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Figure S1 to S17

Table S1 to S9

Activating mutations in mitogen-activated protein kinase kinase 1 (MAP2K1) are involved in a variety of cancers and may be classified according to their RAF dependence. Sensitivity to combined BRAF and MEK treatments is associated with co-mutations of MAP2K1 and BRAF; however, the significance of less frequent MAP2K1 mutations is largely unknown. The transforming potential and drug sensitivity of 100 MAP2K1 variants were evaluated using individual assays and the mixed-all-nominated-in-one method. In addition, A375, a melanoma cell line harboring the BRAF V600E mutation, was used to evaluate the function of the MAP2K1 variants in combination with active RAF signaling. Among a total of 67 variants of unknown significance, 16 were evaluated as oncogenic or likely oncogenic. The drug sensitivity of the individual variants did not vary with respect to BRAF inhibitors, MEK inhibitors (MEKi), or their combination. Sensitivity to BRAF inhibitors was associated with the RAF dependency of the MAP2K1 variants, whereas resistance was higher in RAF-regulated or independent variants compared with RAF-dependent variants. Thus, the synergistic effect of BRAF and MEKis may be observed in RAF-regulated and RAF-dependent variants. MAP2K1 variants exhibit differential sensitivity to BRAF and MEKis, suggesting the importance of individual functional analysis for the selection of optimal treatments for each patient. This comprehensive evaluation reveals precise functional information and provides optimal combination treatment for individual MAP2K1 variants.

Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.

The development of tyrosine kinase inhibitors (TKIs) has improved the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current research priority is to provide viable treatments for patients who have drug-resistant EGFR mutations. We evaluated the drug sensitivity of various EGFR mutants to monotherapies and combination therapies of EGFR-TKIs. In vitro, the transforming potential and drug sensitivity of 357 EGFR variants were assessed. In vivo, we tested the sensitivity of EGFR variants to different regimens of EGFR-TKIs by examining changes in the proportion of each variant within the tumor. Out of 357 variants thoroughly examined for transforming activities, 144 (40.3%) and 282 (79.0%) transformed 3T3 and Ba/F3 cells, respectively. Among the latter variants, 50 (17.7%) were found to be resistant or only partly resistant to osimertinib or afatinib. Four of 25 afatinib-resistant variants (16%) were sensitive to osimertinib, whereas 25 of 46 osimertinib-resistant variants (54.3%) were sensitive to afatinib. Despite the lack of a synergistic impact, TKI combination treatment effectively reduced in vivo the heterogeneous tumors composed of 3T3 cells with different EGFR variants. Regimens starting with afatinib and subsequently switched to osimertinib suppressed tumor development more efficiently than the opposite combination. Combination EGFR-TKI treatment may decrease tumor growth and prevent the development of resistant variants. This work created an experimental model of a heterogeneous tumor to find the best combination therapy regimen and proposes a basic notion of EGFR-TKI combination therapy to enhance the prognosis of NSCLC patients.

A 30-year-old man presented with constipation and abdominal pain. He was suspected of having ulcerative colitis, and administration of 2400mg/day of oral mesalazine was initiated. After 10 days of treatment, he experienced fever and chest pain. Blood examination, electrocardiography, and cardiac ultrasonography revealed elevated cardiac enzymes, ST-segment elevation, and diffuse hypokinesis, respectively. Mesalazine-induced acute myocarditis was diagnosed based on a positive drug-induced lymphocyte stimulation test and the absence of other myocarditis-causing conditions. Prompt cessation of mesalazine quickly improved his heart function and test results. Although rare, clinicians should consider the possibility of cardiac adverse events caused by mesalazine.

1998年5月から1年間に大阪府下の病院外心停止症例についてウツタイン様式に準じて記録集計を行い,救急隊により目撃された心停止症例について検討した。5,047例の中で,救急隊により目撃された心停止は312例で発生頻度は100万人当たり35.3人であった。うち175例が心原性,137例が非心原性で,1年後の生存率は心原性では175例中11例(6.2%),非心原性では137例中6例(4.4%)であった。心原性で初期調律が心室細動であった症例は30例あったが,そのうち除細動が施行されたのは30例中12例(40%)のみであった。また心停止目撃後,除細動が施行されるまで5.7±4.9分を要していた。除細動が施行された症例では1年後12例中4例が生存したが,施行されなかった症例では1年後の生存例は1例のみであった。海外のウツタイン・スタディーとの比較では発生頻度,とくに心原性の発生頻度が少なかった。予後は非心原性では差がなかったのに心原性では悪かった。その原因のひとつとして初期調律が心室細動症例の数が少ないことが関連していると考えられたが,救命士による早期除細動の問題も関連しているのではないかと考えられた。

