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1.
J Clin Oncol ; 41(24): 4045-4053, 2023 08 20.
Article in English | MEDLINE | ID: mdl-37267580

ABSTRACT

Data-driven basic, translational, and clinical research has resulted in improved outcomes for children, adolescents, and young adults (AYAs) with pediatric cancers. However, challenges in sharing data between institutions, particularly in research, prevent addressing substantial unmet needs in children and AYA patients diagnosed with certain pediatric cancers. Systematically collecting and sharing data from every child and AYA can enable greater understanding of pediatric cancers, improve survivorship, and accelerate development of new and more effective therapies. To accomplish this goal, the Childhood Cancer Data Initiative (CCDI) was launched in 2019 at the National Cancer Institute. CCDI is a collaborative community endeavor supported by a 10-year, $50-million (in US dollars) annual federal investment. CCDI aims to learn from every patient diagnosed with a pediatric cancer by designing and building a data ecosystem that facilitates data collection, sharing, and analysis for researchers, clinicians, and patients across the cancer community. For example, CCDI's Molecular Characterization Initiative provides comprehensive clinical molecular characterization for children and AYAs with newly diagnosed cancers. Through these efforts, the CCDI strives to provide clinical benefit to patients and improvements in diagnosis and care through data-focused research support and to build expandable, sustainable data resources and workflows to advance research well past the planned 10 years of the initiative. Importantly, if CCDI demonstrates the success of this model for pediatric cancers, similar approaches can be applied to adults, transforming both clinical research and treatment to improve outcomes for all patients with cancer.


Subject(s)
Neoplasms , Adolescent , United States/epidemiology , Humans , Child , Young Adult , Neoplasms/therapy , Ecosystem , Data Collection , National Cancer Institute (U.S.)
2.
Thromb Res ; 226: 100-106, 2023 06.
Article in English | MEDLINE | ID: mdl-37141794

ABSTRACT

Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 109/L (95%CI: 234-273 × 109/L) compared at 307 × 109/L (283-331 × 109/L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors.


Subject(s)
Blood Coagulation Disorders , Cancer Survivors , Neoplasms , Thromboembolism , Child , Humans , Thrombin , Cohort Studies , Neoplasms/complications , Blood Coagulation , Biomarkers
3.
Cardiooncology ; 9(1): 26, 2023 May 19.
Article in English | MEDLINE | ID: mdl-37208775

ABSTRACT

BACKGROUND: 25% of all breast cancer patients have HER-2 overexpression. Breast Cancer patients with HER-2 overexpression are typically treated with HER-2 inhibitors such as Trastuzumab. Trastuzumab is known to cause a decrease in left ventricular ejection fraction. The aim of this study is to create a cardiac risk prediction tool among women with Her-2 positive breast cancer to predict cardiotoxicity. METHOD: Using a split sample design, we created a risk prediction tool using patient level data from electronic medical records. The study included women 18 years of age and older diagnosed with HER-2 positive breast cancer who received Trastuzumab. Outcome measure was defined as a drop in LVEF by more than 10% to less than 53% at any time in the 1-year study period. Logistic regression was used to test predictors. RESULTS: The cumulative incidence of cardiac dysfunction in our study was 9.4%. The sensitivity and specificity of the model are 46% and 84%, respectively. Given a cumulative incidence of cardiotoxicity of 9%, the negative predictive value of the test was 94%. This suggests that in a low-risk population, the interval of screening for cardiotoxicity may be performed less frequently. CONCLUSION: Cardiac risk prediction tool can be used to identify Her-2 positive breast cancer patients at risk of developing cardiac dysfunction. Also, test characteristics in addition to disease prevalence may inform a rational strategy in performing cardiac ultrasound in Her-2 breast cancer patients. We have developed a cardiac risk prediction model with high NPV in a low-risk population which has an appealing cost-effectiveness profile.

