Clifford Bogue | Yale University School of Medicine (original) (raw)

Papers by Clifford Bogue

Genes & development, 2016

Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesi... more Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16(INK4a) and p19(ARF), which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.

The Journal of Pediatrics, 1992

ABSTRACT : In this review of recently reported studies in pediatric critical care, we focus on fo... more ABSTRACT : In this review of recently reported studies in pediatric critical care, we focus on four topics. First, several studies of surfactant use in preterm infants are compared. The use of surfactant for the adult respiratory distress syndrome and meconium aspiration is discussed. Second, studies of high-frequency jet and oscillatory ventilation are reviewed. These two modes of ventilation have limited clinical indications and need more study. Third, studies of cardiopulmonary interactions during positive pressure ventilation are included; these studies provide insight into the effects of positive pressure ventilation on the cardiovascular system. Finally, the measurement of pulmonary mechanical function in children is reviewed, with particular emphasis on its application to infants receiving assisted ventilation.

Journal of Pediatric Endocrinology and Metabolism, 2007

Aim: To identify patients aged 10-30 years with probable hyperglycemic hyperosmolar syndrome (HHS... more Aim: To identify patients aged 10-30 years with probable hyperglycemic hyperosmolar syndrome (HHS), to describe demographic and clinical profiles, and to attempt to assess risk factors for poor outcomes. Study design: Retrospective cohort study (medical records review). Setting: A 944-bed tertiary care teaching and research hospital and a 425-bed affiliated facility. Patients: 10-30 year-old patients with a primary or secondary discharge diagnosis of HHS or diabetic ketoacidosis (DKA). Patients with a serum glucose >600 mg/dl in the absence of significant ketoacidosis (possible HHS) were profiled. Further stratification based on measured or calculated serum osmolarity >320 mOsm/kg (probable HHS) was undertaken. Interventions: Patients received treatment for hyperglycemic crises, consisting primarily of fluids, electrolyte replacement and insulin. Measurements and main results: Of the 629 admissions, 10 with a diagnosis of HHS and 33 with a diagnosis of DKA met the initial study criteria for HHS. 60% were African Americans and 89% were new-onset diabetics. From this group, 20 admissions had serum osmolarity >320 mOsm/kg. Fisher's exact test and Pearson coefficients were used to examine associations

Genes & Development, 2014

The homeodomain transcription factor HHEX (hematopoietically expressed homeobox) has been repeate... more The homeodomain transcription factor HHEX (hematopoietically expressed homeobox) has been repeatedly linked to type 2 diabetes mellitus (T2DM) using genome-wide association studies. We report here that within the adult endocrine pancreas, Hhex is selectively expressed in the somatostatin-secreting δ cell. Using two mouse models with Hhex deficiency in the endocrine pancreas, we show that Hhex is required for δ-cell differentiation. Decreased somatostatin levels in Hhex-deficient islets cause disrupted paracrine inhibition of insulin release from β cells. These findings identify Hhex as the first transcriptional regulator specifically required for islet δ cells and suggest compromised paracrine control as a contributor to T2DM.

Development, 2004

The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and fore... more The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex–/– mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2)hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreas...

Bogue, Clifford W. Invited Review: Functional genomics in the mouse: powerful techniques for unra... more Bogue, Clifford W. Invited Review: Functional genomics in the mouse: powerful techniques for unraveling the basis of human development and disease. J Appl Physiol 94: 2502–2509, 2003; 10.1152/japplphysiol.00209. 2003.—Now that near-complete DNA sequences of both the mouse and human genomes are available, the next major challenge will be to determine how each of these genes functions, both alone and in combination with other genes in the genome. The mouse has a long and rich history in biological research, and many consider it a model organism for the study of human development and disease. Over the past few years, exciting progress has been made in developing techniques for chromosome engineering, mutagenesis, mapping and maintenance of mutations, and identification of mutant genes in the mouse. In this minireview, many of these powerful techniques will be presented along with their application to the study of development, physiology, and disease.

ulates promoter of the Na1-dependent bile acid cotrans-porter. Am J Physiol Gastrointest Liver Ph... more ulates promoter of the Na1-dependent bile acid cotrans-porter. Am J Physiol Gastrointest Liver Physiol 279: G347–G355, 2000.—The divergent homeobox gene Hex is expressed in both developing and mature liver. A putative Hex binding site was identified in the promoter region of the liver-specific Na1-bile acid cotransporter gene (ntcp), and we hypothesized that Hex regulates the ntcp promoter through this site. Successive 59-deletions of the ntcp promoter in a luciferase reporter construct transfected into Hep G2 cells confirmed a Hex response element (HRE) within the ntcp promoter (nt 2733/2714). Moreover, p-CMHex transacti-vated a heterologous promoter construct containing HRE multimers (p4xHRELUC), whereas a 5-bp mutation of the core HRE eliminated transactivation. A dominant negative form of Hex (p-Hex-DN) suppressed basal luciferase activity

Nature communications, Jul 13, 2018

Formation of the lymphatic system requires the coordinated expression of several key regulators: ... more Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulatio...

Pediatrics, 2017

The "7 Great Achievements in Pediatric Research" campaign noted discoveries in the past... more The "7 Great Achievements in Pediatric Research" campaign noted discoveries in the past 40 years that have improved child and adult health in the United States and around the globe. This article predicts the next 7 great pediatric research advancements, including new immunizations, cancer immunotherapy, genomic discoveries, identification of early antecedents of adult health, impact of specific social-environmental influences on biology and health, quality improvement science, and implementation and dissemination research to reduce global poverty. It is an extraordinary time of new research tools that include electronic health records, technological ability to manage big data and measure "omics," and new functional and structural imaging modalities. These tools will discern mechanisms leading to health and disease with new prevention targets and cures. This article further discusses the challenges and opportunities to accelerate these exciting pediatric research ...

