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1.
Hum Pathol ; 146: 23-27, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38442781

ABSTRACT

Gangliocytic paragangliomas are rare neoplasms occurring almost exclusively in the ampullary region of the gastrointestinal tract. Although these tumors are not typically considered in the differential diagnosis of primary pulmonary neoplasia, 5 cases of primary pulmonary gangliocytic paragangliomas have been previously reported. Herein we report our experience with 3 additional examples, all referred to our Anatomic Pathology Consultation service. The patients (a 32-year-old man, a 69-year-old woman and a 55-year-old man) each presented with an endobronchial (2 cases) or upper lobe lung mass, ranging from 1.5 to 2.5 cm in maximum dimension. Biopsy and endobronchial debulking specimens demonstrated the classic triphasic morphology of gangliocytic paraganglioma, with epithelial, spindled and ganglion-like cells. By immunohistochemistry, the tumors were positive for keratin, synaptophysin and chromogranin A in the epithelial component, S100 protein and glial fibrillary acidic protein (GFAP) in the Schwannian spindled cells, and synaptophysin in ganglion cells. TTF1 expression was seen in the epithelial components of 2 cases. The Ki-67 labelling index was low (<2%). Primary pulmonary gangliocytic paragangliomas should be distinguished from carcinoid tumors, given the different natural histories and risk stratification approaches for these morphologically similar tumors. Awareness that gangliocytic paraganglioma may occur in the lung and appropriate immunohistochemical studies are key to correct diagnosis.


Subject(s)
Biomarkers, Tumor , Carcinoid Tumor , Immunohistochemistry , Lung Neoplasms , Humans , Lung Neoplasms/pathology , Lung Neoplasms/diagnosis , Male , Female , Middle Aged , Aged , Diagnosis, Differential , Biomarkers, Tumor/analysis , Adult , Carcinoid Tumor/pathology , Carcinoid Tumor/diagnosis , Carcinoid Tumor/chemistry , Paraganglioma/pathology , Paraganglioma/diagnosis , Biopsy , Predictive Value of Tests
2.
ACS Chem Neurosci ; 14(11): 1971-1980, 2023 06 07.
Article in English | MEDLINE | ID: mdl-37200505

ABSTRACT

Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence.


Subject(s)
Peptides , Protein Serine-Threonine Kinases , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/chemistry , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Dimerization , Leucine/metabolism , Protein Serine-Threonine Kinases/genetics , Peptides/pharmacology , Peptides/metabolism , Mutation
3.
J Bronchology Interv Pulmonol ; 30(2): 155-162, 2023 Apr 01.
Article in English | MEDLINE | ID: mdl-36066326

ABSTRACT

BACKGROUND: Robotic assisted bronchoscopy (RAB) is designed to increase bronchoscopic accessibility for difficult to reach pulmonary lesions. One limitation to success of RAB is computed tomography (CT) to body divergence. Real time imaging with cone beam CT is increasingly utilized for confirmation of correct navigation and tool-in-lesion during RAB. O-arm CT is a 3-dimensional imaging modality, which has not previously been described for use with RAB. Our purpose is to display the feasibility, ease of use, and high rate of confirmation of tool-in-lesion when using O-arm CT during RAB. METHODS: Single center, retrospective review of 75 patients undergoing RAB with intraprocedural use of O-arm CT. RESULTS: Median patient age was 65 years. Forty-nine percent of cases involved nodules ≤2 cm. Bronchus sign was absent in 44% of cases. Median procedure time was 80 minutes. Median number of O-arm CT runs per case was 2. The median effective dose of radiation was 7.2 millisieverts. Tool-in-lesion was confirmed in 97% (77 of 79) of cases. Definitive diagnosis was reached in 61 to 68 of 79 cases (77% to 86%). There were 2 cases of pneumothorax (2.5%), one of which needed intervention with tube thoracostomy. CONCLUSIONS: O-arm CT is an effective, and convenient alternative to other 3-dimensional imaging modalities for intraprocedural confirmation of tool-in-lesion during RAB.