4.
Am J Physiol Heart Circ Physiol ; 323(1): H130-H145, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35657614

ABSTRACT

Childhood cancer survivors (CCSs) face lifelong side effects related to their treatment with chemotherapy. Anthracycline agents, such as doxorubicin (DOX), are important in the treatment of childhood cancers but are associated with cardiotoxicity. Cardiac toxicities represent a significant source of chronic disability that cancer survivors face; despite this, the chronic cardiotoxicity phenotype and how it relates to acute toxicity remains poorly defined. To address this critical knowledge gap, we studied the acute effect of DOX on murine cardiac nonmyocytes in vivo. Determination of the acute cellular effects of DOX on nonmyocytes, a cell pool with finite replicative capacity, provides a basis for understanding the pathogenesis of the chronic heart disease that CCSs face. To investigate the acute cellular effects of DOX, we present single-cell RNA sequencing (scRNAseq) data from homeostatic cardiac nonmyocytes and compare it with preexisting datasets, as well as a novel CyTOF datasets. SCANPY, a python-based single-cell analysis, was used to assess the heterogeneity of cells detected in scRNAseq and CyTOF. To further assist in CyTOF data annotation, joint analyses of scRNAseq and CyTOF data using an artificial neural network known as sparse autoencoder for clustering, imputation, and embedding (SAUCIE) are performed. Lastly, the panel is tested on a mouse model of acute DOX exposure at two time points (24 and 72 h) after the last dose of doxorubicin and examined with joint clustering. In sum, we report the first ever CyTOF study of cardiac nonmyocytes and characterize the effect of acute DOX exposure with scRNAseq and CyTOF.NEW & NOTEWORTHY We describe the first mass cytometry studies of murine cardiac nonmyocytes. The mass cytometry panel is compared with single-cell RNA sequencing data. Homeostatic cardiac nonmyocytes are characterized by mass cytometry to identify and quantify four major cell populations: endothelial cells, fibroblasts, leukocytes, and pericytes. The single-cell acute nonmyocyte response to doxorubicin is studied at 24 and 72 h after doxorubicin exposure given daily for 5 days at a dose of 4 mg/kg/day.


Subject(s)
Cardiotoxicity , Endothelial Cells , Animals , Antibiotics, Antineoplastic/toxicity , Doxorubicin/toxicity , Endothelial Cells/pathology , Heart , Mice , Myocytes, Cardiac
5.
iScience ; 25(1): 103722, 2022 Jan 21.
Article in English | MEDLINE | ID: mdl-35005527

ABSTRACT

SARS-CoV-2 is a newly identified coronavirus that causes the respiratory disease called coronavirus disease 2019 (COVID-19). With an urgent need for therapeutics, we lack a full understanding of the molecular basis of SARS-CoV-2-induced cellular damage and disease progression. Here, we conducted transcriptomic analysis of human PBMCs, identified significant changes in mitochondrial, ion channel, and protein quality-control gene products. SARS-CoV-2 proteins selectively target cellular organelle compartments, including the endoplasmic reticulum and mitochondria. M-protein, NSP6, ORF3A, ORF9C, and ORF10 bind to mitochondrial PTP complex components cyclophilin D, SPG-7, ANT, ATP synthase, and a previously undescribed CCDC58 (coiled-coil domain containing protein 58). Knockdown of CCDC58 or mPTP blocker cyclosporin A pretreatment enhances mitochondrial Ca2+ retention capacity and bioenergetics. SARS-CoV-2 infection exacerbates cardiomyocyte autophagy and promotes cell death that was suppressed by cyclosporin A treatment. Our findings reveal that SARS-CoV-2 viral proteins suppress cardiomyocyte mitochondrial function that disrupts cardiomyocyte Ca2+ cycling and cell viability.

6.
Eur J Cancer ; 156: 127-137, 2021 10.
Article in English | MEDLINE | ID: mdl-34450551

ABSTRACT

BACKGROUND: Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. AIM: To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. METHODS: A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. RESULTS: 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. CONCLUSION: These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.


