ABSTRACT
Population aging and the associated increase in cardiovascular disease rates pose serious threats to global public health. Different forms of fasting have become an increasingly attractive strategy to directly address aging and potentially limit or delay the onset of cardiovascular diseases. A growing number of experimental studies and clinical trials indicate that the amount and timing of food intake as well as the daily time window during which food is consumed, are crucial determinants of cardiovascular health. Indeed, intermittent fasting counteracts the molecular hallmarks of cardiovascular aging and promotes different aspects of cardiometabolic health, including blood pressure and glycemic control, as well as body weight reduction. In this report, we summarize current evidence from randomized clinical trials of intermittent fasting on body weight and composition as well as cardiovascular and metabolic risk factors. Moreover, we critically discuss the preventive and therapeutic potential of intermittent fasting, but also possible detrimental effects in the context of cardiovascular aging and related disease. We delve into the physiological mechanisms through which intermittent fasting might improve cardiovascular health, and raise important factors to consider in the design of clinical trials on the efficacy of intermittent fasting to reduce major adverse cardiovascular events among aged individuals at high risk of cardiovascular disease. We conclude that despite growing evidence and interest among the lay and scientific communities in the cardiovascular health-improving effects of intermittent fasting, further research efforts and appropriate caution are warranted before broadly implementing intermittent fasting regimens, especially in elderly persons.
Subject(s)
Aging , Cardiovascular Diseases , Intermittent Fasting , Humans , Aging/physiology , Cardiovascular Diseases/prevention & control , Cardiovascular System/physiopathology , Intermittent Fasting/adverse effects , Intermittent Fasting/physiology , Risk Assessment/methods , Risk FactorsABSTRACT
BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.
Subject(s)
Cardiomyopathies , Heart Failure , Humans , Mice , Animals , Ventricular Remodeling , Cardiomyopathies/complications , Heart Failure/radiotherapy , Heart Failure/drug therapy , Heart Failure/etiology , Myocytes, Cardiac/metabolism , Ventricular Function , FibrosisABSTRACT
Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury.
ABSTRACT
Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.
Subject(s)
Cardiotoxicity , Heart Failure , Mice , Humans , Animals , Cardiotoxicity/metabolism , Doxorubicin/toxicity , Autophagy , Myocytes, Cardiac/metabolism , Fasting , Heart Failure/chemically induced , Heart Failure/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Lysosomes/metabolismABSTRACT
OBJECTIVE: To create an efficient and robust mass spectrometric method for the simultaneous quantitation of podocin and podocalyxin in urine samples and to evaluate urinary podocin and podocalyxin levels in patients with nephrotic syndrome (NS). METHODS: A mass spectrometric method was generated for the measurement of tryptic peptides in urine sediment. Separation of peptides was achieved via liquid chromatography, and mass spectrometric analyses were conducted by electrospray ionization triple-quadrupole mass spectrometry in the multiple reaction monitoring mode. RESULTS: Intra- and interassay precision values were below 12% and accuracies ranged from 87% to 111% for both of peptides. The validated method was successfully applied to detect these peptides in patients with NS. Urine podocin and podocalyxin levels were significantly higher in patients with NS compared to healthy controls. CONCLUSIONS: This proposed mass spectrometric method provides technological evidence that will benefit the clinical field in the early diagnosis and follow-up of NS.
Subject(s)
Nephrotic Syndrome , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid , Female , Humans , Intracellular Signaling Peptides and Proteins , Male , Membrane Proteins , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/urine , Peptides , Sialoglycoproteins , Tandem Mass Spectrometry/methodsABSTRACT
AIM: To demonstrate the changes in Grade II and III glial tumors after WHO 2016 Brain Tumors Classification. MATERIAL AND METHODS: The previous diagnoses and postoperative treatment of the 83 patients were recorded. We used real-time PCR (mutation assay) for the analysis of IDH1 and IDH2, while we used FISH test to determine 1p/19q codeletion. The integrated diagnosis was compared with classical histopathological diagnoses. RESULTS: We studied 13 oligodendendrogliomas, 41 astrocytomas and 29 oligoastrocytomas patients with classical histopathological diagnosis group. IDH mutation was detected in 51 of the patients after genetic analysis, whereas 1p/19q codeletion was detected in 20 patients. We found that grade II IDH-mut astrocytoma patients had significantly better survival outcomes compared to grade III IDH-mut astrocytoma patients. CONCLUSION: Grade II and III gliomas are separated into more homogeneous diagnostic groups for survival after molecular marker analyses. Compared to histopathological diagnosis, the WHO 2016 glioma classification with molecular markers provides new perspectives in patient prognosis and treatment. However, due to the costs of using molecular markers, the extent to which it can be used remains questionable.
