Kathryn Wikenheiser-brokamp - Academia.edu (original) (raw)
Papers by Kathryn Wikenheiser-brokamp
Thorax
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the... more Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal. The LCA offers a variety of interactive options for investigators to search, visualise and reanalyse comprehensive single-cell multiomics data sets to reveal dysregulated genetic programmes at transcriptomic, epigenomic and cell–cell connectome levels.
ABSTRACTLymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly af... more ABSTRACTLymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM is characterized by the infiltration of the lungs by abnormally proliferating smooth muscle-like cells of unknown origin via an estrogen-dependent metastatic mechanism. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. Sirolimus, an FDA approved mTORC1 inhibitor and current best-choice medication for LAM stabilizes lung function in most LAM patients. However, it requires sustained application and remains inefficacious in some patients. The greatest barriers to finding a cure for LAM include its undetermined origin and unclear underlying pathogenesis. Our study aims to advance knowledge on the origin of LAM, and ultimately serve as a premise for the development of novel therapeutic targets ...
Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart... more Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart, kidneys and lungs. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting exclusively women. Both are caused by mutations in TSC1 and TSC2, resulting in mTORC1 hyperactivation. Single cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid pathway. Independent validation studies showed that acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzyme for regulating sphingolipid and ceramide metabolism, were significantly increased in TSC2-null cells, and their expression and activity were rapamycin-insensitive. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids. Suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) markedly decreased the viability of TSC2-null cells. In vivo, 17a significantly decreased the growth of Tsc2-null cell derived mouse xenografts. When combined with rapamycin, 17a more...
Journal of bronchology & interventional pulmonology, 2017
Transbronchial lung cryobiopsy (TBLC) has been used to establish the diagnosis of interstitial lu... more Transbronchial lung cryobiopsy (TBLC) has been used to establish the diagnosis of interstitial lung disease (ILD) in recent years. The technique and diagnostic yield vary among institutions. We report a new 2-scope technique and the results of TBLC in our institution. This is a retrospective chart review of patients who underwent TBLC for evaluation of ILD. Bronchoscopy with TBLC was performed by a board-certified interventional pulmonologist with a 2-scope technique under general anesthesia. A total of 74 patients underwent TBLC with a 2-scope technique. Their mean age was 54±14 years. The mean tissue surface area was 63.54±6.76 mm. The average anesthesia time was 80.66 minutes. The diagnostic yield was 87.84%. The most common diagnosis was sarcoidosis pneumothorax, which occurred in 5 cases (7%). There was 1 case with bronchoscopic-related respiratory failure associated with significant bleeding. Death occurred in 3 cases (4%), which is comparable to recent mortality data for &quo...
Annals of the American Thoracic Society, Jan 7, 2016
Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiol... more Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiolitis and lymphoid interstitial pneumonia, are commonly seen in association with Sjögren's syndrome. While the predominant computed tomographic (CT) findings in patients with lymphoid interstitial pneumonia/follicular bronchiolitis include poorly defined centrilobular nodules and ground glass attenuation, cystic changes can be seen in approximately two-thirds of these patients. The objective of this study was to define the clinical, radiological, and histopathological features of cyst-predominant lymphoid interstitial pneumonia/follicular bronchiolitis in patients with Sjögren's syndrome. We present 4 patients who were referred to our institution with diffuse cystic changes on chest CT imaging. All 4 had a presumptive diagnosis of lymphangioleiomyomatosis, but were subsequently found to have Sjögren's syndrome. The was established based on the clinical symptoms of xerostomia a...
American journal of respiratory and critical care medicine, Jan 23, 2015
The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous process... more The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction or replacement of alveolar septa, distal airways and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those due to low grade or high grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking related diseases, and inte...