Subject(s)
Antineoplastic Agents/adverse effects , Cancer Survivors , Coronary Artery Disease/epidemiology , Diagnostic Screening Programs/standards , Neoplasms/therapy , Radiation Injuries/epidemiology , Adolescent , Adult , Age of Onset , Cardiotoxicity , Child , Child, Preschool , Coronary Artery Disease/diagnostic imaging , Female , Humans , Incidence , Male , Middle Aged , Neoplasms/epidemiology , Predictive Value of Tests , Prevalence , Prognosis , Radiation Injuries/diagnostic imaging , Radiotherapy/adverse effects , Risk Assessment , Risk Factors , Time Factors , Young Adult
7.
Compr Physiol ; 9(3): 905-931, 2019 06 12.
Article in English | MEDLINE | ID: mdl-31187890

ABSTRACT

Doxorubicin-induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk for cardiovascular disease is steadily increasing, as five-year survival rates for all types of childhood cancers continue to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients, childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late-onset toxicity is increasing in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors and over 50,000 of them will suffer from doxorubicin-induced cardiotoxicity. The majority of the research to-date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes through well-designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early- and late-onset cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu are impacted by doxorubicin exposure. The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin-induced cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for the coming years. Well-designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin-induced cardiotoxicity and directly lead to better diagnosis, treatment, and prevention. © 2019 American Physiological Society. Compr Physiol 9:905-931, 2019.


Subject(s)
Antibiotics, Antineoplastic/adverse effects , Cardiotoxicity/etiology , Doxorubicin/adverse effects , Age Factors , Antibiotics, Antineoplastic/pharmacology , Cardiotoxicity/diagnosis , Cardiotoxicity/metabolism , Cardiotoxicity/pathology , Child , DNA Damage , Doxorubicin/pharmacology , Endothelium, Vascular/drug effects , ErbB Receptors/metabolism , Humans , Mitochondria, Heart/drug effects , Myocytes, Cardiac/drug effects , Neuregulins/physiology , Reactive Oxygen Species/metabolism
8.
JAMA Oncol ; 5(6): 864-871, 2019 Jun 01.
Article in English | MEDLINE | ID: mdl-30703192

ABSTRACT

IMPORTANCE: Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children's Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin. OBJECTIVE: To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005. EXPOSURES: Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records. MAIN OUTCOMES AND MEASURES: Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories. RESULTS: Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model. CONCLUSIONS AND RELEVANCE: In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.


Subject(s)
Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Cancer Survivors/statistics & numerical data , Cardiotoxicity/epidemiology , Mitoxantrone/adverse effects , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Risk , Young Adult
9.
J Clin Oncol ; 36(21): 2135-2144, 2018 07 20.
Article in English | MEDLINE | ID: mdl-29874141

ABSTRACT

Cardiovascular disease (CVD), which includes cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction, is a major concern for long-term survivors of childhood cancer. There is clear evidence of increased risk of CVD largely attributable to treatment exposures at a young age, most notably anthracycline chemotherapy and chest-directed radiation therapy, and compounded by traditional cardiovascular risk factors accrued during decades after treatment exposure. Preclinical studies are limited; thus, it is a high priority to understand the pathophysiology of CVD as a result of anticancer treatments, taking into consideration the growing and developing heart. Recently developed personalized risk prediction models can provide decision support before initiation of anticancer therapy or facilitate implementation of screening strategies in at-risk survivors of cancer. Although consensus-based screening guidelines exist for the application of blood and imaging biomarkers of CVD, the most appropriate timing and frequency of these measures in survivors of childhood cancer are not yet fully elucidated. Longitudinal studies are needed to characterize the prognostic importance of subclinical markers of cardiovascular injury on long-term CVD risk. A number of prevention trials across the survivorship spectrum are under way, which include primary prevention (before or during cancer treatment), secondary prevention (after completion of treatment), and integrated approaches to manage modifiable cardiovascular risk factors. Ongoing multidisciplinary collaborations between the oncology, cardiology, primary care, and other subspecialty communities are essential to reduce therapeutic exposures and improve surveillance, prevention, and treatment of CVD in this high-risk population.


