Medical Record Survey after Comprehensive Health Checkup Referral and Its Contribution to the Early Detection of Cancer.

Comprehensive health checkups in Japan are a preventive method to detect cancer and metabolic diseases. Unlike group medical examinations, individual examinations in health checkups are possible, with additional tests possible for disease detection. However, it is difficult to accurately ascertain the results from only the report after referral to a medical institution in individuals suspected of having cancer who need to be examined. We aimed to conduct a medical record survey of patients referred to the Hospital after undergoing a comprehensive health checkup and investigate the contribution of comprehensive health checkups to the detection of cancer more accurately. The subjects were 1763 examinees who were referred to various departments of our hospital because of doubtful cancer from 23,128 examinees who underwent comprehensive health checkups in our center from January 2018 to December 2022 for 5 years. The medical record survey demonstrated that cancer was detected in more than twice as many individuals as reported and other sources. Early-stage cancers require a significantly longer time to establish a definitive diagnosis. In conclusion, short-term reports from the referring hospital are insufficient for a final diagnosis, and long-term follow-up is extremely important to increase the diagnosis rates of cancer for comprehensive health checkups.

Premature Acute Myocardial Infarction in a Young Patient With Sitosterolemia.

Sitosterolemia is a rare, inherited, autosomal recessive disorder of lipid metabolism characterized by increased levels of plant sterols, such as sitosterol and campesterol, xanthomas, and accelerated atherosclerosis. In a 15-year-old boy exhibiting ST-elevation acute myocardial infarction, lipid panels, including plant sterol, and genetic testing for the ATP-binding cassette sub-family G member 5 (ABCG5) gene mutation, confirmed the diagnosis of sitosterolemia. A comprehensive lipid panel and genetic testing should be considered in patients with premature coronary artery disease to prevent disease progression through dietary and pharmacologic interventions specific to sitosterolemia.

La sitostérolémie est une maladie génétique rare à transmission autosomique récessive touchant le métabolisme des lipides, qui est caractérisée par une augmentation des taux de stérols végétaux comme le sitostérol et le campestérol, la présence de xanthomes et une athérosclérose accélérée. Chez un garçon âgé de 15 ans ayant subi un infarctus aigu du myocarde avec élévation du segment ST, le diagnostic de sitostérolémie a été confirmé par un bilan lipidique comprenant un dosage des stérols d'origine végétale et un test génétique de dépistage de la mutation du gène ABCG5 (ATP-binding cassette sub-family G member 5). Un bilan lipidique exhaustif et un test génétique doivent être envisagés chez les patients présentant une coronaropathie prématurée afin de prévenir la progression de la maladie grâce à des interventions d'ordre tant diététique que pharmacologique propres à la sitostérolémie.

Development of a High-Efficacy Reprogramming Method for Generating Human Induced Pluripotent Stem (iPS) Cells from Pathologic and Senescent Somatic Cells.

Induced pluripotent stem (iPS) cells are a type of artificial pluripotent stem cell induced by the epigenetic silencing of somatic cells by the Yamanaka factors. Advances in iPS cell reprogramming technology will allow aging or damaged cells to be replaced by a patient's own rejuvenated cells. However, tissue that is senescent or pathologic has a relatively low reprogramming efficiency as compared with juvenile or robust tissue, resulting in incomplete reprogramming; iPS cells generated from such tissue types do not have sufficient differentiation ability and are therefore difficult to apply clinically. Here, we develop a new reprogramming method and examine it using myofibroblasts, which are pathologic somatic cells, from patient skin tissue and from each of the four heart chambers of a recipient heart in heart transplant surgery. By adjusting the type and amount of vectors containing transcriptional factors for iPS cell reprogramming, as well as adjusting the transfection load and culture medium, the efficiency of iPS cell induction from aged patient skin-derived fibroblasts was increased, and we successfully induced iPS cells from myocardial fibroblasts isolated from the pathologic heart of a heart transplant recipient.

Mid-term predictive value of calciprotein particles in maintenance hemodialysis patients based on a gel-filtration assay.

BACKGROUND AND AIMS: Calciprotein particles (CPPs), nano-aggregates containing fetuin-A-bound calcium-phosphate, are associated with aortic stiffness and coronary calcification in maintenance hemodialysis patients. A novel gel-filtration assay can detect low-density small CPPs, which are actually a major form of circulating CPPs in vivo. We sought to investigate whether circulating CPP levels measured by gel-filtration method would accurately predict hard endpoints in maintenance hemodialysis patients. METHODS: This study used a prospective, multicenter, longitudinal, and observational design. One-hundred eight patients enrolled in this study were followed-up for about 2 years. We reported all-cause death and cardiovascular events, which included major adverse cardiac, cerebrovascular, and limb events. RESULTS: Kaplan-Meier analysis showed no significant difference between patients with the higher (>median) and lower (

Cardiac magnetic resonance imaging-based myocardial strain study for evaluation of cardiotoxicity in breast cancer patients treated with trastuzumab: A pilot study to evaluate the feasibility of the method.

