The role of SPP1 as a prognostic biomarker and therapeutic target in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies and has a low 5-year survival rate. Mounting evidence suggests that oral potentially malignant disorders, such as oral leukoplakia (OLK), may progress to HNSCC. Given that OLK and HNSCC are often insidious and asymptomatic, the identification of markers of OLK malignant transformation and therapeutic targets in HNSCC is critical. Using various online tools and publicly available gene expression datasets, the secreted phosphoprotein 1 gene (SPP1) was identified as a significant differentially expressed gene among OLK, HNSCC, and non-cancerous tissues. SPP1 mRNA levels were elevated in HNSCC tissues and were associated with cancer stage, tumor grade, and human papillomavirus infection status. High SPP1 mRNA levels were correlated with poor overall survival of HNSCC patients. In contrast, SPP1 mutations were not significantly associated with overall survival, although their frequency in HNSCC was very low (0.6%). Furthermore, SPP1 expression levels in HNSCC were positively correlated with the infiltration of CD4⁺ cells, macrophages, neutrophils, and dendritic cells. The study results suggest that SPP1 may represent a diagnostic and prognostic biomarker, as well as a potential therapeutic target in HNSCC.     

Automatic segmentation of thoracic CT images using three deep learning models

PurposeDeep learning (DL) techniques are widely used in medical imaging and in particular for segmentation. Indeed, manual segmentation of organs at risk (OARs) is time-consuming and suffers from inter- and intra-observer segmentation variability. Image segmentation using DL has given very promising results. In this work, we present and compare the results of segmentation of OARs and a clinical target volume (CTV) in thoracic CT images using three DL models.Materials and methodsWe used CT images of 52 patients with breast cancer from a public dataset. Automatic segmentation of the lungs, the heart and a CTV was performed using three models based on the U-Net architecture. Three metrics were used to quantify and compare the segmentation results obtained with these models: the Dice similarity coefficient (DSC), the Jaccard coefficient (J) and the Hausdorff distance (HD).ResultsThe obtained values of DSC, J and HD were presented for each segmented organ and for the three models. Examples of automatic segmentation were presented and compared to the corresponding ground truth delineations. Our values were also compared to recent results obtained by other authors.ConclusionThe performance of three DL models was evaluated for the delineation of the lungs, the heart and a CTV. This study showed clearly that these 2D models based on the U-Net architecture can be used to delineate organs in CT images with a good performance compared to other models. Generally, the three models present similar performances. Using a dataset with more CT images, the three models should give better results.     

Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform ( https://oncotools.elixir.no ), and can also be accessed as a stand-alone R package ( https://github.com/sigven/oncoEnrichR ).     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.     

Annexins as potential targets in ocular diseases

Annexins (AnxAs) are Ca²⁺/phospholipid-binding proteins extensively studied and generally involved in several diseases. Although evidence exists regarding the distribuition of AnxAs in the visual system, their exact roles and the exact cell types of the eye where these proteins are expressed are not well-understood. AnxAs have pro-resolving roles in infectious, autoimmune, degenerative, fibrotic and angiogenic conditions, making them an important target in ocular tissue homeostasis. This review summarizes the current knowledge on the distribution and function of AnxA1–8 isoforms under normal and pathological conditions in the visual system, as well as perspectives for ophthalmologic treatments, including the potential use of the AnxA1 recombinant and/or its mimetic peptide Ac_2–26.     

Post-cardiac arrest intensive care in Sweden: A survey of current clinical practice

Background

European guidelines recommend targeted temperature management (TTM) in post-cardiac arrest care. A large multicentre clinical trial, however, showed no difference in mortality and neurological outcome when comparing hypothermia to normothermia with early treatment of fever. The study results were valid given a strict protocol for the assessment of prognosis using defined neurological examinations. With the current range of recommended TTM temperatures, and applicable neurological examinations, procedures may differ between hospitals and the variation of clinical practice in Sweden is not known.

Aim

The aim of this study was to investigate current practice in post-resuscitation care after cardiac arrest as to temperature targets and assessment of neurological prognosis in Swedish intensive care units (ICUs).

Methods

A structured survey was conducted by telephone or e-mail in all Levels 2 and 3 (= 53) Swedish ICUs during the spring of 2022 with a secondary survey in April 2023.

Results

Five units were not providing post-cardiac arrest care and were excluded. The response rate was 43/48 (90%) of the eligible units. Among the responding ICUs, normothermia (36–37.7°C) was applied in all centres (2023). There was a detailed routine for the assessment of neurological prognosis in 38/43 (88%) ICUs. Neurological assessment was applied 72–96 h after return of spontaneous circulation in 32/38 (84%) units. Electroencephalogram and computed tomography and/or magnetic resonance imaging were the most common technical methods available.

Conclusion

Swedish ICUs use normothermia including early treatment of fever in post-resuscitation care after cardiac arrest and almost all apply a detailed routine for the assessment of neurological prognosis. However, available methods for prognostic evaluation varies between hospitals.     

Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

胸段食管鳞癌术后复发模式及术后放疗靶区的研究北大核心

目的:研究胸段食管鳞癌术后复发模式,为术后放疗靶区勾画提供参考。方法:回顾分析我院2012年7月至2017年5月收治术后复发的81例胸段食管鳞癌患者的临床资料,参照AJCC第八版食管癌分期,将第1-8M站定义为上中纵隔淋巴结区,8Lo、9、15站定义为下纵隔淋巴结区,16-20站定义为上腹部淋巴结区。标记患者的复发部位,并分析局部复发、区域复发和远处转移的模式。结果:中位复发时间为12个月(2~103个月)。6例(7.4%)患者发生单纯局部复发,64例(79.0%)患者发生区域复发,11例(13.6%)患者发生远处转移。区域淋巴结复发中最高危的复发区域为上中纵隔淋巴引流区,此区域包含了82.8%的复发淋巴结,其次为上腹部淋巴结引流区(13.6%)。11例患者发生上腹部淋巴结复发,其中10(90.9%)例为胸下段,7例(63.6%)患者术后分期≥Ⅲ_(b)期。结论:胸段食管鳞癌术后复发模式以区域淋巴结复发为主,上中纵隔淋巴引流区为最高危复发区域,术后放疗靶区应重点包含。对于术后分期较晚的胸下段食管鳞癌,上腹部淋巴结引流区可能需要涵盖在放疗靶区内。吻合口、瘤床和下纵隔复发风险低,可不必常规涵盖在放疗靶区内。     

Knockdown of DEAD-box 51 inhibits tumor growth of esophageal squamous cell carcinoma via the PI3K/AKT pathway

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.