could provide a new possibility for the prevention of treatment of MRONJ.

Aldosterone affects various systems and organs, including the cardiovascular system, through mineralocorticoid receptors. We here report a primary aldosteronism patient with severe cardiac dysfunction who showed dramatic improvement after laparoscopic adrenalectomy. The 57-year-old man presented with acute heart failure exacerbation. Performance status was 4, and New York Heart Association classification was 4. Echocardiography showed diffuse hypokinetic wall motion with an ejection fraction of 20%. The patient was found to have a high plasma level of brain natriuretic peptide (4,935 pg/mL), hypokalemia (2.7 mEq/L), an extremely elevated plasma aldosterone concentration (1,804 pg/mL), and high aldosterone-to-renin ratio [plasma aldosterone concentration (pg/mL)/plasma renin activity (ng/mL/hr)] (9,002). Computed tomography revealed a tumor 42 mm in diameter in the right adrenal gland. Primary aldosteronism was diagnosed with adrenal venous sampling. Medical treatment for heart failure was continued for several months, but the cardiac function was not sufficiently improved, suggesting the indication of heart transplantation. However, the patient could not be considered a candidate because of the adrenal tumor. Laparoscopic adrenalectomy was therefore performed. Immediately after surgery, echocardiography showed improved wall motion with an ejection fraction of 36%. Performance status and New York Heart Association classification were improved to 0 and 2, respectively. The present case has shown the efficacy of laparoscopic adrenalectomy for primary aldosteronism patients with severe heart failure.

The antibodies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have provided survival benefits in patients with advanced malignant melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab are considered superior to the anti-CTLA-4 antibody ipilimumab as first-line therapy, suggesting that ipilimumab should be administered to patients with anti-PD-1 antibody-refractory melanoma in the second-line setting. However, there is limited evidence regarding the efficacy and safety of ipilimumab after disease progression on anti-PD-1 antibody therapy. Moreover, in patients with mucosal melanoma, a rare and aggressive subtype, evidence is extremely poor. This study aimed to clarify the efficacy and safety of ipilimumab among Japanese patients with nivolumab-refractory advanced mucosal melanoma. We retrospectively analyzed the seven patients with advanced mucosal melanoma who were treated with ipilimumab after disease progression on nivolumab at our hospital between September 2015 and December 2017. No patient achieved complete response or partial response to ipilimumab therapy. However, six patients achieved stable disease, and of these patients, three achieved a decline in the tumor size. All the three patients with a decline in tumor size developed grade 3 toxicity: two patients developed colitis and one patient experienced alanine aminotransferase elevation. The median progression-free survival (PFS) for prior nivolumab therapy was 148 days. The median PFS for ipilimumab therapy after disease progression with nivolumab was 193 days. The median overall survival was 661 days. In conclusion, although even partial response was undetectable with ipilimumab therapy, ipilimumab could produce additional PFS among nivolumab-refractory advanced mucosal melanoma patients.

The Tohoku Medical Megabank biobank (TMM biobank) is the first major population-based biobank established in Japan. The TMM biobank was established based on two population cohorts and is a reconstruction program from the Great East Japan Earthquake and Tsunami of 2011. The biobank stores more than 3.4 million tubes of biospecimens and associated health and analytic data obtained from approximately 150,000 TMM cohort participants between May 2013 and December 2018, and the TMM biobank currently shares high-quality specimens and data. Various biospecimens, including peripheral and cord blood mononuclear cells, buffy coat, plasma, serum, urine, breast milk and saliva have been collected in the TMM biobank. To minimize human error and maintain the quality of data and specimens, we have been utilizing laboratory information management system into various biobank procedures from registration to storage with various automation systems, such as liquid dispensing, DNA extraction and their storage. The biobank procedures for the quality management system (ISO 9001:2015) and information security management system (ISO 27001:2013) are certified by the International Organization for Standardization. The quality of our biobank samples fulfills the pre-analytical requirements for researchers conducting next-generation whole genome sequencing, DNA array analyses, proteomics, metabolomics, etc. We established analytical centers to conduct standard genomic and multiomic analyses in-house and share the generated data. Additionally, we generate thousands of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and proliferating T cells for functional studies. The TMM biobank serves as an indispensable infrastructure for academic, clinical and industrial research to actualize next-generation medicine in Japan.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Although the etiology of ICP is not fully understood thus far, some genetic factors might contribute to the development of this condition. Sodium-taurocholate cotransporting polypeptide (NTCP), the protein encoded by the gene Solute Carrier Family 10, Member 1 (SLC10A1), is the primary transporter expressed in the basolateral membrane of the hepatocyte to uptake conjugated bile salts from the plasma. NTCP deficiency arises from biallelic SLC10A1 mutations which impair the NTCP function and cause intractably elevated levels of total bile acids (TBA) in the plasma (hypercholanemia). In this study, all the SLC10A1 exons and their flanking sequences were analyzed by Sanger sequencing to investigate the etiology for hypercholanemia in two male infants aged 2 and 20 months, respectively, from two unrelated families. As a result, both patients are homozygous for the reported pathogenic variant c.800C>T (p.Ser267Phe) that could impair the NTCP function to uptake bile acids, and the diagnosis of NTCP deficiency was thus made. Their mothers are also homozygotes of the same variant and both had been diagnosed to have ICP in the third trimester, with one of them undergoing cesarean section. The father of the first patient in this paper has the same SLC10A1 genotype c.800C>T/c.800C>T, also exhibiting slight hypercholanemia with a plasma TBA level of 21.5 μmol/L. In conclusion, we suggest that with hypercholanemia being a common laboratory change, NTCP deficiency may be a genetic factor leading to ICP and even cesarean section in clinical practice.