Infectious Diseases in Clinical Practice, 2007
A 46-year-old male from Mauritania, West Africa, was referred to the pulmonary clinic for an abno... more A 46-year-old male from Mauritania, West Africa, was referred to the pulmonary clinic for an abnormal screening chest radiograph obtained at the tuberculosis clinic. The patient had been in the United States for 6 years and recently completed a course of isoniazid for latent tuberculosis. He denied all symptoms except back pain on history and review of systems. No medical history was reported, and his surgical history was noncontributory. The patient had a 5 pack-year history of smoking but quit 20 years prior. The patient visited Mauritania 3 years ago but otherwise denied travel or sick contacts. Physical examination demonstrated normal vital signs and blood oxygen saturation. Findings from cardiac, pulmonary, and abdominal examinations were unremarkable. The frontal chest radiograph revealed a large oval masslike density in the right mid to lower lung (Fig. 1). Computed tomography (CT) of the chest demonstrated a large fluid-filled cystic mass in the right lung, abutting the major and minor fissures, which contained a daughter cyst in its posteromedial aspect (Fig. 2). Abdomen CT additionally showed a septated cystic lesion in the inferior tip of the right hepatic lobe (Fig. 3). Laboratory data including complete blood count, basic metabolic panel, liver function tests, coagulation profile, and echinococcal IgG and IgM were all within reference range. Results of pulmonary function tests were also normal. The patient was referred to thoracic surgery to be evaluated for resection of the right lung cystic lesion with preoperative and postoperative treatment of albendazole (400 mg twice daily for 3 cycles of 28 days on and 14 days off the drug). Operative treatment was chosen, including cystotomy and capitonnage. Under general anesthesia with lung isolation via a double-lumen endotracheal tube, a right (serratus-sparing) posterolateral thoracotomy was performed in the fifth intercostal space. A white cystic structure was identified in the right middle lobe (Fig. 4). Spillage of cyst contents was meticulously avoided. Povidone iodine-soaked sponges were packed around the cyst. It was needle aspirated to decrease intracystic pressure. The cyst was then opened (cystotomy), the remaining fluid was aspirated, the germinative membrane was removed, and the cavity was irrigated with povidone iodine.
Nature Communications, 2020
Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have... more Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.
Pediatric and Developmental Pathology, 2015
Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in child... more Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in children. Like other solid dysontogenic neoplasms, this tumor typically presents before 7 years of age. The earliest manifestation is the presence of a lung cyst(s), which is usually recognized in the first year of life and is difficult to differentiate on the basis of imaging studies from nonneoplastic cysts of early childhood. From a multilocular cyst, PPB has the potential to progress to a high-grade multipatterned primitive sarcoma. More than 65% of all affected children have a heterozygous germline mutation in DICER1. The DICER1 PPB familial tumor predisposition syndrome is initially recognized in most cases on the basis of PPB alone but also by several other unique and characteristic extrapulmonary tumors, including pediatric cystic nephroma, nasal chondromesenchymal hamartoma, nodular lesions of the thyroid, embryonal rhabdomyosarcoma of the cervix, and ciliary body medulloepithelioma.
The Journal of Pediatrics, 2015
Training fellows, the next generation of academic pediatricians, is challenging in rapidly changi... more Training fellows, the next generation of academic pediatricians, is challenging in rapidly changing and expanding clinical and research environments. Research methods and techniques are revolutionizing both translational and basic research. Investigators who can seamlessly transfer research from bench-to-bedside have become a critical asset. This benchto-bedside approach has benefited greatly from more rigorous research in quality improvement and education, 1-3 shifting from process to focus on patient outcomes. 4-6 Academic institutions, their faculty, and fellowship programs must be equipped to effectively train fellows in these research methodologies, employing collaborative and interdisciplinary approaches to foster team science and allow all programs to utilize the array of institutional resources. Institutional Need for Standardized Fellowship Training Accreditation Council for Graduate Medical Education (ACGME) accredited fellowships are designed to train the next generation of clinicians, researchers, and leaders. 7 Although fellowships are often structured to emphasize scholarship, limited divisional resources and mentorship can impact fellows' abilities to achieve the desired outcomes. An informal needs assessment by institutional leadership raised concern for such limitations and noted variability in recruitment, research training and collaboration. The Office of Pediatric Clinical Fellowships (OPCF) was developed to address this gap by augmenting research and recruitment support. Utilizing a Logic Model to Conceptualize the OPCF Institutional and graduate medical education leadership utilized a logic model framework 8,9 to build the OPCF. We envisioned exceptional, multidisciplinary, interdivisional research training with diminished variability between fellowship programs (Figure; available at www. jpeds.com). The leadership team and key stakeholders defined OPCF elements, highlighting how the OPCF program (inputs/resources) would lead to desired products (outputs/activities). Both short-and long-term outcomes were conceived as critical
The Journal of pathology, Jan 15, 2014
Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing ... more Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological processes critical in development and disease pathogenesis. Significant challenges in defining the role of DICER1 in human disease are identifying cause-effect relationships and generating manipulatable systems that model the complexity of organ development and disease pathogenesis. Here we report the generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for the development of cystic lungs that histologically and phenotypically model PPB. Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype ...
