PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.

Reversal of Clinically Significant Portal Hypertension After Immunosuppressive Treatment in a Patient With Sarcoidosis.

Sarcoidosis is a multisystemic disease which features non-necrotizing granulomas in lungs and other organs. Hepatic involvement in sarcoidosis varies between a mild asymptomatic disease and a progressive inflammatory granulomatous disease with or without cirrhosis. In this case presentation, we present a case of hepatic sarcoidosis complicated by clinically significant portal hypertension including splenomegaly and gastroesophageal varices successfully treated with immunosuppression to achieve portal hypertension reversal.

Endovascular steerable and endobronchial precurved guiding sheaths for transbronchial needle delivery under augmented fluoroscopy and cone beam CT image guidance.

BACKGROUND: Endobronchial navigation is performed in a variety of ways, none of which are meeting all the clinicians' needs required to reach diagnostic success in every patient. We sought to characterize precurved and steerable guiding sheaths (GS) in endobronchial targeting for lung biopsy using cone beam computed tomography (CBCT) based augmented fluoroscopy (AF) image guidance. METHODS: Four precurved GS (EdgeTM 45, 90, 180, 180EW, Medtronic) and two steerable GS [6.5 F Destino Twist (DT), Oscor; 6 F Morph, BioCardia] were evaluated alone and in combination with an electromagnetic tracking (EM) guide and biopsy needles in three experimental phases: (I) bench model to assess GS deflection and perform biopsy simulations; (II) ex vivo swine lung comparing 2 steerable and 2 precurved GS; and (III) in vivo male swine lung to deliver a needle (n=2 swine) or to deliver a fiducial marker (n=2 swine) using 2 steerable GS. Ex vivo and in vivo image guidance was performed with either commercial or prototype AF image guidance software (Philips) based on either prior CT or procedural CBCT. Primary outcomes were GS delivery angle (θGS) and needle delivery angle (θN) in bench evaluation and needle delivery error (mm) (mean ± se) for ex vivo and in vivo studies. RESULTS: The steerable DT had the largest range of GS delivery angles (θN: 0-114°) with either the 21 G or 19 G biopsy needle in the bench model. In ex vivo swine lung, needle delivery errors were 8.7±0.9 mm (precurved Edge 90), 5.4±1.9 mm (precurved Edge 180), 4.7±1.2 mm (steerable DT), and 5.6±2.4 mm (steerable Morph). In vivo, the needle delivery errors for the steerable GS were 6.0±1.0 mm (DT) and 15±7.0 mm (Morph). In vivo marker coil delivery was successful for both the steerable DT and morph GS. A case report demonstrated successful needle biopsy with the steerable DT. CONCLUSIONS: Endobronchial needle delivery with AF guidance is feasible without a bronchoscope with steerable GS providing comparable or improved accuracy compared to precurved GS.

Optimizing routine screening for cardiac sarcoidosis through use of commonly available studies.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder with unclear etiology. Morbidity and mortality vary based on organ involvement, with cardiac sarcoidosis (CS) associated with higher mortality; despite this, CS remains underdiagnosed. The Heart Rhythm Society (HRS) expert consensus statement recommends screening sarcoidosis patients for CS utilizing a symptom screen, EKG, and echocardiogram (TTE), while the American Thoracic Society (ATS) guideline recommends only EKG and symptom screening. These recommendations, however, are based on limited data with recommendations for further studies. RESEARCH QUESTION: The purpose is to evaluate the prevalence of abnormal screening tests in patients with sarcoidosis and the correlation of these tests with the subsequent diagnosis of CS. A specific emphasis was placed on evaluating the sensitivity of the recommendations versus the sensitivity of a modified criteria. STUDY DESIGN: and Methods: This study retrospectively evaluated a database of prospectively enrolled patients from a tertiary military academic center. All patients who underwent imaging with cardiac MRI and/or FDG-PET were identified. These results were correlated with screening studies (symptom screen, EKG, TTE, and ambulatory rhythm monitoring (ARM)) and used to calculate sensitivity, specificity, and positive and negative predictive values for each test. Using a clinical diagnosis of CS as the reference standard, the sensitivity and specificity of the HRS criteria were calculated and compared to a modified screening rubric developed a priori, consisting of minor changes to the criteria and the addition of ARM. RESULTS: This study evaluated 114 patients with sarcoidosis with 132 advanced imaging events, leading to a diagnosis of CS in 36 patients. Utilizing HRS screening recommendations, the sensitivity for CS was 63.9%, while the modified criteria increased sensitivity to 94.4%. INTERPRETATION: This study suggests that the HRS guidelines lack sensitivity to effectively screen for CS and that a modified screening model which includes ARM may be more effective.

Pulmonary Function in Patients With Multiple Endocrine Neoplasia 2B.

CONTEXT: Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B. OBJECTIVE: This study characterized the pulmonary function of patients with MEN2B. DESIGN: This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health. RESULTS: Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of -2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035). CONCLUSIONS: This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort.

