Bronchoscopic lung volume reduction in emphysema: a review.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) poses a substantial burden on the healthcare system and is currently considered the sixth leading cause of death in the United States. Emphysema, as evidenced by severe air-trapping in patients with COPD, leads to significant dyspnea and morbidity. Lung volume reduction via surgery or minimally invasive endobronchial interventions are currently available, which improve lung function and quality of life. RECENT FINDINGS: Newer studies have noted a survival benefit in patients post bronchoscopic lung volume reduction vs. those subjected to standard of care. The presence of collateral ventilation is one of the most common impeding factors to placing endobronchial valves, and if placed, these patients might not achieve lobar atelectasis; however, there are newer modalities that are now available for patients with collateral ventilation which we have described. SUMMARY: Combining standard of care treatment that includes smoking cessation, bronchodilators, preventive care including vaccinations, pulmonary rehabilitation, and endobronchial treatment using various interventions in decreasing hyperinflation improves quality of life and may improve survival and hence significantly reduce the burden of COPD on healthcare.

A CT-based radiomics integrated model for discriminating pulmonary cryptococcosis granuloma from lung adenocarcinoma-a diagnostic test.

Background: Chest computed tomography (CT) is a critical tool in the diagnosis of pulmonary cryptococcosis as approximately 30% of normal immunity individuals may not exhibit any significant symptoms or laboratory findings. Pulmonary cryptococcosis granuloma and lung adenocarcinoma can appear similar on noncontrast chest CT. This study evaluates the use of an integrated model that was developed based on radiomic features combined with demographic and radiological features to differentiate pulmonary cryptococcosis nodules from lung adenocarcinomas. Methods: Preoperative chest CT images for 215 patients with solid pulmonary nodules with histopathologically confirmed lung adenocarcinoma and cryptococcosis infection were collected from two clinical centers (108 cases in the training set and 107 cases in the test set divided by the different hospitals). Radiomics models were constructed based on nodular lesion volume (LV), 5-mm extended lesion volume (ELV), and perilesion volume (PLV). A demoradiological model was constructed using logistic regression based on demographic information (age, sex) and 12 radiological features (location, number, shape and specific imaging signs). Both models were used to build an integrated model, the performance of which was assessed using the test set. A junior and a senior radiologist evaluated the nodules. Receiver operating characteristic (ROC) curve analysis was conducted, and areas under the curve (AUCs), sensitivity (SEN), and specificity (SPE) of the models were calculated and compared. Results: Among the radiomics models, AUCs of the LV, ELV, and PLV were 0.558, 0.757, and 0.470, respectively. Age, lesion number, and lobular sign were identified as independent discriminative features providing an AUC of 0.77 in the demoradiological model (SEN 0.815, SPE 0.642). The integrated model achieved the highest AUC of 0.801 (SEN 0.759, SPE 0.755), which was significantly higher than that obtained by a junior radiologist (AUC =0.689, P=0.024) but showed no significant difference from that of the senior radiologist (AUC =0.784, P=0.388). Conclusions: An integrated model with radiomics and demoradiological features improves discrimination of cryptococcosis granulomas from solid adenocarcinomas on noncontrast CT. This model may be an effective strategy for machine complementation to discrimination by radiologists, and whole-lung automated recognition methods might dominate in the future.

The role of bronchoscopy in the multidisciplinary approach to benign tracheal stenosis.

Benign tracheal stenosis can cause dyspnea, wheezing, and cough mimicking other obstructive lung diseases which often leads to a delay in the diagnosis. Risk factors and etiologies for tracheal strictures include autoimmune diseases, infection, gastro-esophageal reflux disease (GERD), radiation injury and iatrogenic factors such as post-intubation and post-tracheostomy. Once suspected, tracheal strictures are diagnosed by performing a thorough evaluation involving clinical exam, laboratory workup, pulmonary function test, chest imaging and bronchoscopy. Bronchoscopy plays a pivotal role in the diagnosis of stenosis and along with the imaging and physiologic assessments leads to a proper description of the stenosis based on all parameters that matters for management. Surgical resection provides a definitive management in most patients with idiopathic or post intubation/tracheostomy stenosis, however, factors such as severe co-morbidities, length and location of the stricture can preclude patients from undergoing curative surgery. Several bronchoscopic interventions including mechanical or laser assisted dilation, electrosurgery (ES), airway stenting and pharmacological treatment with mitomycin C (MMC) and intralesional steroid have been reported in the literature for management of patients who are not surgical candidates. Herein, we review the role of bronchoscopy and illustrate the importance of a multi-disciplinary team (MDT) approach comprising of interventional pulmonologists, thoracic surgeons and otorhinolaryngologists in the diagnosis and management of patients with benign tracheal stenosis.