Science, 2009
A rare form of lung cancer in children is associated with mutational disruption of an enzyme that... more A rare form of lung cancer in children is associated with mutational disruption of an enzyme that generates small noncoding RNAs.
Cancer Research, 2010
Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and presents as metas... more Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and presents as metastatic diseases in ∼50% of patients. Patients with metastatic MTC are typically incurable because of the poor tumor response to current chemotherapeutics and radiation treatment. MTC occurs as sporadic tumors in ∼75% of cases. The remaining cases are familial and associated with either multiple neuroendocrine neoplasia syndromes or familial MTC syndrome. The Rearranged during Transfection (RET) proto-oncogene plays a key role in MTC development: however, the absence of RET mutations in ∼50% of sporadic cases and the variable clinical manifestations in patients with the same RET mutation provide compelling evidence that other genetic alterations are involved in MTC pathogenesis. Recent studies in human tumors and mouse models suggest that the Rb and p53 pathways cooperate to suppress MTC evolution. Although some p53 mutations cause a loss of function, most p53 mutations detected in human c...
American Journal of Respiratory and Critical Care Medicine, 2014
is a rare, neoplastic lung disease that affects women more often than men, and is associated with... more is a rare, neoplastic lung disease that affects women more often than men, and is associated with cystic destruction of the lung (1, 2). Over 65% of patients with LAM develop pneumothorax during the course of their illness, followed by two or more recurrences, on average (3, 4). An attempt at pleural symphysis with the first pneumothorax is therefore recommended, despite pleurodesis failure rates that exceed those of Author disclosures are available with the text of this letter at www.atsjournals.org.
American Journal of Respiratory and Critical Care Medicine, 2013
American journal of respiratory and critical care medicine, Jan 23, 2015
The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophys... more The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. While lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutati...
Stem Cell Reports, 2016
Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types ... more Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types at least in part by preferentially utilizing error-free homologous recombination (HR) for DNA repair. Many endogenous metabolites cause DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway using HR. To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway. Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally. Mechanistic studies revealed that G2-phase FA-deficient iPSCs possess large gH2AX-RAD51 foci indicative of accrued DNA damage, which correlated with activated DNA-damage signaling through CHK1. CHK1 inhibition specifically rescued the growth of FA-deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities. These studies reveal that PSCs possess hyperactive CHK1 signaling that restricts their selfrenewal in the absence of error-free DNA repair.
Thorax
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the... more Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal. The LCA offers a variety of interactive options for investigators to search, visualise and reanalyse comprehensive single-cell multiomics data sets to reveal dysregulated genetic programmes at transcriptomic, epigenomic and cell–cell connectome levels.
ABSTRACTLymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly af... more ABSTRACTLymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM is characterized by the infiltration of the lungs by abnormally proliferating smooth muscle-like cells of unknown origin via an estrogen-dependent metastatic mechanism. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. Sirolimus, an FDA approved mTORC1 inhibitor and current best-choice medication for LAM stabilizes lung function in most LAM patients. However, it requires sustained application and remains inefficacious in some patients. The greatest barriers to finding a cure for LAM include its undetermined origin and unclear underlying pathogenesis. Our study aims to advance knowledge on the origin of LAM, and ultimately serve as a premise for the development of novel therapeutic targets ...
Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart... more Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart, kidneys and lungs. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting exclusively women. Both are caused by mutations in TSC1 and TSC2, resulting in mTORC1 hyperactivation. Single cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid pathway. Independent validation studies showed that acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzyme for regulating sphingolipid and ceramide metabolism, were significantly increased in TSC2-null cells, and their expression and activity were rapamycin-insensitive. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids. Suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) markedly decreased the viability of TSC2-null cells. In vivo, 17a significantly decreased the growth of Tsc2-null cell derived mouse xenografts. When combined with rapamycin, 17a more...
Journal of bronchology & interventional pulmonology, 2017
Transbronchial lung cryobiopsy (TBLC) has been used to establish the diagnosis of interstitial lu... more Transbronchial lung cryobiopsy (TBLC) has been used to establish the diagnosis of interstitial lung disease (ILD) in recent years. The technique and diagnostic yield vary among institutions. We report a new 2-scope technique and the results of TBLC in our institution. This is a retrospective chart review of patients who underwent TBLC for evaluation of ILD. Bronchoscopy with TBLC was performed by a board-certified interventional pulmonologist with a 2-scope technique under general anesthesia. A total of 74 patients underwent TBLC with a 2-scope technique. Their mean age was 54±14 years. The mean tissue surface area was 63.54±6.76 mm. The average anesthesia time was 80.66 minutes. The diagnostic yield was 87.84%. The most common diagnosis was sarcoidosis pneumothorax, which occurred in 5 cases (7%). There was 1 case with bronchoscopic-related respiratory failure associated with significant bleeding. Death occurred in 3 cases (4%), which is comparable to recent mortality data for &quo...
