Abstract Funding Acknowledgements N/A Background/Introduction: The benefit of statins in patients with heart failure (HF) remains controversial and the mechanism of action is largely speculative. We investigated whether survival benefit with statins differs according to left ventricular (LV) geometry and myocardial contractility in acute HF patients. Methods We enrolled 1792 acute HF patients receiving statins and 2296 patients not receiving statins admitted from 2009 to 2016. The LV and right ventricular (RV) global longitudinal strain (GLS) was assessed as a measure of myocardial contractility. Patients were classified into 2 groups based on ischemic etiology of HF and further divided into 4 subgroups according to the median values of LV-GLS or RV-GLS. The primary outcome was 5-year all-cause mortality. The study protocol was approved by the ethics committee at each institute and complied with the Declaration of Helsinki. The need for written informed consent was waived. Results During the 5-year follow-up, 1740 (40.4%) patients died and they had more unfavorable baseline characteristics. Statin therapy was significantly associated with improved survival in overall patients and in both groups with and without ischemic etiology (all p <0.001). Patients with concentric remodeling/hypertrophy and eccentric hypertrophy demonstrated survival benefit with statin therapy (P = 0.033, 0.004, and 0.008, respectively), while those with normal geometry did not (p = 0.123). In the non-ischemic HF group, survival benefit with statin therapy was confined to patients with low LV-GLS (p = 0.045) or those with low RV-GLS p = 0.003). On the contrary, in ischemic HF group, survival benefit with statin therapy was observed in all patients regardless of the values of LV-GLS or RV-GLS. Significant interactions were present between statin use and diabetes mellitus and IHD (p for interaction = 0.027 and 0.003, respectively) regarding mortality. Conclusions LV geometry and myocardial contractility may modulate the effects of statins in patients with acute HF. These echocardiographic measures can provide prognostic information to guide tailored statin treatment in this population. Our findings may also help to develop more well-designed prospective studies, in terms of a more homogenous study population, to confirm survival benefit with statin therapy. Abstract P785 Figure. Multivariate Cox survival curves
Abstract Background Under conditions of hypoxia, cancer cells with hypoxia inducible factor-1α (HIF-1α) from heterogeneous tumor cells show greater aggression and progression in an effort to compensate for harsh environmental conditions. Extensive study on the stability of HIF-1α under conditions of acute hypoxia in cancer progression has been conducted, however, understanding of its involvement during the chronic phase is limited. Methods In this study, we investigated the effect of SIRT1 on HIF1 stability in a typical chronic hypoxic conditon that maintains cells for 24 h under hypoxia using Western blotting, co-IP, measurement of intracellular NAD + and NADH levels, semi-quantitative RT-PCR analysis, invasion assay, gene knockdown. Results Here we demonstrated that the high concentration of pyruvate in the medium, which can be easily overlooked, has an effect on the stability of HIF-1α. We also demonstrated that NADH functions as a signal for conveyance of HIF-1α degradation via the SIRT1 and VHL signaling pathway under conditions of chronic hypoxia, which in turn leads to attenuation of hypoxically strengthened invasion and angiogenic activities. A steep increase in the level of NADH occurs during chronic hypoxia, leading to upregulation of acetylation and degradation of HIF-1α via inactivation of SIRT1. Of particular interest, p300-mediated acetylation at lysine 709 of HIF-1α is recogonized by VHL, which leads to degradation of HIF-1α via ubiquitin/proteasome machinary under conditions of chronic hypoxia. In addition, we demonstrated that NADH-elevation-induced acetylation and subsequent degradation of HIF-1α was independent of proline hydroxylation. Conclusions Our findings suggest a critical role of SIRT1 as a metabolic sensor in coordination of hypoxic status via regulation of HIF-1α stability. These results also demonstrate the involvement of VHL in degradation of HIF-1α through recognition of PHD-mediated hydroxylation in normoxia and p300-mediated HIF-1α acetylation in hypoxia.
Recent studies reporting trans-differentiation of mononucleated cells derived from human umbilical cord blood into neuronal cells aroused interest among investigators for their clinical implication and significance in regenerative medicine. In the present study, purified populations of hematopoietic stem cells were isolated via magnetic bead sorting and fluorescence-activated cell sorter (FACS) using a specific CD133 antibody, a cell type-specific marker for hematopoietic stem cells, and grown in culture in the presence of retinoic acid (RA). CD133+ hematopoietic stem cells expressed neuronal and glial phenotypes after RA treatment. RT-PCR analysis indicated that the RA treated CD133+ cells expressed mRNA transcripts for ATP-binding cassettes transporter ABCG2 (a universal stem cell marker), nestin (a specific cell type marker for neural stem cells), Musashi1 (a specific marker for neural stem cells) and RA receptors (RAR) including RAR-alpha, RAR-beta, and retinoid X receptor (RXR)-gamma. RA-treated CD133+ cells expressed mRNA transcripts for neuron-specific markers neurofilament proteins (NF-L, -M, -H) and synaptophysin as determined by RT-PCR, structural proteins characteristic of neurons including tubulin beta III and neuron specific enolase (NSE) by Western blot, and neuron-specific markers NeuN and microtubule-associated protein-2 (MAP2) by immunocytochemistry. RA-treated CD133+ cells also expressed the astrocyte-specific marker glial fibrillary acidic protein (GFAP), as demonstrated by RT-PCR, Western blot, and immunocytochemistry. In addition, RA-treated CD133+ cells expressed cell type-specific markers for oligodendrocytes including myelin basic protein (MBP) as shown by RT-PCR, proteolipid protein (PLP) by Western blot analysis, and cyclic nucleotide phosphodiesterase (CNPase) by immunostaining. Upregulated expression of several basic helix-loop-helix (bHLH) transcription factors important for early neurogenesis, including Otx2, Pax6, Wnt1, Olig2, Hash1 and NeuroD1, was also demonstrated in CD133+ cells after RA treatment. These results indicate that human cord blood-derived CD133+ hematopoietic stem cells could trans-differentiate into neural cell types of neuron-like cells, astrocytes, and oligodendrocytes by RA treatment.