Subject(s)
Cancer Survivors/statistics & numerical data , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Anthracyclines/administration & dosage , Anthracyclines/adverse effects , Cardiovascular Diseases/physiopathology , Child , Humans , Neoplasms/drug therapy , Neoplasms/epidemiology
10.
J Pediatr Hematol Oncol ; 40(3): 208-215, 2018 04.
Article in English | MEDLINE | ID: mdl-29557918

ABSTRACT

We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared with control animals. Interestingly, moderate aerobic exercise during Doxo treatment significantly mitigated decreases in ejection fraction and fractional shortening. In contrast, these protective effects of exercise were not observed when exercise was started after completion of Doxo treatments. Moreover, in the TB-NM model, Doxo caused a decrease in heart mass: tibia length and in body weight that was prevented by exercise, whereas NTB-IC mice exhibited no change in these measurements. Doxo delivery to the hearts of TB-NM was decreased by consistent moderate aerobic exercise before Doxo injection. These findings demonstrate the important but subtle differences in cardiotoxicity observed in different mouse models. Collectively, these results also strongly suggest that aerobic exercise during early-life Doxo exposure mitigates cardiotoxicity, possibly through altered delivery of Doxo to myocardial tissue.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Cardiotoxicity/physiopathology , Doxorubicin/toxicity , Heart/drug effects , Physical Conditioning, Animal , Animals , Cardiotoxicity/etiology , Cardiotoxicity/prevention & control , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Nude , Neoplasms, Experimental/physiopathology
11.
Lancet ; 390(10112): 2545, 2017 12 09.
Article in English | MEDLINE | ID: mdl-29231830
12.
Am J Physiol Heart Circ Physiol ; 307(10): H1379-89, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25217655

ABSTRACT

Since the modern era of cancer chemotherapy that began in the mid-1940s, survival rates for children afflicted with cancer have steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related health effects; 25% are afflicted with a severe or life-threatening medical condition, with cardiovascular disease being a primary risk (96). Childhood cancer survivors have markedly elevated incidences of stroke, congestive heart failure (CHF), coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2 times higher than expected (93). Anthracyclines are a key component of most curative chemotherapeutic regimens used in pediatric cancer, and approximately half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to an increased risk of developing cardiomyopathy and CHF, often decades after treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well described; however, myocardial tissue is comprised of additional resident cell types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will summarize the current literature regarding the cellular and molecular responses to anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as well as those that mediate the myocardial injury response.


Subject(s)
Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Heart Diseases/chemically induced , Myocytes, Cardiac/drug effects , Survivors , Age Factors , Animals , Gene Expression Regulation/drug effects , Heart Diseases/genetics , Heart Diseases/metabolism , Heart Diseases/mortality , Heart Diseases/pathology , Humans , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Prognosis , Risk Assessment , Risk Factors , Signal Transduction/drug effects , Time Factors
13.
Cell Rep ; 7(1): 79-85, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24656816

ABSTRACT

Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.


Subject(s)
Myocytes, Cardiac/metabolism , Transcription Factors/metabolism , Animals , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Echocardiography , Energy Metabolism/genetics , Homeostasis , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myocytes, Cardiac/cytology , PPAR alpha/genetics , PPAR alpha/metabolism , RNA Polymerase II/metabolism , Transcription Factors/genetics , Transcription, Genetic
14.
Echocardiography ; 31(3): 375-84, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24103064

ABSTRACT

Echocardiography is a robust tool for assessing cardiac function in both humans and laboratory animals. Conventional echocardiographic measurements, including chamber dimensions, wall thickness, and ejection fraction are routinely obtained to assess cardiac function in mice. Recently, myocardial strain and strain rate measurements have been added to functional assessments to provide additional details on regional abnormalities that are not evident using conventional measurements. To date, all studies of strain and strain rate in mice or rats have involved adult animals. This study serves to outline methods for acquiring echocardiographic images in pediatric mice and to provide myocardial strain and strain rate values for healthy C57BL/6J mice between 3 and 11 weeks old. Between weeks 3 and 11, left ventricular radial strain ranged from 32 to 43% and longitudinal strain ranged from -15 to -19%, with analysis over time showing no significant changes with aging (radial strain, P = 0.192 and longitudinal strain, P = 0.264; n = 4 for each time point evaluated). In conclusion, myocardial strain analysis in pediatric mice is technically feasible and has potential application in studying the pathophysiology of pediatric cardiovascular disease.


