Driver gene KRAS aggravates cancer-associated stroke outcomes

The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015

Versatile strategy using vaccinia virus-capping enzyme to synthesize functional 5′ cap-modified mRNAs

様々な5'キャップ構造をもつ機能的なmRNAの汎用的な合成方法 酵素を用いて簡便かつ効率的に. 京都大学プレスリリース. 2023-02-03.Development of a versatile method to synthesize functional mRNAs with diverse 5' cap structures. 京都大学プレスリリース. 2023-02-03.The potential of synthetic mRNA as a genetic carrier has increased its application in scientific fields. Because the 5′ cap regulates the stability and translational activity of mRNAs, there are concerted efforts to search for and synthesize chemically-modified 5′ caps that improve the functionality of mRNA. Here, we report an easy and efficient method to synthesize functional mRNAs by modifying multiple 5′ cap analogs using a vaccinia virus-capping enzyme. We show that this enzyme can introduce a variety of GTP analogs to the 5′ end of RNA to generate 5′ cap-modified mRNAs that exhibit different translation levels. Notably, some of these modified mRNAs improve translation efficiency and can be conjugated to chemical structures, further increasing their functionality. Our versatile method to generate 5′ cap-modified mRNAs will provide useful tools for RNA therapeutics and biological research

Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan

BACKGROUND: Data on the risk of cardiovascular-related mortality in patients with cancer are limited. METHODS AND RESULTS: This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. CONCLUSIONS: Cancer survivors have a higher risk of fatal heart disease than the general population.Gon Y., Zha L., Sasaki T., et al. Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan. Journal of the American Heart Association 12, e029967 (2023); https://doi.org/10.1161/JAHA.123.029967

Predictors of Survival in Patients With Ischemic Stroke and Active Cancer: A Prospective, Multicenter, Observational Study

BACKGROUND: Limited data exist on the prognostic factors for patients with ischemic stroke and active cancer. METHODS AND RESULTS: We conducted a prospective, multicenter, observational study in Japan, including patients with acute ischemic stroke and active cancer, to investigate the prognostic factors. We followed up the patients for 1 year after stroke onset. The patients were divided into 2 groups according to cryptogenic stroke and known causes (small-vessel occlusion, large-artery atherosclerosis, cardioembolism, and other determined cause), and survival was compared. The hazard ratios (HRs) and 95% CIs for mortality were calculated using Cox regression models. We identified 135 eligible patients (39% women; median age, 75 years). Of these patients, 51% had distant metastasis. A total of 65 (48%) and 70 (52%) patients had cryptogenic stroke and known causes, respectively. Patients with cryptogenic stroke had significantly shorter survival than those with known causes (HR [95% CI], 3.11 [1.82–5.32]). The multivariable Cox regression analysis revealed that distant metastasis, plasma D-dimer levels, venous thromboembolism (either deep venous thrombosis or pulmonary embolism) complications at stroke onset were independent predictors of mortality after adjusting for potential confounders. Cryptogenic stroke was associated with prognosis in univariable analysis but was not significant in multivariable analysis. The plasma D-dimer levels stratified the prognosis of patients with ischemic stroke and active cancer. CONCLUSIONS: The prognosis of patients with acute ischemic stroke and active cancer varied considerably depending on stroke mechanism, distant metastasis, and coagulation abnormalities. The present study confirmed that coagulation abnormalities were crucial in determining the prognosis of such patients.Gon Y., Sakaguchi M., Yamagami H., et al. Predictors of Survival in Patients With Ischemic Stroke and Active Cancer: A Prospective, Multicenter, Observational Study. Journal of the American Heart Association 12, e029618 (2023); https://doi.org/10.1161/JAHA.123.029618

野球のピッチング動作における踏み出し脚の運動がボール初速度に与える影響

This study deals with how stepping leg and waist motion are related to initial velocity, while practicing baseball pitching. Six pitchers belonging to the university baseball team did the actual pitching for this study and were filmed using the direct linear transformation method of three-dimensional (3D) videography. Several factors determine the initial velocity. Toyoshima^ mentions that the sharp rotation of the waist is one of the big factors. Moreover, the importance of the lower limbs is frequently mentioned on the actual coaching scene. The results of this study are mentioned below. 1. The waist changes its motion from advance to rotating 0.1 sec before the foot lands on the ground, and the right trochanter major speeds up by slowing down the left trochanter major while the waist rotates sharply. 2. It is possible to speed up the waist angular velocity by fixing the joints of the knee and the legs when the foot is landing

サッカーのインステップキックにおけるボール速度と支持脚との関係とその基本的役割

The purpose of this study is to investigate the relation between the joint angle and horizontal velocity of the supporting leg and the velocity of the ball by an instep kick as powerful as possible. Subjects were 3 male students who were skilled members of the college soccer club and 3 male non-skilled persons. In this study, the velocity of the ball, foot, greater trochanters and knee and angle of the knee were analyzed three-dimensionally (3-D). The results were as follows : (1) A significant correlation (r=0.903) was found between the velocity of the ball and the velocity of the foot. (2) Skilled persons kicked the ball using good waist rotation. This rotation is a factor which increases the velocity of the ball. (3) Skilled persons fixed the supporting leg, the angle of the knee was about 150 degrees and the velocity of the knee was lower than in non-skilled persons

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193

Oseltamivir-Resistant Influenza Viruses A (H1N1) during 2007–2009 Influenza Seasons, Japan

Prevalence of these viruses increased during the 2008–09 season