The Faseb Journal, Mar 1, 2007

Pediat Inf Dis J, 1990

Cat-scratch disease is usually a benign, self-limited disease that causes regional lymphadenopath... more Cat-scratch disease is usually a benign, self-limited disease that causes regional lymphadenopathy. Occasionally, it may present with systemic symptoms and have a prolonged course. To date, antibiotic therapy has not been proved to be of value. We describe three patients with cat-scratch disease who were treated successfully with gentamicin sulfate. Two patients had extensive hepatic involvement, and one patient had regional lymphadenopathy. All three patients responded within 48 hours to intravenous gentamicin. Extensive follow-up has shown no recurrence of symptoms. These cases suggest that gentamicin may be efficacious in shortening the course of cat-scratch disease. Prospective, randomized trials should be performed to confirm these results.

The Pediatric Infectious Disease Journal, 1995

1096 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 14, No. 12, Dec, 1995 pitalization, many widel... more 1096 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 14, No. 12, Dec, 1995 pitalization, many widely dispersed fine discrete red-dish violet pinpoint petechiae were noted on all extrem-ities including both palms and soles. In addition there were several 1-to ...

Journal of Applied Physiology, 2003

Journal of Diabetes Science and Technology, 2012

BackgroundThe practice of glycemic control with intravenous insulin in critically ill patients ha... more BackgroundThe practice of glycemic control with intravenous insulin in critically ill patients has brought clinical focus on understanding the effects of hypoglycemia, especially in children. Very little is published on the impact of hypoglycemia in this population. We aimed to review the existing literature on hypoglycemia in critically ill neonates and children.MethodsWe performed a systematic review of the literature up to August 2011 using PubMed, Ovid MEDLINE and ISI Web of Science using the search terms “hypoglycemia or hypoglyc*” and “critical care or intensive care or critical illness”. Articles were limited to “all child (0–18 years old)” and “English”.ResultsA total of 513 articles were identified and 132 were included for review. Hypoglycemia is a significant concern among pediatric and neonatal intensivists. Its definition is complicated by the use of a biochemical measure (i.e., blood glucose) for a pathophysiologic problem (i.e., neuroglycopenia). Based on associated outcomes, we suggest defining hypoglycemia as <40–45 mg/dl in neonates and <60–65 mg/dl in children. Below the suggested threshold values, hypoglycemia is associated with worse neurological outcomes, increased intensive care unit stay, and increased mortality. Disruptions in carbohydrate metabolism increase the risk of hypoglycemia incritically ill children. Prevention of hypoglycemia, especially in the setting of intravenous insulin use, will be best accomplished by the combination of accurate measuring techniques, frequent or continuous glucose monitoring, and computerized insulin titration protocols.ConclusionStudies on hypoglycemia in critically ill children have focused on spontaneous hypoglycemia. With the current practice of maintaining blood glucose within a narrow range with intravenous insulin, the risk factors and outcomes associated with insulin-induced hypoglycemia should be rigorously studied to prevent hypoglycemia and potentially improve outcomes of critically ill children.

Gene, May 1, 2000

The orphan homeobox gene, Hex, has a limited domain of expression which includes the developing a... more The orphan homeobox gene, Hex, has a limited domain of expression which includes the developing and adult mouse liver. Hex is expressed in the developing liver coincident with the forkhead/winged helix transcription factor, Hepatocyte Nuclear Factor 3beta (HNF3beta). Although preliminary characterization of the mouse Hex promoter has recently been reported, the identity of the molecular regulators that drive liver expression is not known. We hypothesized that putative HNF3beta and GATA-4 elements within the Hex promoter would confer liver-enriched expression. A series of Hex promoter-driven luciferase reporter constructs were transfected in liver-derived HepG2 and fibroblast-like Cos cells+/-HNF3beta or GATA expression plasmids. The Hex promoter region from nt -235/+22 conferred basal activity in both HepG2 and Cos cells, with the region from -103/+22 conferring liver-enriched activity. HNF3beta and GATA-4 transactivated the promoter via response elements located within nt -103/+22, whereas Sp1 activated the -235/+22 construct. Mutation of the HNF3 element significantly reduced promoter activity in HepG2 cells, whereas this element in isolation conferred HNF3beta responsiveness to a heterologous promoter. Electrophoretic mobility shift assays were performed to confirm transcription factor:DNA binding. We conclude that HNF3beta and GATA-4 contribute to liver-enriched expression of Hex.

Pediatric Research, 2015

, the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of acce... more , the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of accelerating children's medical advances by creating an independent global Pediatric Clinical Trials Network. The Forum identified challenges posed by the US and global clinical trial systems regarding testing and disseminating drugs and devices for pediatric patients. Stakeholders mapped a vision to improve the safety and efficacy of pediatric drugs, biological products, and medical devices by creating a global Pediatric Clinical Trials Network. Such a Network would act as a central infrastructure for pediatric subspecialties and enable dedicated staff to provide clinical research sites with scientific, medical, and operational support. A Network would facilitate development and availability of innovative, high-quality therapies to extend and enhance the lives of neonates, infants, children, adolescents, and young adults. Participants expressed strong interest in forming such a Network, since drugs and devices still come to market without adequate pediatric indications-particularly in neonatology and rare diseases. Participants developed a Consensus Statement expressing their shared vision for a Network: Attendees of the Pediatric Clinical Trials Stakeholder Forum resolved to establish a Global Pediatric Clinical Trials Network and are committed to engage in the work to create and sustain it.