A new signal transducer and activator of transcription 3 inhibitor, BBI608, in malignant mesothelioma cell lines

　Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma as a result of asbestos exposure. Signal transducer and activator of transcription 3 (STAT3) signaling is a major pathway for cancer inflammation. The purpose of this study was to investigate the effectiveness of a new STAT3 inhibitor, BBI608, on mesothelioma cells in vitro and in vivo . The results showed that BBI608 blocked STAT3 phosphorylation, with and without suppression of IL-6. The effects of BBI608 on STAT3 downstream target genes such as cyclin D1 and survivin involved a decrease in cell viability with induction of apoptosis and cell cycle arrest. Nuclear translocation of phosphorylated STAT3 was blocked by BBI608. In addition, the agent showed significant antitumor activity in xenograft mouse models implanted with mesothelioma cells. These findings suggest that BBI608 may be a novel agent for malignant mesothelioma

SEX DIFFERENCES IN RACE PROFILE AND STROKE VARIABLES DURING 200-M SPRINT IN JUNIOR KAYAKERS

The purpose of present study was to examine sex differences in race profile and stroke variables during 200-m sprint in junior kayakers. 200-m race time of the male kayakers showed 11% shorter than the female kayakers. In both groups, significant positive correlations were found between kayak velocity and stroke rate. In the three part of duration (Initial: 0-25m, Middle: 100-125m, Finish: 175-Zoom), male kayakers were faster than female kayakers. Kayak velocity of male kayakers significantly decreased in the finish part from the middle part, while the kayak velocity of female kayakers showed a most constant. In conclusion, these different raw profiles might be explained by physiological differences in the upper body power or anaerobic capacities between males and females

Fatal interstitial pneumonia caused by panitumumab-containing chemotherapy: a case report

A 49-year-old Japanese man visited our institution for the treatment of metastatic rectal cancer. He had no history of interstitial pneumonia or smoking. Although he achieved partial remission with combination chemotherapy consisting of 5-fluorouracil, leucovorin, and oxaliplatin plus bevacizumab, this regimen failed after 46 courses. A salvage chemotherapy consisting of 5-fluorouracil, leucovorin, and irinotecan plus panitumumab was initiated. However, 6 days after treatment initiation, asymptomatic hypoxia was detected. Chest computed tomography revealed interstitial lung disease; therefore, chemotherapy was discontinued and corticosteroid pulse therapy was immediately started. Chest computed tomography on day 20 of the salvage chemotherapy revealed progressive interstitial lesions with lung volume loss and mediastinal emphysema. He passed away a few days later because of respiratory failure. In conclusion, physicians should be aware of the adverse event wherein administration of chemotherapy containing an anti-epidermal growth factor receptor monoclonal antibody might result in a fatal outcome

RGMa inhibition promotes axonal growth and recovery after spinal cord injury

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA–Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration

A new cancer diagnostic system based on a CDK profiling technology

AbstractA series of molecular pathological investigations of the molecules that stimulate the cyclin dependent kinases (CDK1, 2, 4, and 6) have led to enormous accumulation of knowledge of the clinical significance of these molecules for cancer diagnosis. However, the molecules have yet to be applied to clinical cancer diagnosis, as there is no available technology for application of the knowledge in a clinical setting. We hypothesized that the direct measurement of CDK activities and expressions (CDK profiling) might produce clinically relevant values for the diagnosis. This study investigated the clinical relevance of CDK profiling in gastrointestinal carcinoma tissues by using originally developed expression and activity analysis methods. We have established novel methods and an apparatus for analyzing the expression and activities of the CDK molecules in lysate of tumor tissue in a clinical setting, and examined 30 surgically dissected gastrointestinal carcinomas and corresponding normal mucosal specimens. We demonstrate here that remarkably elevated CDK2 activity is evident in more than 70% of carcinoma tissues. Moreover, a G1-CDK activity profiling accurately mirrored the differences in proliferation between tumor and normal colonic tissues. Our results suggest that CDK profiling is a potent molecular–clinical approach to complement the conventional pathological diagnosis, and to further assist in the individualized medications

Dietary fiber intake and risk of incident disabling dementia: the Circulatory Risk in Communities Study