Subject(s)
Brain Neoplasms , Glioma , Oligodendroglioma , Brain Neoplasms/genetics , Glioma/diagnosis , Glioma/genetics , Humans , Isocitrate Dehydrogenase/genetics , PrognosisABSTRACT
BACKGROUND: The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs, including the colon. Accordingly, studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression. Although Numb, Itch, and seven in absentia homolog-1 (Siah-1) have been shown to contribute to the regulation of Notch signaling, their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date. AIM: To evaluate Numb, Itch, and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior. METHODS: Expression of Notch-1, Numb, Itch, and Siah-1 was investigated in 50 colorectal carcinomas, 30 adenomas, and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analyses. RESULTS: In contrast to Notch-1, which is expressed at higher levels in tumor tissues and adenomas, expression of Numb, Itch, and Siah-1 was stronger and more frequent in normal mucosa (P < 0.01). There was a positive correlation between Notch-1 expression and high histological grade, the presence of lymph node metastasis, and advanced-stage tumors, whereas expression of Numb, Itch, and Siah-1 was absent or reduced in tumors with these clinicopathological parameters (P < 0.05). In survival analysis, expression of Notch was related to poor prognosis but that of Numb, Itch, and Siah-1 correlated with improved survival (P < 0.05). Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis (P < 0.05). CONCLUSION: Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb, Itch, and Siah-1 expression is associated with carcinogenesis. Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma (CRC) progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.
Subject(s)
Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , Signal Transduction , Aged , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Female , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Receptor, Notch1ABSTRACT
OBJECTIVE: ROS1 is an orphan receptor protein tyrosine kinase which is supposed to undergo genetic rearrangement in carcinogenesis. In the current study, we aimed to investigate the frequency and clinicopathologic features associated with ROS1 gene fusion and ROS1 protein expression in patients with ovarian serous carcinoma or serous borderline tumors. MATERIALS AND METHODS: Tissue samples of 102 patients with high or low grade serous carcinoma and borderline serous tumors were selected randomly from the archives of Department of Gyneco-pathology, and analyzed for ROS1 gene expression. (Fluorescence in situ hybridization (FISH) method was used to assess ROS1 gene rearrangement, while ROS1 protein expression was analyzed using immunohistochemistry. RESULTS: The study consisted of 94 cases of high-grade serous carcinoma (92.1%), 2 cases of low-grade serous carcinoma (%2) and 6 cases of serous borderline tumor (5.9%). ROS1 gene rearrangement analysis revealed that 4 patients (3.9%) were FISH-positive; whereas the immunohistochemical analysis yielded only 1 patient (0.9%) exhibiting faint positive expression of ROS1 protein. Given the low incidences of ROS1 gene rearrangement and protein expression, their relationships with clinicopathologic parameters could not be statistically analyzed. CONCLUSION: Although rare, patients with ovarian serous carcinoma or serous borderline tumor may exhibit ROS1 gene rearrangement and ROS1 protein expression. Further large-scale studies are necessary to explore the clinicopathologic significance of ROS1 gene expression in ovarian serous carcinoma.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/metabolism , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/metabolism , Protein-Tyrosine Kinases/biosynthesis , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Oncogene FusionABSTRACT
PURPOSE: Facial emotion recognition is a basic element in non-verbal communication. Although some researchers have shown that recognizing facial expressions may be important in the interaction between doctors and patients, there are no studies concerning facial emotion recognition in nurses. Here, we aimed to investigate facial emotion recognition ability in nurses and compare the abilities between nurses from psychiatry and other departments. METHODS: In this cross-sectional study, sixty seven nurses were divided into two groups according to their departments: psychiatry (n=31); and, other departments (n=36). A Facial Emotion Recognition Test, constructed from a set of photographs from Ekman and Friesen's book "Pictures of Facial Affect", was administered to all participants. RESULTS: In whole group, the highest mean accuracy rate of recognizing facial emotion was the happy (99.14%) while the lowest accurately recognized facial expression was fear (47.71%). There were no significant differences between two groups among mean accuracy rates in recognizing happy, sad, fear, angry, surprised facial emotion expressions (for all, p>0.05). The ability of recognizing disgusted and neutral facial emotions tended to be better in other nurses than psychiatry nurses (p=0.052 and p=0.053, respectively) Conclusion: This study was the first that revealed indifference in the ability of FER between psychiatry nurses and non-psychiatry nurses. In medical education curricula throughout the world, no specific training program is scheduled for recognizing emotional cues of patients. We considered that improving the ability of recognizing facial emotion expression in medical stuff might be beneficial in reducing inappropriate patient-medical stuff interaction.
