Bacteriophage: A new therapeutic player to combat neutrophilic inflammation in chronic airway diseases

Persistent respiratory bacterial infections are a clinical burden in several chronic inflammatory airway diseases and are often associated with neutrophil infiltration into the lungs. Following recruitment, dysregulated neutrophil effector functions such as increased granule release and formation of neutrophil extracellular traps (NETs) result in damage to airway tissue, contributing to the progression of lung disease. Bacterial pathogens are a major driver of airway neutrophilic inflammation, but traditional management of infections with antibiotic therapy is becoming less effective as rates of antimicrobial resistance rise. Bacteriophages (phages) are now frequently identified as antimicrobial alternatives for antimicrobial resistant (AMR) airway infections. Despite growing recognition of their bactericidal function, less is known about how phages influence activity of neutrophils recruited to sites of bacterial infection in the lungs. In this review, we summarize current in vitro and in vivo findings on the effects of phage therapy on neutrophils and their inflammatory mediators, as well as mechanisms of phage-neutrophil interactions. Understanding these effects provides further validation of their safe use in humans, but also identifies phages as a targeted neutrophil-modulating therapeutic for inflammatory airway conditions

Frequency of Occurrence of Diagnostic Cytologic Parameters in Basal Cell Carcinoma. A Retrospective Review of 25 Cases

Twenty-five cases of cytologic preparations from basal cell carcinomas documented by subsequent tissue material were obtained. The cases were retrospectively analyzed to evaluate the frequency of occurrence of various features that could either be helpful or misleading in the diagnosis. These features included peripheral palisading, Bowenoid nuclei, and keratinized cells. Results from the study include the fact that a major criterion for the histologic diagnosis of basal cell carcinoma (peripheral palisading) could seldom be appreciated in the cytology preparations. Large clusters of cells with crowded nuclei were found in every case and thus represent a useful cytologic parameter. However, because of the frequent absence of peripheral palisading, the study suggests there could be diagnostic confusion with lesions of small cell squamous carcinoma

GLUT1 expression in human breast carcinoma: Correlation with known prognostic markers

Background: Breast cancers have been shown to have increased glucose uptake and utilization, and to express the facilitative glucose transporter Glut1. The aim of this study was to determine the biological significance of Glut1 expression in breast cancer. Methods: Paraffin sections of 118 breast cancers were immunostained with antibody to Glut1. The percent of Glut1-positive cancer cells in each tumor was correlated with known prognostic markers, and with patient outcome. Results: Glut1 was expressed in 42% of the tumors. Glut1 immunoreactivity correlated positively with the proliferative activity as determined by Ki-67 immunostaining, and with the total histologic score, and showed negative correlation with bcl-2 immun immunostaining. There was no correlation between the percent of Glut1-immunoreactive cancer cells and estrogen receptor status, tumor size, or lymph node status. Conclusions: 1) Glut1 expression is increased in breast cancers with higher grade and proliferative activity, and 2) glucose transport in the majority of breast cancers may be mediated by a glucose transporters other than Glut1

WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell-cell signaling, and extracellular matrix, Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg), TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8-9 months of age, Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia; and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression, Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2, Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma, The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary oncogenesis

Estimating the proliferative activity in breast cancer: Is Ki-67 immunostaining necessary?

The proliferative,activity (PA) of tumor cells has been shown to be a significant prognostic indicator in breast cancer. Ki-67 immunoreactivity in paraffin-embedded tissue has been shown to correlate with S-phase fraction as determined by flow cytometry. The aim of this work is to determine whether PA by Ki-67 immunostaining has significant advantage over mitotic figure count per ten high power fields (MF/1OHPF) or mitotic index (MI). Sections of formalin-fixed paraffin-embedded tissue of invasive breast cancer from 118 women were evaluated for MF/10HPF, MI, and immunostained for Ki-67 using the monoclonal antibody MIB-1. We found that PA determined by any of the three methods was a significant predictor of survival with p values of 0.016, 0.008, and 0.049 for PA determined by MI, MF/1OHPF, and Ki-67 respectively. We conclude that determining PA by KI-67 immunostaining does not have advantage over the traditional methods

Pulmonary Paragonimiasis Diagnosed by Fine-Needle Aspiration Biopsy▿

We report a case of paragonimiasis involving a 12-year-old Latin American boy. The diagnosis was made by fine-needle aspiration biopsy of a pulmonary nodule. Identification of the species by morphometric analysis of the eggs indicated that the infection was caused by Paragonimus mexicanus

Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization

Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. Phage therapy is one possible alternative or adjunct to current antibiotics with activity against antimicrobial-resistant pathogens. How phages are administered will depend on the site of infection. For respiratory infections, a number of factors must be considered to deliver active phages to sites deep within the lung. The inhalation of phages via nebulization is a promising method of delivery to distal lung sites; however, it has been shown to result in a loss of phage viability. Although preliminary studies have assessed the use of nebulization for phage therapy both in vitro and in vivo, the factors that determine phage stability during nebulized delivery have yet to be characterized. This review summarizes current findings on the formulation and stability of liquid phage formulations designed for nebulization, providing insights to maximize phage stability and bactericidal activity via this delivery method