Subject(s)
Lung Neoplasms , Robotic Surgical Procedures , Surgery, Computer-Assisted , Humans , Aged , Tomography, X-Ray Computed/methods , Bronchoscopy/methods , Imaging, Three-Dimensional , Lung Neoplasms/pathology
4.
ACS Med Chem Lett ; 13(4): 570-576, 2022 Apr 14.
Article in English | MEDLINE | ID: mdl-35450347

ABSTRACT

Wiskott-Aldrich Syndrome Protein Family (WASF) members regulate actin cytoskeletal dynamics, and WASF3 is directly associated with breast cancer metastasis and invasion. WASF3 forms a heteropentameric complex with CYFIP, NCKAP, ABI, and BRK1, called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF3. Since aberrant deployment of the WRC is observed in cancer metastasis and invasion, its disruption provides a novel avenue for targeting motility in breast cancer cells. Here, we report the development of a second generation WASF3 mimetic peptide, WAHMIS-2, which was designed using a combination of structure-guided design, homology modeling, and in silico optimization to disrupt binding of WASF3 to the WRC. WAHMIS-2 was found to permeate cells and inhibit cell motility, invasion, and MMP9 expression with greater potency than its predecessor, WAHM1. Targeted disruption of WASF3 from the WRC may serve as a useful strategy for suppression of breast cancer metastasis.

5.
ACS Chem Biol ; 16(11): 2326-2338, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34496561

ABSTRACT

Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein with dual kinase and GTPase function that is commonly mutated in both familial and idiopathic Parkinson's Disease (PD). While dimerization of LRRK2 is commonly detected in PD models, it remains unclear whether inhibition of dimerization can regulate catalytic activity and pathogenesis. Here, we show constrained peptides that are cell-penetrant, bind LRRK2, and inhibit LRRK2 activation by downregulating dimerization. We further show that inhibited dimerization decreases kinase activity and inhibits ROS production and PD-linked apoptosis in primary cortical neurons. While many ATP-competitive LRRK2 inhibitors induce toxicity and mislocalization of the protein in cells, these constrained peptides were found to not affect LRRK2 localization. The ability of these peptides to inhibit pathogenic LRRK2 kinase activity suggests that disruption of dimerization may serve as a new allosteric strategy to downregulate PD-related signaling pathways.


Subject(s)
Enzyme Inhibitors/pharmacology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Parkinson Disease/enzymology , Peptides/pharmacology , Allosteric Regulation , Amino Acid Sequence , Apoptosis/drug effects , Dimerization , Enzyme Activation , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Neurons/drug effects , Parkinson Disease/pathology , Peptides/chemistry , Protein Binding , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
6.
JPEN J Parenter Enteral Nutr ; 43(8): 1037-1043, 2019 11.
Article in English | MEDLINE | ID: mdl-30756402

ABSTRACT

BACKGROUND: The utility of vitamin D (VITD) supplementation during critical illness and whether it may alter outcomes, including mortality and ventilator-free days, is unclear. We performed a retrospective cohort study in a generalizable population to investigate this question. METHODS: We included all mechanically ventilated adults admitted to the medical intensive care unit (ICU) service at a tertiary center from 2009 to 2012 who were in the ICU for at least 72 hours. Patients were grouped as having received or not received VITD at any time during the first 7 days of their ICU stay, and we adjusted for the following covariates with multivariable analyses: simplified acute physiology score, age, gender, admission diagnosis, race/ethnicity, admission season, admission day of the week, and VITD supplementation prior to admission. RESULTS: Among the 610 included patients, 281 received VITD, and 329 did not. There were no differences in outcomes between these groups. However, we did find significantly more ventilator-free days (21.0±2.6 [adjusted mean days±standard error] vs 17.6±2.4, P=0.04) and ICU-free days (18.5±2.5 vs 16.3±2.3, P=0.03) in patients who were taking VITD prior to admission (n=91) vs those who were not (n=519). No patients who were taking VITD before admission died vs 34.5% of those who were not (estimated odds ratio=4.9×10-7 , 95% CI=3.1×10-7 to 7.5×10-7 , P<0.0001). CONCLUSION: These results suggest that VITD supplementation during critical illness may not provide benefit and that further research investigating potential supplementation in ambulatory patients at high risk of ICU admission (eg, severe underlying chronic disease) is warranted.


