Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway.

Pancreatic cancer (PAAD) is a fatal malignancy with a poor prognosis. The treatment strategies are quite limited and gemcitabine is the canonical one, which has been proven to improve the prognosis of PAAD patients. However, the treatment efficiency of gemcitabine is far from satisfactory and remains to be further improved. DEAD-Box Helicase 46 (DDX46) is a kind of RNA helicase, which promotes multiple cancers development. However, its role in PAAD is largely unknown. In the present study, we found DDX46 was highly expressed in PAAD tissues and correlated with poor prognosis. Knockdown of DDX46 repressed PAAD cell growth in vitro and in vivo and sensitized PAAD cells to gemcitabine treatment. Mechanically, DDX46 bound to JMJD6 and promoted JMJD6/CDK4 signaling pathway. Overexpression of JMJD6 reversed the anti-tumor function of DDX46 knockdown. Our study found a novel pathological mechanism of PAAD progression and provided a potential therapeutic target to improve gemcitabine efficiency.

Single-cell landscape of the cellular microenvironment in three different colonic polyp subtypes in children.

BACKGROUND: The understanding of the heterogeneous cellular microenvironment of colonic polyps in paediatric patients with solitary juvenile polyps (SJPs), polyposis syndrome (PJS) and Peutz-Jeghers syndrome (PJS) remains limited. METHODS: We conducted single-cell RNA sequencing and multiplexed immunohistochemistry (mIHC) analyses on both normal colonic tissue and different types of colonic polyps obtained from paediatric patients. RESULTS: We identified both shared and disease-specific cell subsets and expression patterns that played important roles in shaping the unique cellular microenvironments observed in each polyp subtype. As such, increased myeloid, endothelial and epithelial cells were the most prominent features of SJP, JPS and PJS polyps, respectively. Noticeably, memory B cells were increased, and a cluster of epithelial-mesenchymal transition (EMT)-like colonocytes existed across all polyp subtypes. Abundant neutrophil infiltration was observed in SJP polyps, while CX3CR1hi CD8+ T cells and regulatory T cells (Tregs) were predominant in SJP and JPS polyps, while GZMAhi natural killer T cells were predominant in PJS polyps. Compared with normal colonic tissues, myeloid cells exhibited specific induction of genes involved in chemotaxis and interferon-related pathways in SJP polyps, whereas fibroblasts in JPS polyps had upregulation of myofiber-associated genes and epithelial cells in PJS polyps exhibited induction of a series of nutrient absorption-related genes. In addition, the TNF-α response was uniformly upregulated in most cell subsets across all polyp subtypes, while endothelial cells and fibroblasts separately showed upregulated cell adhesion and EMT signalling in SJP and JPS polyps. Cell-cell interaction network analysis showed markedly enhanced intercellular communication, such as TNF, VEGF, CXCL and collagen signalling networks, among most cell subsets in polyps, especially SJP and JPS polyps. CONCLUSION: These findings strengthen our understanding of the heterogeneous cellular microenvironment of polyp subtypes and identify potential therapeutic approaches to reduce the recurrence of polyps in children.

A safer and more practical tracheotomy in invasive mechanical ventilated patients with COVID-19: A quality improvement study.

Importance: The number of infections and deaths caused by the global epidemic of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) invasion is steadily increasing daily. In the early stages of outbreak, approximately 15%-20% of patients with coronavirus disease 2019 (COVID-19) inevitably developed severe and critically ill forms of the disease, especially elderly patients and those with several or serious comorbidities. These more severe forms of disease mainly manifest as dyspnea, reduced blood oxygen saturation, severe pneumonia, acute respiratory distress syndrome (ARDS), thus requiring prolonged advanced respiratory support, including high-flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), and invasive mechanical ventilation (IMV). Objective: This study aimed to propose a safer and more practical tracheotomy in invasive mechanical ventilated patients with COVID-19. Design: This is a single center quality improvement study. Participants: Tracheotomy is a necessary and important step in airway management for COVID-19 patients with prolonged endotracheal intubation, IMV, failed extubation, and ventilator dependence. Standardized third-level protection measures and bulky personal protective equipment (PPE) may hugely impede the implementation of tracheotomy, especially when determining the optimal pre-surgical positioning for COVID-19 patients with ambiguous surface position, obesity, short neck or limited neck extension, due to vision impairment, reduced tactile sensation and motility associated with PPE. Consequently, the aim of this study was to propose a safer and more practical tracheotomy, namely percutaneous dilated tracheotomy (PDT) with delayed endotracheal intubation withdrawal under the guidance of bedside ultrasonography without the conventional use of flexible fiberoptic bronchoscopy (FFB), which can accurately determine the optimal pre-surgical positioning, as well as avoid intraoperative damage of the posterior tracheal wall and prevent the occurrence of tracheoesophageal fistula (TEF).