Ubiquitin-independent proteasomal degradation driven by C-degron pathways.

Although most eukaryotic proteins are targeted for proteasomal degradation by ubiquitination, a subset have been demonstrated to undergo ubiquitin-independent proteasomal degradation (UbInPD). However, little is known about the molecular mechanisms driving UbInPD and the degrons involved. Utilizing the GPS-peptidome approach, a systematic method for degron discovery, we found thousands of sequences that promote UbInPD; thus, UbInPD is more prevalent than currently appreciated. Furthermore, mutagenesis experiments revealed specific C-terminal degrons required for UbInPD. Stability profiling of a genome-wide collection of human open reading frames identified 69 full-length proteins subject to UbInPD. These included REC8 and CDCA4, proteins which control proliferation and survival, as well as mislocalized secretory proteins, suggesting that UbInPD performs both regulatory and protein quality control functions. In the context of full-length proteins, C termini also play a role in promoting UbInPD. Finally, we found that Ubiquilin family proteins mediate the proteasomal targeting of a subset of UbInPD substrates.

Alzheimer's disease-associated mutant ubiquitin (UBB+1) is secreted through an autophagosome-like vesicle-mediated unconventional pathway.

Misfolded protein aggregation at both intracellular and extracellular milieus is thought to be the major etiology of Alzheimer's disease (AD). UBB+1, a frameshift variant of the ubiquitin B gene (UBB) results in a folded ubiquitin domain fused to a flexible unstructured extension. Accumulation of UBB+1 in extracellular plaques in the brains of AD patients undoubtedly suggests a role of the ubiquitin-proteasome system in AD. However, the exact mechanism of extracellular secretion of UBB+1 remains unknown. In an attempt to understand the molecular mechanism of UBB+1 secretion, we performed a survey of secretory pathways and identified the involvement of unconventional autophagosome-mediated UBB+1 secretion. Expression of UBB+1 was sufficient to stimulate LC3B/Atg8 conversion from LC3B-I to LC3B-II, which indicates initiation of the autophagy pathway. Furthermore, deficiency of ATG5 - a key player in autophagosome formation - inhibited UBB+1 secretion. Based on immunofluorescence 3D structured illumination (SIM) microscopy and co-immunoprecipitation, we provide evidence that UBB+1 is associated with the secretory autophagosome marker, SEC22B, while HSP90 possibly acts as a carrier. Using LC-MS/MS and mutagenesis we found that in cells, UBB+1 is ubiquitinated on lysine 11, 29, and 48, however, this ubiquitination does not contribute to its secretion. By contrast, proteasome or lysosome inhibition slightly enhanced secretion. Taken together, this study suggests that by ridding cells of UBB+1, secretory autophagosomes may alleviate the cellular stress associated with UBB+1, yet simultaneously mediate the spreading of a mutant specie with disordered characteristics to the extracellular milieu.

Advanced Imaging for Robotic Bronchoscopy: A Review.

Recent advances in navigational platforms have led bronchoscopists to make major strides in diagnostic interventions for pulmonary parenchymal lesions. Over the last decade, multiple platforms including electromagnetic navigation and robotic bronchoscopy have allowed bronchoscopists to safely navigate farther into the lung parenchyma with increased stability and accuracy. Limitations persist, even with these newer technologies, in achieving a similar or higher diagnostic yield when compared to the transthoracic computed tomography (CT) guided needle approach. One of the major limitations to this effect is due to CT-to-body divergence. Real-time feedback that better defines the tool-lesion relationship is vital and can be obtained with additional imaging using radial endobronchial ultrasound, C-arm based tomosynthesis, cone-beam CT (fixed or mobile), and O-arm CT. Herein, we describe the role of this adjunct imaging with robotic bronchoscopy for diagnostic purposes, describe potential strategies to counteract the CT-to-body divergence phenomenon, and address the potential role of advanced imaging for lung tumor ablation.

The disappearing hook wire: a case report.