従来のキーワード検索では, キーワードを思い出せないと検索できない, 検索結果を順位付けすることができないなどの問題があった。これらの問題を解決し, キーワード1個からでも連想検索ができる検索手法として意味ベクトルによる連想検索技術を開発中である。この技術を画像検索へ応用した画像データベースを試作した。風景写真など約170枚の画像と, それぞれに付与した説明文からなる画像データベースを構築し, 意味ベクトルを用いた検索を行ったところ, 素人によって数語程度の説明文をつけただけでも, かなりの検索ができることがわかった。

C7α-substituted estradiols bind to estrogen receptors in cell nuclei, yet these derivatives remain little used in bioimaging. Here, we describe a fluorescent derivative of estradiol (E2) with a boron-dipyrromethene (BODIPY) moiety attached to C7α, synthesized by olefin metathesis reaction of 7α-allylestradiol and 9-decenyl-BODIPY. In ovariectomized rats and non-ovariectomized mice, E2-BODIPY promoted the growth of uterine tissue similar to the effect of estradiol. Twenty-four hours after subcutaneous injection of E2-BODIPY in non-ovariectomized mice, we observed fluorescence of E2-BODIPY in the nuclei of uterine epithelial cells. Our findings suggest that fluorescence microscopy can localize this derivative in E2-responsive cells during normal development and tumorigenesis in vivo.

1. The present uses for arthroscopic meniscus surgery are explained. 2. Postoperative care is facilitated by arthroscopic meniscus surgery. However, improvement in surgical instruments and manipulation is necessary in order to complete the surgery in a short time and to make it easy to perform. 3. Total meniscectomy is especially useful in the Japanese because the discoid meniscus was observed in 16.6 per cent in my arthroscopic study. The incidence is considerably higher than that in foreigners. The procedure for arthroscopic total meniscectomy must be improved. 4. The three puncture method is useful. 5. Partial meniscectomy yields excellent results, but there are pitfalls to watch for. 6. A case of combined surgery with partial meniscectomy and meniscorisis is presented.

1. The main factor that determines a satisfactory result is the operative technique; 2. The shelf operation for dislocated hips in spastic paralysis is without value; 3. The age of the patient appears to have little influence on the result; 4. Changes in the ilium induced by shelf implantation appear to be extremely important: 5. When the local condition indicates the need to stabilize a hip in a child, a shelf can be an invaluable asset.

Forty-five patients (49 knees) who had torn complete or incomplete discoid lateral menisci were treated during the period from 1968 to 1980. Both instrumentation and specific techniques considerably evolved in the arthroscopic complete excision the torn discoid meniscus. The current technique involves the initial removal of the anterior portion of the meniscus, as this allows clearer visualization during the procedure, more space for manipulating surgical instruments, and a reduced operative time. Twenty-four knees (22 patients) were followed for a mean of four years three months. Of this group, 78% were rated excellent or good and 21% were rated fair. There were no poor results. The results in the group treated by total meniscectomy were better than those in the group treated with partial meniscectomy. Three patients were treated by peripheral meniscal repair under arthroscopic control, but the long-term results are not available.

In the early days of arthroscopic surgery in Japan, Dr. Masaki Watanabe successfully performed punch biopsy through a separate trocar in 1950, removed a giant cell tumor located in the suprapatellar recess in 1955, removed a loose body in 1961, and accomplished partial meniscectomy in 1962. His studies as a pioneer had a most favorable influence upon me. However, in this article, I would like to talk about my failures. My first paper on the subject of arthroscopic surgery, "Surgery Under Arthroscopic Control," was presented at the Second International Arthroscopy Meeting held in Copenhagen, Denmark, in July 1975. This article was later published in the Journal o f Rheumatology (1). Even in 1975, I could not expect that the use of operative arthroscopy would spread around the world as it has. The surgery discussed in this initial paper was performed with the No. 21 arthroscope. The surgical procedures were as follows