Subject(s)
Critical Illness/therapy , Intensive Care Units , Respiration, Artificial , Vitamin D/administration & dosage , Adult , Aged , Cohort Studies , Critical Illness/mortality , Dietary Supplements , Female , Humans , Male , Middle Aged , Retrospective Studies , Seasons , Treatment Outcome
7.
J Bronchology Interv Pulmonol ; 25(4): 269-273, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29901535

ABSTRACT

BACKGROUND: Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has an excellent diagnostic yield, there remain cases where the diagnosis is not obtained. We hypothesized that additional sampling with a 19-G EBUS-TBNA needle may increase diagnostic yield in a subset of cases where additional tissue sampling was required. METHODS: Indications for use of the 19-G needle following 22-G sampling with rapid on-site cytologic examination were: (1) diagnostic uncertainty of the on-site cytopathologist (eg, nondiagnostic, probable lymphoma, etc.), (2) non-small cell lung cancer with probable need for molecular genetic and/or PD-L1 testing, or (3) need for a larger tissue sample for consideration of inclusion in a research protocol. RESULTS: A 19-G EBUS-TBNA needle was utilized following standard sampling with a 22-G needle in 48 patients (50 sites) during the same procedure. Although the diagnostic yield between the needles was equivalent, the concordance rate was only 83%. The 19-G determined a diagnosis in 4 additional patients (8%) and provided additional histopathologic information in 6 other cases (12%). Conversely, in 3 cases (6%) diagnostic information was provided only by the 22-G needle. Compared with 22-G EBUS-TBNA alone, sampling with both the 22- and 19-G EBUS needles resulted in an increase in diagnostic yield from 92% to 99% (P=0.045) and a number needed to sample of 13 patients to provide one additional diagnosis. There were no significant complications. CONCLUSION: In select cases where additional tissue may be needed, sampling with a 19-G EBUS needle following standard aspiration with a 22-G needle results in an increase in diagnostic yield.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Endoscopic Ultrasound-Guided Fine Needle Aspiration/instrumentation , Lung Neoplasms/diagnostic imaging , Lymphoma/diagnostic imaging , Needles/trends , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Endosonography/methods , Female , Humans , Image-Guided Biopsy/methods , Lung Neoplasms/pathology , Lymphoma/pathology , Male , Middle Aged , Molecular Diagnostic Techniques/methods
9.
J Appl Physiol (1985) ; 107(6): 1763-70, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19797689

ABSTRACT

The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways.


Subject(s)
Bronchial Hyperreactivity/chemically induced , Bronchial Hyperreactivity/immunology , Methacholine Chloride/administration & dosage , Respiratory Mechanics/drug effects , Administration, Inhalation , Aerosols , Analysis of Variance , Animals , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cell Count , Dose-Response Relationship, Drug , Electrocardiography , Female , Heart Rate/drug effects , Heart Rate/immunology , Hydrochloric Acid/toxicity , Inflammation/chemically induced , Inflammation/immunology , Mice , Mice, Inbred BALB C , Respiratory Mechanics/immunology , Time Factors
10.
Am J Physiol Lung Cell Mol Physiol ; 292(6): L1580-9, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17351059

ABSTRACT

Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves and that this would correspond with increasing accumulation of alveolar fibrin. C57BL/6 mice were anesthetized and aspirated 75 microl of HCl (pH 1.8) or buffered normal saline. Subgroups were reanesthetized 4, 14, 24, and 48 h later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH(2)O, and air within the lung (thoracic gas volume) was quantified by microcomputed tomography. Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by microcomputed tomography. The rise in H was greater in acid-injured mice than in controls (P < 0.05) and also increased from 4 to 48 h after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 h (P < 0.05), also confirmed by thoracic gas volume. Lung permeability and alveolar fibrin also increased over the 48-h study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Lung injury worsens progressively in mice during the 48 h following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.


