The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma

Abstract

Background

HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma.

Methods

Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)1. Oropharyngeal tissue was collected from CO₂ laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue.

Results

This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC.

Conclusion

Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology.

http://ift.tt/2kKOnAh

Critical care management of pulmonary hypertension

<span class="paragraphSection">Patients with pulmonary hypertension (PH) can be extremely challenging to manage in the critical care setting. In this article we review the classification, diagnosis, and chronic management of PH. An approach to the management of the critically unwell PH patient is discussed. Initial management involves treating underlying precipitants of deterioration and optimizing right ventricular (RV) preload. Reduction of RV afterload with pulmonary vasodilators is also required. Augmentation of cardiac function and perfusion pressures with inotropes and vasopressors may additionally be needed. Advanced renal and respiratory support may be appropriate depending on the clinical context. Patients with known PH who have undergone major surgery or who are in the immediate postpartum period are also at significant risk of deterioration and require management in the critical care setting. Although pulmonary vasodilators are associated with improvements in pulmonary haemodynamics and oxygenation in patients with acute respiratory distress syndrome or after cardiac surgery, there is currently no evidence demonstrating improved outcomes.</span>

http://ift.tt/2lmzN0G

Diabetes medication pharmacology

<span class="paragraphSection">1A022A033A06</span>

http://ift.tt/2maT1ER

Hypoxic pulmonary vasoconstriction

<span class="paragraphSection">1A012CO23G00</span>

http://ift.tt/2maOEcK

The effects of venous ensheathment on facial nerve repair in the rat

Objective

To investigate the protective effect of autologous venous ensheathment on sutured rat facial nerve and to test whether the ensheathment could improve the functional recovery of repaired nerve and accuracy of axonal growth.

Study Design

In vivo study.

Methods

Forty-six rats were examined, with six rats serving as normal controls and 40 receiving facial nerve transection and suture repair (SR) or transection and suture repair with an additional venous ensheathment (VE). The rats were then subjected to functional testing, histological assessment of nerve specimens, or retrograde tracing, respectively.

Results

At the postoperative day (POD) 60, the venous ensheathment showed no adhesion at the surrounding tissues. No significant difference in neuroma formation was found between the two surgical manipulations (SR and VE groups) (P < 0.05). Retrogradely labeled motoneurons in facial nuclei were extremely disorganized after the facial nerve undertook surgical manipulation. In all manipulated groups, double retrogradely labeled neurons, indicative of aberrant axonal branching during regeneration, could be observed after peripheral manipulation across all time points. With the two facial surgical manipulations, the average count of double-labeled neurons at POD 60 was significantly less than at POD 21 (P < 0.05).

Conclusion

Autologous venous ensheathment could not help with the functional recovery of facial nerve or improve the accuracy of axonal regeneration. Further studies are warranted to elucidate the effects of venous ensheathment in other motor and sensory nerve models.

Level of Evidence

NA. Laryngoscope, 2017

http://ift.tt/2kYo6Kb

Pepsin as a biomarker for laryngopharyngeal reflux in children with laryngomalacia

Objectives/Hypothesis

Laryngomalacia is a common cause of newborn stridor. Laryngopharyngeal reflux (LPR) has been associated with laryngomalacia. Although pepsin, a component of LPR, has been associated with inflammatory diseases of the aerodigestive tract, its presence in the airways of laryngomalacia patients is unknown.

Study Design

Prospective case-control study comparing patients under age 3 years with laryngomalacia to children without laryngomalacia.

Methods

Children less than 3 years old undergoing supraglottoplasty for laryngomalacia or surgery unrelated to the airway, without a history of laryngomalacia, reflux, or respiratory disease, were offered enrollment. Supraglottic lavage samples (3 mL) were obtained from all subjects. Two-millimeter arytenoid biopsies were collected from laryngomalacia patients. Pepsin Western blot and enzyme-linked immunosorbent assay were performed.

Results

Ten laryngomalacia and five control subjects were enrolled. Pepsin was detected in lavages of laryngomalacia patients (8/10) but absent in controls (0/5; P = .007). Pepsin was observed more frequently in lavages (8/10) than biopsies (4/10; P = .046) of laryngomalacia subjects. Higher median pepsin concentration was observed in laryngomalacia than control lavages (P = .025).

Conclusions

Pepsin in supraglottic specimens demonstrated an association with laryngomalacia, supporting a role for refluxed pepsin in laryngomalacia. These data corroborate previous work implicating pepsin in inflammatory diseases of the upper airways. Further studies are warranted to investigate the contribution of pepsin to the pathophysiology of laryngomalacia.

Level of Evidence

3b. Laryngoscope, 2017

http://ift.tt/2m6G2He

The current status of human laryngeal transplantation in 2017: A state of the field review

Objectives

Human laryngeal allotransplantation has long been contemplated as a surgical option following laryngectomy, but there is a paucity of information regarding the indications, surgical procedure, and patient outcomes. Our objectives were to identify all human laryngeal allotransplants that have been undertaken and reported in the English literature and to evaluate the success of the procedure.

Data Sources

MEDLINE, Embase, Current Index to Nursing and Allied Health Literature, Web of Science and Scopus, and the Gray literature.

Review Methods

A comprehensive search strategy was undertaken across multiple databases. Inclusion criteria were case reports of patients who had undergone human laryngeal allotransplantation. Information regarding indications, operative techniques, complications, graft viability, and functional outcomes were extracted.

Results

A total of 5,961 articles, following removal of duplicates, matched the search criteria and were screened, with five case reports relating to two patients, ultimately fulfilling the entry criteria.

Conclusions

Two laryngeal transplants have been reported in the medical literature. Although both patients report improved quality of life relating to their ability to communicate with voice, further research is necessary to shape our understanding of this complicated operation, its indications, and its functional outcomes. Laryngoscope, 2017

http://ift.tt/2ltXyCo