BACKGROUND: Trastuzumab, used to treat breast cancer overexpressing human epidermal growth factor receptor 2, may be cardiotoxic. Cardiac magnetic resonance (CMR) imaging with myocardial strain studies has been used to evaluate subclinical biventricular myocardial changes, however, its clinical utility during chemotherapy has not been evaluated. METHODS: The clinical outcomes, CMR and cardiac biomarkers of 9 women aged 62.3 ± 12.6 years with early or locally advanced breast cancer were evaluated at baseline, and at 3, 6 and 12 months after the initiation of trastuzumab. RESULTS: None of the patients developed heart failure or elevated serum cardiac biomarkers. Global left ventricular (LV) peak systolic longitudinal and circumferential strains were significantly decreased at 6 months (longitudinal strains, -21.1 ± 1.7% [baseline] vs. -19.5 ± 1.0% [6 months], p = 0.039, and circumferential strains, -23.4 ± 1.8% [baseline] vs. -21.6 ± 2.5% [6 months], p = 0.036). These changes were analogous to those observed in the LV ejection fraction. Right ventricular (RV) free wall peak systolic circumferential strains were decreased at 6 months (-20.9% ± 2.4% [baseline] vs. -19.1% ± 2.3% [6 months], p = 0.049), whereas RV longitudinal strains and ejection fraction remained unchanged. The LV longitudinal strain was the most reproducible of the 4 peak strain parameters. CONCLUSIONS: The LV longitudinal and circumferential strains measured by CMR decreased during trastuzumab therapy, although their predictive value for later heart failure or association with RV parameters was not determined. These techniques may be a useful means of diagnosing and monitoring trastuzumab-related cardiotoxicity.

Percutaneous Coronary Intervention for Septic Emboli in the Left Main Trunk as a Complication of Infective Endocarditis.

Infective endocarditis (IE) complicated by acute myocardial infarction (AMI) is frequently fatal and may require emergent interventions. However, the optimal treatment of this rare condition remains controversial as it lacks established guidelines. We successfully treated a patient with IE complicated by AMI during the acute phase using percutaneous coronary intervention (PCI) followed by surgery. A 73-year-old man was diagnosed with IE of the mitral and aortic valves caused by Streptococcus oralis. Four weeks after the initiation of antibiotics sensitive to the causative bacteria, he suddenly developed AMI manifested by chest pain and dyspnoea with cardiovascular collapse. Emergent coronary angiography revealed that the myocardial infarction was secondary to septic emboli in the left main trunk. Emergent PCI comprising aspiration and stent deployment, was successfully performed, and his vital signs were immediately stabilised. He subsequently underwent mitral and aortic valve replacement and debridement without major post-operative complications. Although the optimal treatment strategy for haemodynamically unstable AMI secondary to IE requires further discussion, the present case indicates the importance of early diagnosis and the potential effectiveness of aggressive PCI as a bridge to the following surgery.

Promyelocytic leukemia zinc finger protein activates GATA4 transcription and mediates cardiac hypertrophic signaling from angiotensin II receptor 2.

BACKGROUND: Pressure overload and prolonged angiotensin II (Ang II) infusion elicit cardiac hypertrophy in Ang II receptor 1 (AT(1)) null mouse, whereas Ang II receptor 2 (AT(2)) gene deletion abolishes the hypertrophic response. The roles and signals of the cardiac AT(2) receptor still remain unsettled. Promyelocytic leukemia zinc finger protein (PLZF) was shown to bind to the AT(2) receptor and transmit the hypertrophic signal. Using PLZF knockout mice we directed our studies on the function of PLZF concerning the cardiac specific transcription factor GATA4, and GATA4 targets. METHODOLOGY AND PRINCIPAL FINDINGS: PLZF knockout and age-matched wild-type (WT) mice were treated with Ang II, infused at a rate of 4.2 ng·kg(-1)·min(-1) for 3 weeks. Ang II elevated systolic blood pressure to comparable levels in PLZF knockout and WT mice (140 mmHg). WT mice developed prominent cardiac hypertrophy and fibrosis after Ang II infusion. In contrast, there was no obvious cardiac hypertrophy or fibrosis in PLZF knockout mice. An AT(2) receptor blocker given to Ang II-infused wild type mice prevented hypertrophy, verifying the role of AT(2) receptor for cardiac hypertrophy. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that PLZF bound to the GATA4 gene regulatory region. A Luciferase assay verified that PLZF up-regulated GATA4 gene expression and the absence of PLZF expression in vivo produced a corresponding repression of GATA4 protein. CONCLUSIONS: PLZF is an important AT(2) receptor binding protein in mediating Ang II induced cardiac hypertrophy through an AT(2) receptor-dependent signal pathway. The angiotensin II-AT(2)-PLZF-GATA4 signal may further augment Ang II induced pathological effects on cardiomyocytes.