Bone Marrow-Derived Mesenchymal Stromal Cells (MSCs) Modulate the Inflammatory Character of Alveolar Macrophages from Sarcoidosis Patients.

Sarcoidosis is a devastating inflammatory disease affecting many organs, especially the lungs and lymph nodes. Bone marrow-derived mesenchymal stromal cells (MSCs) can "reprogram" various types of macrophages towards an anti-inflammatory phenotype. We wanted to determine whether alveolar macrophages from sarcoidosis subjects behave similarly by mounting an anti-inflammatory response when co-cultured with MSCs. Fifteen sarcoidosis and eight control subjects underwent bronchoscopy and bronchoalveolar lavage (BAL). Unselected BAL cells (70-94% macrophages) were isolated and cultured with and without MSCs from healthy adults. Following stimulation of the cultured cells with lipopolysaccharide, the medium was removed to measure interleukin 10 and tumor necrosis factor alpha (IL-10 and TNF-α). In two additional sarcoidosis subjects, flow cytometry was used to study intracellular cytokines and surface markers associated with alveolar macrophages to confirm the results. Unselected BAL cells from sarcoidosis subjects co-cultured with MSCs showed a reduction in TNF-α (pro-inflammatory M1) and an increase in IL-10 (anti-inflammatory M2) in 9 of 11 samples studied. Control subject samples showed few, if any, differences in cytokine production. Unselected BAL cells from two additional patients analyzed by flow cytometry confirmed a switch towards an anti-inflammatory state (i.e., M1 to M2) after co-culture with MSCs. These results suggest that, similarly to other macrophages, alveolar macrophages also respond to MSC contacts by changing towards an anti-inflammatory phenotype. Based on our results, we hypothesize that mesenchymal stromal cells applied to the airways might alleviate lung inflammation and decrease steroid need in patients with sarcoidosis.

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis.

Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMPs). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels were previously shown to distinguish active from latent TB, as well as successfully treated Mycobacterium tuberculosis infection. MMP-1 expression is also associated with active TB. In this study, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations, as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other nontuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied the expression of HO-1 and MMP-1 in M. tuberculosis-infected human and murine macrophages. We found that infection of macrophages with live virulent M. tuberculosis is required for robust induction of high levels of HO-1 but not MMP-1. In addition, we observed that CO, a product of M. tuberculosis-induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients.

Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics.

Sarcoidosis is a multisystem granulomatous disorder that most often affects the lungs and may cause significant morbidity. Sarcoidosis can manifest as neurological disease, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, dysrhythmias, cardiomyopathy, hypercalcemia, and renal failure. Sarcoidosis persists as chronic disease in approximately one-third of those affected. Clinical pitfalls and misconceptions about the course of disease place this population at risk for delayed or inadequate care. While noncaseating granulomas are the histopathological hallmark of sarcoidosis, they also are nonspecific. No pathognomonic diagnostic test exists for sarcoidosis, so the diagnosis remains one of exclusion. While the etiology of sarcoidosis is still unknown, recent insights into its immunopathogenesis have moved investigators closer to finding more effective treatments. Corticosteroids remain the standard of care when treatment is indicated, despite their adverse effect profile. Clinical investigations of novel drugs and biological agents targeting mechanisms involving CD4 type 1 helper T cells may provide more effective, better tolerated therapies.

Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis.

BACKGROUND: The prevalence of pneumothorax associated with travel in patients with interstitial lung diseases is unknown. In patients with lymphangioleiomyomatosis (LAM), in whom pneumothorax is common, patients are often concerned about the occurrence of a life-threatening event during air travel. The aim of this study was to determine the prevalence of pneumothorax associated with air travel in patients with LAM, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. METHODS: Records and imaging studies of 449 patients traveling to the National Institutes of Health were reviewed. RESULTS: A total of 449 patients traveled 1,232 times; 299 by airplane (816 trips) and 150 by land (416 trips). Sixteen of 281 LAM patients arrived at their destination with a pneumothorax. In 5 patients, the diagnosis was made by chest roentgenogram, and in 11 patients by CT scans only. Of the 16 patients, 14 traveled by airplane and 2 by land. Seven of the 16 patients, 1 of whom traveled by train, had a new pneumothorax; 9 patients had chronic pneumothoraces. A new pneumothorax was more likely in patients with large cysts and more severe disease. The frequency of a new pneumothorax for LAM patients who traveled by airplane was 2.9% (1.1 per 100 flights) and by ground transportation, 1.3% (0.5 per 100 trips). No IPF (n = 76) or sarcoidosis (n = 92) patients presented with a pneumothorax. CONCLUSIONS: In interstitial lung diseases with a high prevalence of spontaneous pneumothorax, there is a relatively low risk of pneumothorax following air travel. In LAM, the presence of a pneumothorax associated with air travel may be related to the high incidence of pneumothorax and not to travel itself.