E3 ubiquitin ligases in lung cancer: Emerging insights and therapeutic opportunities.

Aim In this review, we have attempted to provide the readers with an updated account of the role of a family of proteins known as E3 ligases in different aspects of lung cancer progression, along with insights into the deregulation of expression of these proteins during lung cancer. A detailed account of the therapeutic strategies involving E3 ligases that have been developed or currently under development has also been provided in this review. MATERIALS AND METHODS: The review article employs extensive literature search, along with differential gene expression analysis of lung cancer associated E3 ligases using the DESeq2 package in R, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/). Protein expression analysis of CPTAC lung cancer samples was carried out using the UALCAN webtool (https://ualcan.path.uab.edu/index.html). Assessment of patient overall survival (OS) in response to high and low expression of selected E3 ligases was performed using the online Kaplan-Meier plotter (https://kmplot.com/analysis/index.php?p=background). KEY FINDINGS: SIGNIFICANCE: The review provides an in-depth understanding of the role of E3 ligases in lung cancer progression and an up-to-date account of the different therapeutic strategies targeting oncogenic E3 ligases for improved lung cancer management.

USP7 imparts partial EMT state in colorectal cancer by stabilizing the RNA helicase DDX3X and augmenting Wnt/ß-catenin signaling.

Epithelial mesenchymal transition (EMT) is a fundamental and highly regulated process that is normally observed during embryonic development and tissue repair but is deregulated during advanced cancer. Classically, through the process of EMT, cancer cells gradually transition from a predominantly epithelial phenotype to a more invasive mesenchymal phenotype. Increasing studies have, however, brought into light the existence of unique intermediary states in EMT, often referred to as partial EMT states. Through our studies we have found the deubiquitinase USP7 to be strongly associated with the development of such a partial EMT state in colon cancer cells, characterized by the acquisition of mesenchymal characteristics but without the reduction in epithelial markers. We found USP7 to be overexpressed in colon adenocarcinomas and to be closely associated with advancing tumor stage. We found that functional inhibition or knockdown of USP7 is associated with a marked reduction in mesenchymal markers and in overall migration potential of cancer cells. Starting off with a proteomics-based approach we were able to identify and later on verify the DEAD box RNA helicase DDX3X to be an interacting partner of USP7. We then went on to show that USP7, through the stabilization of DDX3X, augments Wnt/ß-catenin signaling, which has previously been shown to be greatly associated with colorectal cancer cell invasiveness. Our results indicate USP7 as a novel key player in establishing a partial mesenchymal phenotype in colorectal cancer.

Ubiquitination and deubiquitination in the regulation of epithelial-mesenchymal transition in cancer: Shifting gears at the molecular level.

The process of conversion of non-motile epithelial cells to their motile mesenchymal counterparts is known as epithelial-mesenchymal transition (EMT), which is a fundamental event during embryonic development, tissue repair, and for the maintenance of stemness. However, this crucial process is hijacked in cancer and becomes the means by which cancer cells acquire further malignant properties such as increased invasiveness, acquisition of stem cell-like properties, increased chemoresistance, and immune evasion ability. The switch from epithelial to mesenchymal phenotype is mediated by a wide variety of effector molecules such as transcription factors, epigenetic modifiers, post-transcriptional and post-translational modifiers. Ubiquitination and de-ubiquitination are two post-translational processes that are fundamental to the ubiquitin-proteasome system (UPS) of the cell, and the shift in equilibrium between these two processes during cancer dictates the suppression or activation of different intracellular processes, including EMT. Here, we discuss the complex and dynamic relationship between components of the UPS and EMT in cancer.

Extracellular Vesicles in Glioma: From Diagnosis to Therapy.

Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next-generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed.

Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study.

OBJECTIVE: To assess five physical signs to see whether they can assist in the screening of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and potentially lead to quicker treatment. METHODS: This was a diagnostic accuracy study with inter-rater agreement assessment. Participants recruited from two National Health Service hospitals, local CFS/ME support groups and the community were examined by three practitioners on the same day in a randomised order. Two allied health professionals (AHPs) performed independent examinations of physical signs including: postural/mechanical disturbances of the thoracic spine, breast varicosities, tender Perrin's point, tender coeliac plexus and dampened cranial flow. A physician conducted a standard clinical neurological and rheumatological assessment while looking for patterns of illness behaviour. Each examination lasted approximately 20 min. RESULTS: Ninety-four participants were assessed, 52 patients with CFS/ME and 42 non-CFS/ME controls, aged 18-60. Cohen's kappa revealed that agreement between the AHPs was substantial for presence of the tender coeliac plexus (κ=0.65, p<0.001) and moderate for postural/mechanical disturbance of the thoracic spine (κ=0.57, p<0.001) and Perrin's point (κ=0.56, p<0.001). A McNemar's test found no statistically significant bias in the diagnosis by the experienced AHP relative to actual diagnosis (p=1.0) and a marginally non-significant bias by the newly trained AHP (p=0.052). There was, however, a significant bias in the diagnosis made by the physician relative to actual diagnosis (p<0.001), indicating poor diagnostic utility of the clinical neurological and rheumatological assessment. CONCLUSIONS: Using the physical signs appears to improve the accuracy of identifying people with CFS/ME and shows agreement with current diagnostic techniques. However, the present study concludes that only two of these may be needed. Examining for physical signs is both quick and simple for the AHP and may be used as an efficient screening tool for CFS/ME. This is a small single-centre study, and therefore, further validation in other centres and larger populations is needed.

Pulmonary lymphangioleiomyomatosis--a silent killer?

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder presenting with remarkable features like recurrent pneumothorax or chylothorax, usually in young women. We report a case of sporadic LAM who presented with nothing but recent onset exertional dyspnoea and it was this unobtrusive presentation that led to delay in diagnosis.

Botulinum Toxin in the management of hitchhiker's toe.

INTRODUCTION: Hyperextension of the extensor hallucis longus (EHL) muscle is a well recognised disabling sequel of either pyramidal or extrapyramidal lesions causing what is known as striated or hitchhiker's toe. Surgery was the only effective strategy to manage EHL hyperextension before botulinum toxin's use to manage muscular dystonia and spasticity became widely popular. METHODS: A multicentre retrospective study. A standard proforma was sent to specialists in neurological rehabilitation dealing routinely with this problem. The data was analysed using descriptive statistics. RESULTS: Four consultants and two trainees representing five separate neurological rehabilitation services agreed to participate in the study. Full data was available from the 29 proformas completed. The subjects were 15 females with an age range between 20 and 78 years (mean 58.7). Stroke was the primary diagnosis in 18 subjects. Four subjects had bilateral involvement. 16 subjects had either an associated foot drop or equino varus deformity. Dysport® was used in 15 subjects with an average dose of 170 units per injection and Botox® in the other 14 with an average dose of 65 units. The treatment was effective in 24 subjects (83%). All patients receiving Dysport® responded to the treatment. Whilst 5 Botox® treated patients failed to respond to it (35% failure rate). Most of the non respondents seemed to receive insufficient doses of Botox® (below 60 units). Surgical management was successful in 3 out of the 5 non respondent cases. CONCLUSION: Botilinum Toxin is an effective and safe method to manage hitchhicker's toe. In our study the conversion ratio between Dysport® and Botox® was 2.5:1. Third of the patients receiving Botox® failed to respond to the treatment most probably due to insufficient doses used.