Annals of the American Thoracic Society, Jan 7, 2016
Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiol... more Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiolitis and lymphoid interstitial pneumonia, are commonly seen in association with Sjögren's syndrome. While the predominant computed tomographic (CT) findings in patients with lymphoid interstitial pneumonia/follicular bronchiolitis include poorly defined centrilobular nodules and ground glass attenuation, cystic changes can be seen in approximately two-thirds of these patients. The objective of this study was to define the clinical, radiological, and histopathological features of cyst-predominant lymphoid interstitial pneumonia/follicular bronchiolitis in patients with Sjögren's syndrome. We present 4 patients who were referred to our institution with diffuse cystic changes on chest CT imaging. All 4 had a presumptive diagnosis of lymphangioleiomyomatosis, but were subsequently found to have Sjögren's syndrome. The was established based on the clinical symptoms of xerostomia a...
American journal of respiratory and critical care medicine, Jan 23, 2015
The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous process... more The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction or replacement of alveolar septa, distal airways and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those due to low grade or high grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking related diseases, and inte...
Infectious Diseases in Clinical Practice, 2007
A 46-year-old male from Mauritania, West Africa, was referred to the pulmonary clinic for an abno... more A 46-year-old male from Mauritania, West Africa, was referred to the pulmonary clinic for an abnormal screening chest radiograph obtained at the tuberculosis clinic. The patient had been in the United States for 6 years and recently completed a course of isoniazid for latent tuberculosis. He denied all symptoms except back pain on history and review of systems. No medical history was reported, and his surgical history was noncontributory. The patient had a 5 pack-year history of smoking but quit 20 years prior. The patient visited Mauritania 3 years ago but otherwise denied travel or sick contacts. Physical examination demonstrated normal vital signs and blood oxygen saturation. Findings from cardiac, pulmonary, and abdominal examinations were unremarkable. The frontal chest radiograph revealed a large oval masslike density in the right mid to lower lung (Fig. 1). Computed tomography (CT) of the chest demonstrated a large fluid-filled cystic mass in the right lung, abutting the major and minor fissures, which contained a daughter cyst in its posteromedial aspect (Fig. 2). Abdomen CT additionally showed a septated cystic lesion in the inferior tip of the right hepatic lobe (Fig. 3). Laboratory data including complete blood count, basic metabolic panel, liver function tests, coagulation profile, and echinococcal IgG and IgM were all within reference range. Results of pulmonary function tests were also normal. The patient was referred to thoracic surgery to be evaluated for resection of the right lung cystic lesion with preoperative and postoperative treatment of albendazole (400 mg twice daily for 3 cycles of 28 days on and 14 days off the drug). Operative treatment was chosen, including cystotomy and capitonnage. Under general anesthesia with lung isolation via a double-lumen endotracheal tube, a right (serratus-sparing) posterolateral thoracotomy was performed in the fifth intercostal space. A white cystic structure was identified in the right middle lobe (Fig. 4). Spillage of cyst contents was meticulously avoided. Povidone iodine-soaked sponges were packed around the cyst. It was needle aspirated to decrease intracystic pressure. The cyst was then opened (cystotomy), the remaining fluid was aspirated, the germinative membrane was removed, and the cavity was irrigated with povidone iodine.
Nature Communications, 2020
Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have... more Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.
Pediatric and Developmental Pathology, 2015
Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in child... more Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in children. Like other solid dysontogenic neoplasms, this tumor typically presents before 7 years of age. The earliest manifestation is the presence of a lung cyst(s), which is usually recognized in the first year of life and is difficult to differentiate on the basis of imaging studies from nonneoplastic cysts of early childhood. From a multilocular cyst, PPB has the potential to progress to a high-grade multipatterned primitive sarcoma. More than 65% of all affected children have a heterozygous germline mutation in DICER1. The DICER1 PPB familial tumor predisposition syndrome is initially recognized in most cases on the basis of PPB alone but also by several other unique and characteristic extrapulmonary tumors, including pediatric cystic nephroma, nasal chondromesenchymal hamartoma, nodular lesions of the thyroid, embryonal rhabdomyosarcoma of the cervix, and ciliary body medulloepithelioma.