Background: The migration of hook wire used for lung nodule localization to the pulmonary artery is an extremely rare complication. We report a case of migration of hook wire used for lung nodule localization to the main pulmonary artery and discuss the management. Case Description: The patient was a 50-year-old female with multiple pulmonary nodules, the largest of which was 7 mm and located in right lower lob. Since the size of the nodules were very small, three computed tomography (CT)-guided percutaneous hook wires were placed to localize the nodules prior to surgery. After entering the thorax, the wires were unable to be located in the right lower lobe and an intraoperative urgent chest CT demonstrated that the markers had migrated to the pulmonary artery. Therefore, the original surgical incision was extended and the superior tip subsegment of the pulmonary artery of the right lung was dissected open and the positioning needle was successfully removed. The patient was recovered without further complication and discharged 5 days later. Conclusions: When the exact location of a hook wire utilized for lung nodule localization cannot be determined, an exhaustive radiographic evaluation is required to determine the wire's specific location. If conditions permit, it is best to remove the hook wire directly using video-assisted thoracoscopic surgery (VATS). With careful perioperative assessment, surgeons can avoid additional complications and further surgery if they encounter a migrated nodule localization wire.

Single-Use and Reusable Flexible Bronchoscopes in Pulmonary and Critical Care Medicine.

Flexible bronchoscopy plays a critical role in both diagnostic and therapeutic management of a variety of pulmonary disorders in the bronchoscopy suite and the intensive care unit. In the set-ting of the ongoing viral pandemic, single-use flexible bronchoscopes (SUFB) have garnered attention as various professional pulmonary societies have released guidelines regarding uses for SUFB given the concern for risk of viral transmission when using reusable flexible bronchoscopes (RFB). In addition to offering sterility, SUFBs are portable, easily accessible, and may be more cost-effective than RFB when considering the potential costs of treating bronchoscopy-related infections. Furthermore, since SUFBs are one time use, they do not require reprocessing after use, and therefore may translate to reduced cleaning and storage costs. Despite these advantages, RFBs are still routinely used to perform advanced diagnostic and therapeutic bronchoscopic procedures given the need for optimal maneuverability, handling, angle of deflection, image quality, and larger channel size for passing of ancillary instruments. Here, we review the published evidence on the applications of single-use and reusable bronchoscopes in bronchoscopy suites and intensive care units. Specifically, we will discuss the advantages and disadvantages of these devices as pertinent to fundamental, advanced, and therapeutic bronchoscopic interventions.

Loss of GSK-3ß mediated phosphorylation in HtrA2 contributes to uncontrolled cell death with Parkinsonian phenotype.

HtrA2, a proapoptotic mitochondrial serine protease, promotes cellular protection against oxidative damage. Literature reports show positive correlation between loss of HtrA2 protease activity and Parkinson's Disease (PD) susceptibility. Homozygous loss-of-function mutations in murine-HtrA2, and when they rarely occur in humans result in severe neurodegeneration and infantile death. Here, we report a novel heterozygous pathogenic HTRA2 variant, c.725C > T (p.T242M) in Indian PD patients. Although, this mutation exhibits no significant conformational changes compared to the wild-type, functional studies with HtrA2-T242M transfected neurons reveal common features of PD pathogenesis such as dysfunction, altered morphology and mitochondrial membrane depolarization. Despite exhibiting two-fold decrease in enzyme activity, observation of excessive cell-death due to over-expression of the mutant has been correlated with it being constitutively active. This interesting behavioral anomaly has been attributed to the loss of phosphorylation-mediated regulatory checkpoint at the T242M mutation site that is otherwise controlled by glycogen synthase kinase-3ß (GSK-3ß). This study, with seamless amalgamation of biophysical and biomedical research unravels a mechanistic pathway of HtrA2 regulation and delineates its biological role in PD. Therefore, this investigation will not only prove beneficial toward devising therapeutic strategies against HtrA2-associated diseases mediated by GSK-3ß but also suggest new avenues for treatment of Parkinsonian phenotype.

Improving diagnostic yield of navigational bronchoscopy for peripheral pulmonary lesions: a review of advancing technology.

With recommendations for low dose CT scan for lung cancer screening, there has been an increase in the finding of lung nodules and peripheral pulmonary lesions (PPLs). Additionally, when there is concern for malignancy, guidelines have recommended performing the least invasive evaluation. Conventional bronchoscopy diagnostic yields for PPLs have reportedly been quite low and prior electromagnetic navigation bronchoscopy (ENB) studies have reported variable yields. Navigation bronchoscopy in addition to endobronchial ultrasound allows a physician to evaluate peripheral lung lesions along with mediastinal and hilar lymph nodes for the diagnosis and staging of suspected malignancy in one procedure. More recent advances in navigational bronchoscopy including the use of augmented fluoroscopy (AF), cone beam CT, and robotic bronchoscopy have pushed the boundaries of capability in evaluating PPLs. These added bronchoscopic technologies have shown to improve diagnostic yield especially when modalities are used in combination. The ultimate goal of endoscopically localized ablative and therapeutic treatment for peripheral lung lesions will require a high level of physician confidence, accuracy, and precision. This article will review the innovative characteristics and data of some of the more recently available navigational bronchoscopy devices.

