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BACKGROUND: Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. Ubiquitin-specific peptidase 18 (USP18) protein has been reported to exert different tumor-related effects in distinct tumor types. Here, we initially investigated the expression and signaling pathways of USP18 in colon adenocarcinoma (COAD).
METHODS: A quantitative real-time PCR was conducted to evaluate the mRNA level of USP18 in cultured cells. Immunohistochemical staining was used to explore the protein expression of USP18 in clinical COAD samples. Specific knockdown was achieved by transient transfection of small interfering RNAs into SW480 and HT29 cells using Lipo3000. Cell conting kit-8 assay, transwell assay and matrigel-transwell assays were conducted to evaluate proliferation, migration and invasion capacities, respectively. Western blotting was performed to analyze downstream signaling pathways. A chi-squared test and univariate and multivariate analyses were used to evaluate the clinical data. Xenografts from mice model were assessed to validate the in vitro findings.
RESULTS: Higher USP18 level was identified in COAD tissues and was positively correlated with advanced tumor stage. High USP18 protein expression indicated poorer prognosis of COAD patients. Silencing USP18 suppressed COAD cell proliferation and invasion via destabilizing extracellular signal-regulated kinase (ERK) protein and suppressing ERK downstream pathways. Simultaneously silencing interferon-stimulated gene 15 (ISG15) with USP18 can partially rescue the tumor cell viability, indicating its involvement in USP18 signaling. The oncogenic effects of USP18 were also confirmed in mice models.
CONCLUSIONS: USP18 plays oncogenic effects in colon adenocarcinoma via ISG15-ERK pathways. High USP18 expression indicates poor clinical outcomes for colon adenocarcinoma patients.

UNASSIGNED: To determine the predisposing factors for lengthy intensive care unit stay of chronic obstructive pulmonary disease patients with acute exacerbation.
METHODS: The retrospective study was conducted after approval from the ethics review committee of Atatürk Sanatorium Training and Research Hospital, Turkey, and comprised data from January 1, 2017, to August 31, 2022, related to acute exacerbation chronic obstructive pulmonary disease patients receiving intensive care unit treatment. Demographics, comorbidities, treatment, length of stay in hospital and in intensive care unit, and nutritional status were evaluated. Data of patients who spent <10 days in intensive care unit formed Group 1, while those having spent 10 days or more formed Group 2 for comparison purposes. Data was analysed using SPSS 22.
RESULTS: Of the 460 patients, 366(79.6%) were in Group 1; 224(61.2%) males and 64(38.8%) females with mean age 70.81±11.57 years. There were 94(20.4%) patients in Group 2; 62(66%) males and 32(34%) females with mean age 72.38±10.88 years (p>0.05). Inotropic agent support, need for haemodialysis, timeframe of invasive mechanical ventilation, length of stay in hospital, 1-month mortality, antibiotic use, use of diuretic agent, acute physiology and chronic health evaluation-ii score, nutrition risk in the critically ill score, history of lung malignancy, and pneumonic infiltration on chest radiograph were significantly more frequenttly observed in Group 2 patients (p<0.05). Age, timeframe of invasive mechanical ventilation, and length of stay in hospital were the factors prolonging intensive care unit stay (p<0.05).
CONCLUSIONS: Higher age, longer invasive mechanical ventilation timeframe and hospital stay with acute exacerbation chronic obstructive pulmonary disease caused a prolonged stay in intensive care unit.

UNASSIGNED: Vitamin D deficiency (VDD, 25-hydroxyvitamin D < 20 ng/mL) has been reported associated with exacerbation of chronic obstructive pulmonary disease (COPD) but sometimes controversial. Research on severe vitamin D deficiency (SVDD, 25-hydroxyvitamin D < 10 ng/mL) in exacerbation of COPD is limited.
UNASSIGNED: We performed a retrospective observational study in 134 hospitalized exacerbated COPD patients. 25-hydroxyvitamin D was modeled as a continuous or dichotomized (cutoff value: 10 or 20 ng/mL) variable to evaluate the association of SVDD with hospitalization in the previous year. Receiver operator characteristic (ROC) analysis was performed to find the optimal cut-off value of 25-hydroxyvitamin D.
UNASSIGNED: In total 23% of the patients had SVDD. SVDD was more prevalent in women, and SVDD group tended to have lower blood eosinophils counts. 25-hydroxyvitamin D level was significantly lower in patients who were hospitalized in the previous year (13.6 vs 16.7 ng/mL, P = 0.044), and the prevalence of SVDD was higher (38.0% vs 14.3%, P = 0.002). SVDD was independently associated with hospitalization in the previous year [odds ratio (OR) 4.34, 95% CI 1.61-11.72, P = 0.004] in hospitalized exacerbated COPD patients, whereas continuous 25-hydroxyvitamin D and VDD were not (P = 0.1, P = 0.9, separately). The ROC curve yielded an area under the curve of 0.60 (95% CI 0.50-0.71) with an optimal 25-hydroxyvitamin D cutoff of 10.4 ng/mL.
UNASSIGNED: SVDD probably showed a more stable association with hospitalization in the previous year in hospitalized exacerbated COPD patients. Reasons for lower eosinophil counts in SVDD group needed further exploration.