The Journal of Pediatrics, 2015
Training fellows, the next generation of academic pediatricians, is challenging in rapidly changi... more Training fellows, the next generation of academic pediatricians, is challenging in rapidly changing and expanding clinical and research environments. Research methods and techniques are revolutionizing both translational and basic research. Investigators who can seamlessly transfer research from bench-to-bedside have become a critical asset. This benchto-bedside approach has benefited greatly from more rigorous research in quality improvement and education, 1-3 shifting from process to focus on patient outcomes. 4-6 Academic institutions, their faculty, and fellowship programs must be equipped to effectively train fellows in these research methodologies, employing collaborative and interdisciplinary approaches to foster team science and allow all programs to utilize the array of institutional resources. Institutional Need for Standardized Fellowship Training Accreditation Council for Graduate Medical Education (ACGME) accredited fellowships are designed to train the next generation of clinicians, researchers, and leaders. 7 Although fellowships are often structured to emphasize scholarship, limited divisional resources and mentorship can impact fellows' abilities to achieve the desired outcomes. An informal needs assessment by institutional leadership raised concern for such limitations and noted variability in recruitment, research training and collaboration. The Office of Pediatric Clinical Fellowships (OPCF) was developed to address this gap by augmenting research and recruitment support. Utilizing a Logic Model to Conceptualize the OPCF Institutional and graduate medical education leadership utilized a logic model framework 8,9 to build the OPCF. We envisioned exceptional, multidisciplinary, interdivisional research training with diminished variability between fellowship programs (Figure; available at www. jpeds.com). The leadership team and key stakeholders defined OPCF elements, highlighting how the OPCF program (inputs/resources) would lead to desired products (outputs/activities). Both short-and long-term outcomes were conceived as critical
The Journal of pathology, Jan 15, 2014
Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing ... more Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological processes critical in development and disease pathogenesis. Significant challenges in defining the role of DICER1 in human disease are identifying cause-effect relationships and generating manipulatable systems that model the complexity of organ development and disease pathogenesis. Here we report the generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for the development of cystic lungs that histologically and phenotypically model PPB. Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype ...
Science, 2009
A rare form of lung cancer in children is associated with mutational disruption of an enzyme that... more A rare form of lung cancer in children is associated with mutational disruption of an enzyme that generates small noncoding RNAs.
Cancer Research, 2010
Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and presents as metas... more Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and presents as metastatic diseases in ∼50% of patients. Patients with metastatic MTC are typically incurable because of the poor tumor response to current chemotherapeutics and radiation treatment. MTC occurs as sporadic tumors in ∼75% of cases. The remaining cases are familial and associated with either multiple neuroendocrine neoplasia syndromes or familial MTC syndrome. The Rearranged during Transfection (RET) proto-oncogene plays a key role in MTC development: however, the absence of RET mutations in ∼50% of sporadic cases and the variable clinical manifestations in patients with the same RET mutation provide compelling evidence that other genetic alterations are involved in MTC pathogenesis. Recent studies in human tumors and mouse models suggest that the Rb and p53 pathways cooperate to suppress MTC evolution. Although some p53 mutations cause a loss of function, most p53 mutations detected in human c...
American Journal of Respiratory and Critical Care Medicine, 2014
is a rare, neoplastic lung disease that affects women more often than men, and is associated with... more is a rare, neoplastic lung disease that affects women more often than men, and is associated with cystic destruction of the lung (1, 2). Over 65% of patients with LAM develop pneumothorax during the course of their illness, followed by two or more recurrences, on average (3, 4). An attempt at pleural symphysis with the first pneumothorax is therefore recommended, despite pleurodesis failure rates that exceed those of Author disclosures are available with the text of this letter at www.atsjournals.org.
American Journal of Respiratory and Critical Care Medicine, 2013
American journal of respiratory and critical care medicine, Jan 23, 2015
The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophys... more The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. While lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutati...
Stem Cell Reports, 2016
Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types ... more Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types at least in part by preferentially utilizing error-free homologous recombination (HR) for DNA repair. Many endogenous metabolites cause DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway using HR. To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway. Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally. Mechanistic studies revealed that G2-phase FA-deficient iPSCs possess large gH2AX-RAD51 foci indicative of accrued DNA damage, which correlated with activated DNA-damage signaling through CHK1. CHK1 inhibition specifically rescued the growth of FA-deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities. These studies reveal that PSCs possess hyperactive CHK1 signaling that restricts their selfrenewal in the absence of error-free DNA repair.