Subject(s)
Animals, Newborn , Echocardiography, Doppler/methods , Heart Ventricles/diagnostic imaging , Ventricular Function, Left/physiology , Analysis of Variance , Animals , Mice , Mice, Inbred C57BL , Models, Animal , Myocardial Contraction/physiology , Sensitivity and Specificity , Stroke Volume
15.
Proteomics Clin Appl ; 7(7-8): 516-27, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23532927

ABSTRACT

The left ventricle (LV) responds to a myocardial infarction with an orchestrated sequence of events that result in fundamental changes to both the structure and function of the myocardium. This collection of responses is termed as LV remodeling. Myocardial ischemia resulting in necrosis is the initiating event that culminates in the formation of an extracellular matrix (ECM) rich infarct scar that replaces necrotic myocytes. While the cardiomyocyte is the major cell type that responds to ischemia, infiltrating leukocytes and cardiac fibroblasts coordinate the subsequent wound healing response. The matrix metalloproteinase family of enzymes regulates the inflammatory and ECM responses that modulate scar formation. Matridomics is the proteomic evaluation focused on ECM, while degradomics is the proteomic evaluation of proteases as well as their inhibitors and substrates. This review will summarize the use of proteomics to better understand matrix metalloproteinase roles in post myocardial infarction LV remodeling.


Subject(s)
Extracellular Matrix/metabolism , Proteomics/methods , Ventricular Remodeling , Animals , Extracellular Matrix/pathology , Extracellular Matrix Proteins/metabolism , Humans , Proteolysis
16.
Ann Diagn Pathol ; 16(5): 374-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-21658983

ABSTRACT

Involvement of the female genital tract by myeloid sarcoma as the initial presentation is extremely uncommon, especially in the vagina. The lack of specific histologic features and the unusual location can be a diagnostic challenge to both the surgical pathologist and the clinician. The very few reported cases of myeloid sarcoma occurring in the vagina have been exclusively seen in adults. We report a 16-year-old girl who presented with a vaginal mass of 4 weeks duration. The initial clinical impression was a Bartholin cyst vs an abscess. However, because of persistence of the vaginal mass after a full course of antibiotic treatment, a biopsy was performed. Immunohistochemistry supported the diagnosis of myeloid sarcoma. Peripheral blood and bone marrow studies were normal. The patient received 4 cycles of chemotherapy and remained disease free 5 months from therapy completion. The clinical course, diagnostic workup, and differential diagnosis of our patient are discussed. Reported cases of myeloid sarcoma occurring in the vagina are reviewed and summarized.


Subject(s)
Sarcoma, Myeloid/pathology , Vaginal Neoplasms/pathology , Abscess/diagnosis , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bartholin's Glands/pathology , Biomarkers, Tumor/metabolism , Cysts/diagnosis , Diagnosis, Differential , Female , Humans , Sarcoma, Myeloid/metabolism , Treatment Outcome , Vaginal Neoplasms/metabolism
17.
Clin Cancer Res ; 14(20): 6449-55, 2008 Oct 15.
Article in English | MEDLINE | ID: mdl-18927284

ABSTRACT

PURPOSE: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. EXPERIMENTAL DESIGN AND RESULTS: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. CONCLUSION: These results suggest that both TC-NER-induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , DNA Repair/drug effects , Dioxoles/pharmacology , Neoplasms/enzymology , RNA Polymerase II/metabolism , Tetrahydroisoquinolines/pharmacology , Transcription, Genetic/drug effects , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Blotting, Western , Cell Survival/drug effects , Cells, Cultured , Cockayne Syndrome/enzymology , Cockayne Syndrome/genetics , Cockayne Syndrome/pathology , Cysteine Proteinase Inhibitors/pharmacology , DNA Damage/drug effects , DNA Helicases/genetics , DNA Helicases/metabolism , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Fibroblasts/metabolism , Genetic Complementation Test , Humans , Leupeptins/pharmacology , Neoplasms/genetics , Neoplasms/pathology , Phosphorylation/drug effects , Poly-ADP-Ribose Binding Proteins , RNA Polymerase II/genetics , Sarcoma/enzymology , Sarcoma/genetics , Sarcoma/pathology , Trabectedin , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Xeroderma Pigmentosum/enzymology , Xeroderma Pigmentosum/genetics , Xeroderma Pigmentosum/metabolism , Xeroderma Pigmentosum/pathology , Xeroderma Pigmentosum Group D Protein/genetics , Xeroderma Pigmentosum Group D Protein/metabolism , von Hippel-Lindau Disease/enzymology , von Hippel-Lindau Disease/genetics , von Hippel-Lindau Disease/pathology
19.
J Biol Chem ; 278(22): 20303-12, 2003 May 30.
Article in English | MEDLINE | ID: mdl-12660252