Subject(s)
Disease Models, Animal , Fibrin/metabolism , Mice, Inbred C57BL , Pneumonia, Aspiration/pathology , Respiratory Distress Syndrome/pathology , Animals , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid , Disease Progression , Female , Fibrinolysis/physiology , Hydrochloric Acid/pharmacology , Lung Volume Measurements , Mice , Pneumonia, Aspiration/metabolism , Pneumonia, Aspiration/therapy , Positive-Pressure Respiration , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/therapy , Severity of Illness Index
11.
Am J Respir Crit Care Med ; 171(12): 1363-70, 2005 Jun 15.
Article in English | MEDLINE | ID: mdl-15805183

ABSTRACT

RATIONALE: Tumor necrosis factor alpha (TNF-alpha) has been implicated as a key cytokine in many inflammatory lung diseases. These effects are currently unclear, because a transgenic mouse overexpressing TNF-alpha in the lung has been shown in separate studies to produce elements of both emphysema and pulmonary fibrosis. OBJECTIVES: We sought to elucidate the phenotypic effects of TNF-alpha overexpression in a mouse model. MEASUREMENTS: We established the phenotype by measuring lung impedance and thoracic gas volume, and using micro-computed tomography and histology. MAIN RESULTS: We found that airways resistance in this mouse was not different to control mice, but that lung tissue dampening, elastance, and hysteresivity were significantly elevated. Major heterogeneous abnormalities of the parenchyma were also apparent in histologic sections and in micro-computed tomography images of the lung. These changes included airspace enlargement, loss of small airspaces, increased collagen, and thickened pleural septa. We also found significant increases in lung and chest cavity volumes in the TNF-alpha-overexpressing mice. CONCLUSIONS: We conclude that TNF-alpha overexpression causes pathologic changes consistent with both emphysema and pulmonary fibrosis combined with a general lung inflammation, and consequently does not model any single human disease. Our study thus confirms the pleiotropic effects of TNF-alpha, which has been implicated in multiple inflammatory disorders, and underscores the necessity of using a wide range of investigative techniques to link gene expression and phenotype in animal models of disease.


Subject(s)
Gene Expression Regulation , Inflammation Mediators/metabolism , Pulmonary Emphysema/pathology , Tumor Necrosis Factor-alpha/metabolism , Animals , Disease Models, Animal , Female , Immunohistochemistry , Inflammation Mediators/analysis , Mice , Mice, Transgenic , Pulmonary Emphysema/genetics , Pulmonary Surfactants/analysis , Reference Values , Respiratory Function Tests , Sensitivity and Specificity , Tomography, X-Ray Computed , Total Lung Capacity , Tumor Necrosis Factor-alpha/genetics
12.
Ann Biomed Eng ; 32(10): 1420-7, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15535059

ABSTRACT

We have previously measured thoracic gas volume (VTG) in spontaneously breathing mice using a whole body plethysmograph and have now extended our technique to allow for V(TG) measurements during paralysis. BALB/c mice were anesthetized and placed in a body-box and ventilated via a tracheostomy cannula through the box wall. Box pressure (Pb) and tracheal pressure (Pao) were measured during spontaneous breathing, and again after paralysis while mechanically compressing the chest. V(TG) was much larger after paralysis (0.49+/-0.06 ml, positive end-expiratory pressure = 2 cmH2O) when compared with spontaneous breathing (0.31+/-0.01 ml). External chest compression produced looping in the plots of Pb versus Pao that was attributable to gradual changes in Pb upon release of the mechanical chest compression and had the character of thermal transients. Under the assumption that the rate of heating of the air in the chamber was proportional to the pressure applied to the animal's chest, and that any increase in air temperature was dissipated by heat absorption by the chamber walls, we developed an algorithm that corrected for the thermal events. This yielded similar results for V(TG) (0.30+/-0.02 ml) as obtained during spontaneous efforts. Our method may prove particularly useful when paralysis is required for the precise measurement of lung mechanics.


Subject(s)
Diagnosis, Computer-Assisted/methods , Lung Volume Measurements/methods , Models, Biological , Plethysmography/methods , Respiratory Paralysis/diagnosis , Respiratory Paralysis/physiopathology , Thorax/physiopathology , Tidal Volume , Animals , Computer Simulation , Female , Mice , Mice, Inbred BALB C , Positive-Pressure Respiration/methods
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