OBJECTIVES: It has been hypothesized that dietary fiber intake has a beneficial impact on prevention of dementia, but the epidemiological evidence is scant. We sought to examine whether dietary fiber intake is inversely associated with risk of dementia requiring care under the national insurance (disabling dementia). METHODS: The study setting was the Circulatory Risk in Communities Study, involving 3739 Japanese individuals aged 40-64 years at the dietary surveys (1985-99). Dietary fiber intake was estimated using the 24-hour dietary recall method. Incident disabling dementia was followed up from 1999 through 2020. Disabling dementia was further classified into that with or without a history of stroke. Hazard ratios of disabling dementia according to quartiles of total, soluble, and insoluble fiber intake were calculated using the Cox proportional hazards model. RESULTS: During a median 19.7-year follow-up, a total of 670 cases of disabling dementia developed. Dietary fiber intake was inversely associated with risk of dementia: the multivariate hazards ratios (95% confidence intervals) were 0.83 (0.67-1.04), 0.81 (0.65-1.02), and 0.74 (0.57-0.96) for individuals with the second, third, and highest quartiles of dietary fiber intake, respectively, as compared with the lowest quartile (P for trend = 0.03). The inverse association was more evident for soluble fiber intake and was confined to dementia without a history of stroke. As for fiber-containing foods, potatoes, but not vegetables or fruits, showed a similar association. CONCLUSIONS: Dietary fiber intake, especially soluble fiber, was inversely associated with risk of disabling dementia in a general Japanese population

透析患者に発症したアシクロビル脳症の1例

患者は75歳女性で,慢性腎不全に対して近医で透析を受けていた.右足底の帯状疱疹に対し近医皮膚科よりアシクロビル2,400mg/日が投与された.その後しゃべりにくさとふらつき,異常な言動が出現した.近医よりアシクロビル内服中止を指示され,内服を中止したが症状の改善がないため当院へ救急搬送され精査目的で入院した.入院時意識レベルはJCS20～30.構音障害を認め,顔面,口唇,舌,四肢にジスキネジア様の不随意運動を認めた.クレアチニンクリアランスは5.46ml/min/1.73m^2と著明に低下していた.髄液細胞数は正常であった.頭部MRIで左前頭葉の急性期脳梗塞と左頭頂葉の萎縮を認めたが症状と合致しないこと,髄液細胞数が正常であること,アシクロビル投与後に症状が出現していることから,アシクロビル脳症を疑った.透析を継続し,症状は改善を認めた.アシクロビルの血中濃度は,入院日が高値で,当院での第1回目の透析後に速やかに低下していた.アシクロビル脳症は,抗ヘルペスウイルス薬のアシクロビル,塩酸バラシクロビルの投与により誘発される精神神経症状であり,意識障害,振戦,ミオクローヌス,錯乱,混迷,傾眠,幻覚,昏睡など多彩な症状が出現する.本症例のアシクロビル投与量は,添付文書に記載されているクレアチニンクリアランスを考慮した投与量よりも過剰であったことが,脳症発症の一因と思われた.ヘルペスウイルス感染症に対してアシクロビルを投与後に精神神経症状が出現した場合,ウイルス性脳炎とアシクロビル脳症とを早急に鑑別することが重要で,早期に髄液検査や頭部CT,MRI等を施行すべきと考える.また,透析患者にアシクロビルを投与する場合は投与量に十分な注意を払い,脳症が出現する可能性も念頭に置き,慎重な経過観察が重要と考える.We report the case of a 75-year-old woman under hemodialysis who developed aciclovir encephalopathy. She was administered aciclovir at a dose of 2,400 mg/day by a dermatologist because of herpes zoster on her right sole. Later she complained of speech disturbance and dizziness. She said abnormal words. Although she discontinued using aciclovir, her symptoms did not improve. Thus, she was admitted to our hospital. Her consciousness level was JCS20～30. On neurological examination, she had dysarthria and dyskinesia-like involuntary movements in the face, lips, tongue and all extremities. On laboratory data, creatinine clearance was 5.46 ml/min/1.73m^2. Cell count of cerebrospinal fluid was normal. Brain MRI revealed acute cerebral infarction of the left frontal lobe and atrophy of the left parietal lobe. But these findings did not coincide with her symptoms. She was diagnosed with aciclovir encephalopathy. Her symptoms improved after hemodialysis. The serum concentration of aciclovir was 9.20μg/ml on admission, and decreased promptly after the first hemodialysis. Aciclovir encephalopathy is characterized by neuropsychiatric symptoms such as disturbance of consciousness, tremor, myoclonus, confusion, stupor, drowsiness, hallucination, and coma. It can be induced also by valaciclovir. The cause of aciclovir encephalopathy in our patient was assumed to be due to a dose too high for her low creatinine clearance rate. When neuropsychiatric symptoms occur during treatment with aciclovir for herpes viral infection, cerebrospinal fluid cytology and brain CT and/or MRI should be performed to distinguish viral encephalitis from acyclovir encephalopathy. When aciclovir is used in patients under hemodyalysis, attention must be paid to the aciclovir dose and the clinical course should be carefully monitored because of the risk of aciclovir encephalopathy