The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma

BackgroundPleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM.MethodsWe analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA–drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up.ResultsWhile PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm² had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm² had a high risk of death (P=0.03) and a median survival time of 34 months.ConclusionsWe shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.     

Space perception,movement, and insight: attuning to the space of everyday life after major weight loss

Physiotherapists are well placed to help people adjust and engage meaningfully with the world following major weight loss. Recent research indicates that the body size a patient has lived with for years can continue to affect movement and perception even after largescale weight loss. This article explores this discrepancy in depth from the perspective of phenomenology and space perception and through the concepts of body image, body schema, and affordances. It draws on an empirical example in which a nautical engineer described his lived experience of returning to work following bariatric surgery and the discrepancies he experienced while adjusting to his new situation, particularly when moving his smaller body around the ship’s engine room, previously inaccessible to him. Analysis of this empirical example suggests that transitions in weight and size following bariatric surgery are both highly explicit in awareness (i.e., body image) and outside awareness (i.e., body schema). Major weight loss can open up new affordances and possibilities of being in the world, but only after adjustments in body image and body schema. The article suggests ways in which such insights can contribute to physiotherapists’ clinical development and practice when working with patients undergoing major weight loss.     

Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity

Induction of potent and sustained antiviral or antitumor immunity is dependent on the efficient activation of CD8+ and CD4+ T cells. While dendritic cells constitute a powerful platform for stimulating cellular immunity, presentation of endogenous antigens by dendritic cells transfected with nucleic acid-encoded antigens favors the stimulation of CD8+ T cells over that of CD4+ T cells. A short incubation of mRNA-transfected dendritic cells with antisense oligonucleotides directed against the invariant chain enhances the presentation of mRNA-encoded class II epitopes and activation of CD4+ T-cell responses in vitro and in vivo. Immunization of mice with the antisense oligonucleotide-treated dendritic cells stimulates a more potent and longer lasting CD8+ cytotoxic T-cell (CTL) response and enhances the antitumor efficacy of dendritic cell-based tumor vaccination protocols. Transient inhibition of invariant chain expression represents a simple and general method to enhance the stimulation of CD4+ T-cell responses from endogenous antigens.     

Human Papillomavirus Prevalence in Oropharyngeal Cancer before Vaccine Introduction,United States

We conducted a study to determine prevalence of HPV types in oropharyngeal cancers in the United States and establish a prevaccine baseline for monitoring the impact of vaccination. HPV DNA was extracted from tumor tissue samples from patients in whom cancer was diagnosed during 1995–2005. The samples were obtained from cancer registries and Residual Tissue Repository Program sites in the United States. HPV was detected and typed by using PCR reverse line blot assays. Among 557 invasive oropharyngeal squamous cell carcinomas, 72% were positive for HPV and 62% for vaccine types HPV16 or 18. Prevalence of HPV-16/18 was lower in women (53%) than in men (66%), and lower in non-Hispanic Black patients (31%) than in other racial/ethnic groups (68%–80%). Results indicate that vaccines could prevent most oropharyngeal cancers in the United States, but their effect may vary by demographic variables.     

Promoting head CT exams in the emergency department triage using a machine learning model

Neuroradiology - In this study, we aimed to develop a novel prediction model to identify patients in need of a non-contrast head CT exam during emergency department (ED) triage. We collected data...     

Bone regeneration performance of surface-treated porous titanium

The large surface area of highly porous titanium structures produced by additive manufacturing can be modified using biofunctionalizing surface treatments to improve the bone regeneration performance of these otherwise bioinert biomaterials. In this longitudinal study, we applied and compared three types of biofunctionalizing surface treatments, namely acid–alkali (AcAl), alkali–acid–heat treatment (AlAcH), and anodizing-heat treatment (AnH). The effects of treatments on apatite forming ability, cell attachment, cell proliferation, osteogenic gene expression, bone regeneration, biomechanical stability, and bone-biomaterial contact were evaluated using apatite forming ability test, cell culture assays, and animal experiments. It was found that AcAl and AnH work through completely different routes. While AcAl improved the apatite forming ability of as-manufactured (AsM) specimens, it did not have any positive effect on cell attachment, cell proliferation, and osteogenic gene expression. In contrast, AnH did not improve the apatite forming ability of AsM specimens but showed significantly better cell attachment, cell proliferation, and expression of osteogenic markers. The performance of AlAcH in terms of apatite forming ability and cell response was in between both extremes of AnH and AsM. AcAl resulted in significantly larger volumes of newly formed bone within the pores of the scaffold as compared to AnH. Interestingly, larger volumes of regenerated bone did not translate into improved biomechanical stability as AnH exhibited significantly better biomechanical stability as compared to AcAl suggesting that the beneficial effects of cell-nanotopography modulations somehow surpassed the benefits of improved apatite forming ability. In conclusion, the applied surface treatments have considerable effects on apatite forming ability, cell attachment, cell proliferation, and bone ingrowth of the studied biomaterials. The relationship between these properties and the bone-implant biomechanics is, however, not trivial.