Abstract Alien Hand Syndrome (AHS) disrupts hand control, often attributed to corpus callosum (CC) damage, which connects the two brain hemispheres. AHS can also result from damage to the medial frontal cortex, parietal lobe, or thalamus, but its precise causes remain unclear. This study aimed to identify the white matter tracts associated with AHS development using the automated reconstruction of 42 tracts from diffusion tensor imaging (DTI). We included three female AHS patients with anterior cerebral arterial (ACA) infarctions. Additionally, we enrolled 20 age-matched control subjects and six patients with ACA infarctions but without AHS symptoms (N-AHS group) for comparison. DTI was conducted in AHS, N-AHS, and control groups. Fractional anisotropy (FA) and volume values were extracted from the DTI datasets of participants using TRActs Constrained by UnderLying Anatomy (TRACULA) technique. The AHS group showed lower FA values of the CC body (parietal and temporal section), right arcuate fasciculus, corticospinal tract, extreme capsule, inferior longitudinal fasciculus, and superior longitudinal fasciculus than the control group. However, these tracts exhibited no significant difference between N-AHS and control groups. Similarly, the volume value in the genu of CC in the AHS group was lower than controls, but not in other tracts. Our results suggest that the extensive CC lesion, especially in the posterior parietal and temporal section of CC body, is associated with the development of AHS. These results shed light on the neural mechanisms involved in AHS and underscore the significance of considering various white matter tracts beyond CC for understanding this syndrome.
Mad2, a key component of the spindle checkpoint, is closely associated with chromosomal instability and poor prognosis in cancer. p31comet is a Mad2-interacting protein that serves as a spindle checkpoint silencer at mitosis. In this study, we showed that p31comet-induced apoptosis and senescence occur via counteraction of Mad2 activity. Upon retroviral transduction of p31comet, the majority of human cancer cell lines tested lost the ability to form colonies in a low-density seeding assay. Cancer cells with p31comet overexpression underwent distinct apoptosis and/or senescence, irrespective of p53 status, confirming the cytotoxicity of p31comet. Interestingly, both cytotoxic and Mad2 binding activities were eliminated upon deletion of the C-terminal 30 amino acids of p31comet. Point mutation or deletion of the region affecting Mad2 binding additionally abolished cytotoxic activity. Consistently, wild-type Mad2 interacting with p31comet, but not its non-binding mutant, inhibited cell death, indicating that the mechanism of p31comet-induced cell death involves Mad2 inactivation. Our results clearly suggest that the regions of p31comet affecting interactions with Mad2, including the C-terminus, are essential for induction of cell death. The finding that p31comet-induced cell death is mediated by interactions with Mad2 that lead to its inactivation is potentially applicable in anticancer therapy.
Although some sporadic reports reveal the link between the homeobox (HOX) genes and ovarian carcinoma, there is no comprehensive analysis of the expression pattern of the class I homeobox genes in ovarian carcinoma that determines the candidate genes involved in ovarian carcinogenesis.The different patterns of expression of 36 HOX genes were analyzed, including 4 ovarian cancer cell lines and 4 normal ovarian tissues. Using a reverse transcription-polymerase chain reaction (RT-PCR) and quantification analysis, the specific gene that showed a significantly higher expression in ovarian cancer cell lines than in normal ovaries was selected, and western blot analysis was performed adding 7 ovarian cancer tissue specimens. Finally, immunohistochemical and immunocytochemical analyses were performed to compare the pattern of expression of the specific HOX gene between ovarian cancer tissue and normal ovaries.Among 36 genes, 11 genes had a different level of mRNA expression between the cancer cell lines and the normal ovarian tissues. Of the 11 genes, only HOXB4 had a significantly higher level of expression in ovarian cancer cell lines than in normal ovaries (p=0.029). Based on western blot, immunohistochemical, and immunocytochemical analyses, HOXB4 was expressed exclusively in the ovarian cancer cell lines or cancer tissue specimens, but not in the normal ovaries.We suggest HOXB4 may be a novel candidate gene involved in ovarian carcinogenesis.
Sexually dimorphic nucleus of the hypothalamic preoptic area (SDNPOA) is a good model for the study of estrogen-dependent neuroprotecion. Male SDN-POA is much bigger than that of female by neuroprotective effect of estrogen that is converted by aromatase from circulating testosterone during critical period of brain development. We have recently found a neural tissue-specific protein, NELL2, as a potential downstream target of estrogen. NELL2 inhibited cell death of the HiB5 hippocampal neuroprogenitor cells under neurodegenerative conditions. Interestingly, neuroprotective effect of estrogen appears to be mediated by NELL2, because dominant-negative mutant NELL2 lacking with EGF-like domains totally inhibited neuroprotective effect of estrogen, while wild type NELL2 facilitated estrogen-induced neuroprotection. Therefore, we further examined a possible neuroprotective role of NELL2 in the development of the SDN-POA of male rats. Volume of the male rat SDN-POA was decreased when antisense (AS) NELL2 oligodeoxynucleotide (ODN) was injected into the lateral ventricle of the neonatal male rat brains during critical period (postnatal day 0 to day 4). More interestingly, decreased size of the SDN-POA resulted in a decreased sexual behavior such as mounting and intromit. Our data suggest that NELL2 is involved in the estrogen-induced neuroprotection for the development of the male SDN-POA and thus influence the male sexual behavior. (poster)
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