ABSTRACT

DNA double-strand breaks originating from diverse causes in eukaryotic cells are accompanied by the formation of phosphorylated H2AX (gammaH2AX) foci. Here we show that gammaH2AX formation is also a cellular response to topoisomerase I cleavage complexes known to induce DNA double-strand breaks during replication. In HCT116 human carcinoma cells exposed to the topoisomerase I inhibitor camptothecin, the resulting gammaH2AX formation can be prevented with the phosphatidylinositol 3-OH kinase-related kinase inhibitor wortmannin; however, in contrast to ionizing radiation, only camptothecin-induced gammaH2AX formation can be prevented with the DNA replication inhibitor aphidicolin and enhanced with the checkpoint abrogator 7-hydroxystaurosporine. This gammaH2AX formation is suppressed in ATR (ataxia telangiectasia and Rad3-related) deficient cells and markedly decreased in DNA-dependent protein kinase-deficient cells but is not abrogated in ataxia telangiectasia cells, indicating that ATR and DNA-dependent protein kinase are the kinases primarily involved in gammaH2AX formation at the sites of replication-mediated DNA double-strand breaks. Mre11- and Nbs1-deficient cells are still able to form gammaH2AX. However, H2AX-/- mouse embryonic fibroblasts exposed to camptothecin fail to form Mre11, Rad50, and Nbs1 foci and are hypersensitive to camptothecin. These results demonstrate a conserved gammaH2AX response for double-strand breaks induced by replication fork collision. gammaH2AX foci are required for recruiting repair and checkpoint protein complexes to the replication break sites.


Subject(s)
Cell Cycle Proteins/metabolism , DNA Damage , DNA Replication , DNA Topoisomerases, Type I/metabolism , DNA-Binding Proteins/metabolism , Histones/metabolism , Nuclear Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Animals , Blotting, Western , Camptothecin/pharmacology , DNA Repair Enzymes , Enzyme Inhibitors/pharmacology , Humans , Hydrolysis , MRE11 Homologue Protein , Mice , Mice, Knockout , Microscopy, Confocal , Phosphorylation , Topoisomerase I Inhibitors , Tumor Cells, Cultured
20.
Cancer Res ; 62(17): 4899-902, 2002 Sep 01.
Article in English | MEDLINE | ID: mdl-12208738

ABSTRACT

The resistance of tumor cells to chemotherapeutic agents, such as cisplatin,is an important problem to be solved in cancer chemotherapy. One of the mechanisms associated with cisplatin resistance is nucleotide excision repair (NER). There are two pathways in NER, transcription-coupled NER (TC-NER) and global genome NER (GG-NER). Here, we report that TC-NER-deficient cells [xeroderma pigmentosum group A (XP-A), XP-D, XP-F, XP-G, Cockayne syndrome group A (CS-A), and CS-B] are hypersensitive to cisplatin irrespective of their GG-NER status, and that gene complementation with XPA and XPD increases resistance to cisplatin. By contrast, XP-C cells with selective defect in GG-NER but with normal TC-NER have normal resistance to cisplatin. XPC complementation had no effect on cisplatin antiproliferative activity. We propose that one of the pathways related to cisplatin response is TC-NER, not GG-NER.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , DNA Repair/physiology , Cell Line, Transformed , Drug Screening Assays, Antitumor/methods , Fibroblasts/drug effects , Humans , Transcription, Genetic , Tumor Cells, Cultured , Xeroderma Pigmentosum/genetics , Xeroderma Pigmentosum/pathology
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