Structural basis of inactivation of human counterpart of mouse motor neuron degeneration 2 mutant in serine protease HtrA2.

Serine protease high temperature requirement protease A2 (HtrA2) is involved in apoptosis and protein quality control. However, one of its murine inactive mutants (S276C aka mnd2) is associated with motor neuron degeneration 2. Similarly, this conserved mutation in human HtrA2 (hHtrA2) also renders the protease inactive, implicating pathogenicity. However, the structural determinants for its inactivation have not yet been elucidated. Here, using multidisciplinary approach, we studied the structural basis of inactivity associated with this mutation in hHtrA2. Characterization of secondary and tertiary structural properties, protein stability, oligomeric properties, and enzyme activity for both wild-type and mutant has been performed using biophysical and functional enzymology studies. The structural comparison at atomic resolution has been carried out using X-ray crystallography. While enzyme kinetics showed inactivity, spectroscopic probes did not identify any significant secondary structural changes in the mutant. X-ray crystallographic analysis of the mutant protein at 2 Å resolution highlighted the significance of a water molecule that plays important role in mediating intermolecular interactions for maintaining the functional ensemble of the protease. Overall, the crystallographic data along with biophysical and enzymology studies helped decipher the structural basis of inactivity of hHtrA2S276C, which might pave way toward further investigating its correlation with aberration of normal cellular functions, hence pathogenicity.

Localized elasticity measured in epithelial cells migrating at a wound edge using atomic force microscopy.

Restoration of lung homeostasis following injury requires efficient wound healing by the epithelium. The mechanisms of lung epithelial wound healing include cell spreading and migration into the wounded area and later cell proliferation. We hypothesized that mechanical properties of cells vary near the wound edge, and this may provide cues to direct cell migration. To investigate this hypothesis, we measured variations in the stiffness of migrating human bronchial epithelial cells (16HBE cells) approximately 2 h after applying a scratch wound. We used atomic force microscopy (AFM) in contact mode to measure the cell stiffness in 1.5-microm square regions at different locations relative to the wound edge. In regions far from the wound edge (>2.75 mm), there was substantial variation in the elastic modulus in specific cellular regions, but the median values measured from multiple fields were consistently lower than 5 kPa. At the wound edge, cell stiffness was significantly lower within the first 5 microm but increased significantly between 10 and 15 microm before decreasing again below the median values away from the wound edge. When cells were infected with an adenovirus expressing a dominant negative form of RhoA, cell stiffness was significantly decreased compared with cells infected with a control adenovirus. In addition, expression of dominant negative RhoA abrogated the peak increase in stiffness near the wound edge. These results suggest that cells near the wound edge undergo localized changes in cellular stiffness that may provide signals for cell spreading and migration.

Micromechanical properties of demineralized dentin collagen with and without adhesive infiltration.

In a previous study, we reported the upper limit of Young's modulus of the unprotected protein at the dentin/adhesive interface to be 2 GPa. In this study, to obtain a more exact value of the moduli of the components at the d/a interface, we used demineralized dentin collagen with and without adhesive infiltration. The prepared samples were analyzed using micro-Raman spectroscopy (micro RS) and scanning acoustic microscopy (SAM). Using an Olympus UH3 SAM (Olympus Co., Tokyo), measurements were recorded with a 400 MHz burst mode lens (120 degrees aperture angle; nominal lateral resolution, 2.5 microm). A series of calibration curves were prepared using the relationship between the ultrasonically measured elastic moduli of a set of known materials and their SAM response. Finally, both the bulk and bar wave elastic moduli were computed for a set of 13 materials, including polymers, ceramics, and metals. These provided the rationale for using extensional wave measurements of the elastic moduli as the basis for extrapolation of the 400 MHz SAM data to obtain Young's moduli for the samples: E = 1.76 +/- 0.00 GPa for the collagen alone; E = 1.84 +/- 0.65 GPa for the collagen infiltrated with adhesive; E = 3.4 +/- 1.00 GPa for the adhesive infiltrate.