Subject(s)
Facial Expression , Facial Recognition , Nurse Specialists , Nurses , Psychiatric Nursing , Adult , Cross-Sectional Studies , Curriculum , Emotions , Face , Female , Humans , Middle Aged , Young AdultABSTRACT
PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. MYC and BCL2 rearrangements have been reported in a proportion of DLBCLs, where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC and BCL2 translocations in DLBCL and assess the prognostic impact in DLBCL patients. MATERIALS AND METHODS: In the present study, we evaluated the expression patterns of CD 10, BCL6, and MUM 1 by immunohistochemistry in 121 cases with DLBCL in tissue microarray (TMA): 62 cases in germinal center B-cells (GCBs); and 59 cases in activated B-cells (ABCs) of which 60 were females and 61 were males. MYC and BCL2 rearrangements were investigated by interphase fluorescence in situ hybridization on TMAs in 97 DLBCLs. RESULT: MYC rearrangements were observed in 11 of 97 cases. There was no association with other clinical features, including age, sex, and nodal/extranodal disease. MYC rearrangement was associated with significantly worse overall survival (P < 0.01). BCL2 rearrangements were observed in 14 of 97 cases. There was no association with other clinical features including age and sex. BCL2 rearrangement had a worse outcome (P < 0.01). MYC and BCL2 rearrangements were observed in 3 of 97 cases with the age ofâ 53 (female), 53, 63 years old, respectively, died in 24, 18, and 35 months after the diagnosis. Two cases had primary nodal and one case primary extranodal presentations. All these patients had stage IV disease. CONCLUSION: We concluded that C-MYC and BCL2 may contribute to aggressive transformation, and more mechanism-based therapy should be explored. Targeted therapies involving these rearrangements and its associated pathways may change the fate of DLBCLs. Analysis of MYC gene rearrangement along with BCL2 is critical in the identification of high-risk patients with poor prognosis.
Subject(s)
Gene Expression Profiling , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-myc/genetics , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-myc/biosynthesis , Retrospective Studies , Young AdultABSTRACT
Subtelomeric rearrangements are an important cause of both sporadic and familial idiopathic mental retardation (MR) and/or congenital malformation syndromes. We report on a cohort of 107 children with idiopathic MR and normal karyotype 450-550 band level by GTG banding screened for subtelomeric rearrangements by multiprobe fluorescence in situ hybridization (FISH). In these cases, five patients had de novo deletions (1p deletion was found in 2 cases; 3q deletion, 9p and 9q deletions were found in 1 case each) and four patients had unbalanced rearrangements [der(5)t(5;15)(pter;qter)pat in 2 patients who were siblings, rec(10)dup(10p)inv(10)(p13q26)mat in 1 patient and der(18)t(18;22)(qter;qter) de novo in 1 patient]. Our study confirms that the subtelomeric rearrangements are a significant cause of idiopathic MR with dysmorphic features.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Intellectual Disability/genetics , Telomere/genetics , Child , Child, Preschool , Chromosome Banding , Chromosome Deletion , Cohort Studies , Female , Humans , In Situ Hybridization, Fluorescence , Infant , MaleABSTRACT
OBJECTIVE: We report on a case of a triploidy in one fetus of a twin pregnancy who presented with the findings of growth discordance. METHODS: Three weeks' difference between fetuses in ultrasonographic measurements in the first trimester was observed in a twin pregnancy following intracytoplasmic sperm injection (ICSI) treatment for male infertility. Hydrocephaly developed in the growth-discordant fetus subsequently. Amniocentesis for both fetuses and selective feticide for the abnormal one was performed at 19 weeks' gestation through a single insertion. Fetal karyotype of the abnormal one was 69,XXX and the healthy one was 46,XX. CONCLUSION: Early developed growth discordance in a twin pregnancy may be a sign of chromosomal abnormality such as triploidy. Those cases should be karyotyped without delay to decrease preterm delivery risk of possible selective feticide.