Antagonism or synergism. Role of tyrosine phosphatases SHP-1 and SHP-2 in growth factor signaling.

SHP-1 and SHP-2 are two Src homology 2 domain-containing tyrosine phosphatases with major pathological implications in cell growth regulating signaling. They share significant overall sequence identity, but their biological functions are often opposite. SHP-1 is generally considered as a negative signal transducer and SHP-2 as a positive one. However, the precise role of each enzyme in shared signaling pathways is not well defined. In this study, we investigated the interaction of these two enzymes in a single cell system by knocking down their expressions with small interfering RNAs and analyzing the effects on epidermal growth factor signaling. Interestingly, knockdown of either SHP-1 or SHP-2 caused significant reduction in the activation of ERK1/2 but not Akt. Furthermore, SHP-1, SHP-2, and Gab1 formed a signaling complex, and SHP-1 and SHP-2 interact with each other. The interaction of SHP-1 with Gab1 is mediated by SHP-2 because it was abrogated by knockdown of SHP-2, and SHP-2, but not SHP-1, binds directly to tyrosine-phosphorylated Gab1. Together, the data revealed that both SHP-1 and SHP-2 have a positive role in epidermal growth factor-induced ERK1/2 activation and that they act cooperatively rather than antagonistically. The interaction of SHP-1 and SHP-2 may be responsible for previously unexpected novel regulatory mechanism of cell signaling by tyrosine phosphatases.

A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy.

We describe a novel signaling mechanism mediated by the G-protein-coupled receptor (GPCR) angiotensin II (Ang II) type 2 receptor (AT(2)). Yeast two-hybrid studies and affinity column binding assay show that the isolated AT(2) C-terminus binds to the transcription factor promyelocytic zinc finger protein (PLZF). Cellular studies employing confocal microscopy show that Ang II stimulation induces cytosolic PLZF to co-localize with AT(2) at the plasma membrane, then drives AT(2) and PLZF to internalize. PLZF slowly emerges in the nucleus whereas AT(2) accumulates in the perinuclear region. Nuclear PLZF binds to a consensus sequence of the phosphatidylinositol-3 kinase p85 alpha subunit (p85 alpha PI3K) gene. AT(2) enhances expression of p85 alpha PI3K followed by enhanced p70(S6) kinase, essential to protein synthesis. An inactive mutant of PLZF abolishes this effect. PLZF is expressed robustly in the heart in contrast to many other tissues. This cardiac selective pathway involving AT(2), PLZF and p85 alpha PI3K may explain the absence of a cardiac hypertrophic response in AT(2) gene-deleted mice.

Targeted deletion of angiotensin II type 2 receptor caused cardiac rupture after acute myocardial infarction.

BACKGROUND: Accumulating evidence has suggested that the cardiac renin-angiotensin system is activated during the remodeling process after myocardial infarction (MI). Although 2 types of angiotensin II receptors (AT(1) and AT(2)) are upregulated in the infarcted tissue, the contribution of AT(2) to the subsequent fibrogenetic phase of wound healing is less certain. This study was conducted to evaluate the role of AT(2) in wound healing after MI using an in vivo intervention study in mice with MI. METHODS AND RESULTS: We examined myocardial hypertrophy, cardiac fibrosis, and morphological evidence of fibrillar collagen accumulation at the infarcted and noninfarcted regions in male mice lacking the AT(2) receptor (Agtr2-/Y) and age-matched wild-type (WT) animals. Of the Agtr2-/Y mice, 63.6% died of cardiac rupture, whereas 23.5% of the WT mice died of the same cause within 1 week. The extent of fibrosis and that of collagen gene expression in Agtr2-/Y mice were significantly reduced compared with WT mice at 1 week after coronary ligation. Furthermore, MI resulted in a marked increase in the prostaglandin E(2) (PGE(2)) level at 4 days after surgery in Agtr2-/Y mice. In WT mice, the PGE(2) level was also elevated after MI but to a significantly lesser extent than in Agtr2-/Y mice. CONCLUSIONS: A chronic loss of AT(2) by gene targeting prevented the collagen deposition and caused cardiac rupture. The markedly elevated PGE(2) may be a mechanism that inhibits collagen synthesis in the infarcted region of Agtr2-/Y mice.

Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb.

This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.

Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy.

FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca2+ release from the sarcoplasmic reticulum in skeletal muscle and developmental cardiac defects have been reported in FKBP12-deficient mice, but the role of FKBP12.6 in cardiac excitation-contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca2+ release, seen as increases in the amplitude and duration of Ca2+ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation-contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca2+ dysregulation.