UNASSIGNED: Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation rates before and during this pandemic.
UNASSIGNED: Exacerbation patterns were analysed using electronic medical records or claims data of patients with COPD before (2017-2019) and during the COVID-19 pandemic (2020 through early 2022) in France, Germany, Italy, the United Kingdom and the United States. Data from each country were analysed separately. The proportions of patients with COPD receiving maintenance treatment were also estimated.
UNASSIGNED: The proportion of patients with exacerbations fell 45-78% across five countries in 2020 versus 2019. Exacerbation rates in most countries were reduced by >50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53-22.13% in 2019 to 9.94-34.17% in 2021.
UNASSIGNED: Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation.

UNASSIGNED: PLAUR has been found upregulated in various tumors and closely correlated with the malignant phenotype of tumor cells. The aim of this study was to investigate the relationship between PLAUR and clear cell renal cell carcinoma (ccRCC) and its potential mechanism of promoting tumor progression.
UNASSIGNED: The expression levels and clinical significance of PLAUR, along with the associated signaling pathways, were extensively investigated in ccRCC samples obtained from The Cancer Genome Atlas (TCGA). PLAUR expression in 20 pairs of ccRCC tumor tissues and the adjacent tissues was assessed using qRT-PCR and IHC staining. Additionally, a series of in vitro experiments were conducted to investigate the impact of PLAUR suppression on cellular proliferation, migration, invasion, cell cycle progression, and apoptosis in ccRCC. The Western blot analysis was employed to investigate the expression levels of pivotal genes associated with the PI3K/AKT/mTOR signaling pathway.
UNASSIGNED: The expression of PLAUR was significantly upregulated in ccRCC compared to normal renal tissues, and higher PLAUR expression in ccRCC was associated with a poorer prognosis than low expression. The in-vitro functional investigations demonstrated that knockdown of PLAUR significantly attenuated the proliferation, migration, and invasion capabilities of ccRCC cells. Concurrently, PLAUR knockdown effectively induced cellular apoptosis, modulated the cell cycle, inhibited the EMT process, and attenuated the activation of the PI3K/AKT/mTOR signaling pathway. PLAUR may represent a key mechanism underlying ccRCC progression.
UNASSIGNED: The involvement of PLAUR in ccRCC progression may be achieved through the activation of the PI3K/AKT/mTOR signaling pathway, making it a reliable biomarker for the identification and prediction of ccRCC.

Rationale: Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming. Methods: With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions. Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models. Results: MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts. MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 (MYCN), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis. AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells. Conversely, etoposide had better therapeutic effects on MPS-II NB cells. More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice. Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments. Immunologically, MPS-I NB suppressed immune cells via MIF and THBS signaling pathways. Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc. Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications. Conclusions: This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.

At present, the role of many long non-coding RNAs (lncRNAs) as tumor suppressors in the formation and development of cervical cancer (CC) has been studied. However, lncRNA prostate cancer gene expression marker 1 (PCGEM1), whose high expression not only aggravates ovarian cancer but also can induce tumorigenesis and endometrial cancer progression, has not been studied in CC. The objective of this study was to investigate the expression and the underlying role of PCGEM1 in CC. The relative expression of PCGEM1 in CC cells was detected by real-time PCR. After the suppression of PCGEM1 expression by shRNA, the changes in the proliferation, migration, and invasion capacities were detected via CCK-8 assay, EdU assay, and colony formation assay wound healing assay. Transwell assay and the changes in expressions of epithelial-to-mesenchymal transition (EMT) markers were determined by western blot and immunofluorescence. The interplay among PCGEM1, miR-642a-5p, and kinesin family member 5B (KIF5B) was confirmed by bioinformatics analyses and luciferase reporter assay. Results showed that PCGEM1 expressions were up-regulated within CC cells. Cell viabilities, migration, and invasion were remarkably reduced after the suppression of PCGEM1 expression by shRNA in Hela and SiHa cells. N-cadherin was silenced, but E-cadherin expression was elevated by sh-PCGEM1. Moreover, by sponging miR-642a-5p in CC, PCGEM1 was verified as a competitive endogenous RNA (ceRNA) that modulates KIF5B levels. MiR-642a-5p down-regulation partially rescued sh-PCGEM1\'s inhibitory effects on cell proliferation, migration, invasion, and EMT process. In conclusion, the PCGEM1/miR-642a-5p/KIF5B signaling axis might be a novel therapeutic target in CC. This study provides a research basis and new direction for targeted therapy of CC.

Hepatocellular carcinoma (HCC) is the most common and deadliest subtype of liver cancer worldwide and, therefore, poses an enormous threat to global health. Understanding the molecular mechanisms underlying the development and progression of HCC is central to improving our clinical approaches. PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs that bind to PIWI family proteins to regulate gene expression at transcriptional and post-transcriptional levels. A growing body of work shows that the dysregulation of piRNAs plays a crucial role in the progression of various human cancers. In this editorial, we report on the current knowledge of HCC-associated piRNAs and their potential clinical utility. Based on the editorial by Papadopoulos and Trifylli, on the role and clinical evaluation of exosomal circular RNAs in HCC, we highlight this other emerging class of non-coding RNAs.

BACKGROUND: Little is known about ageing and frailty progression in low-income settings. We aimed to describe frailty changes over time in individuals living in rural Burkina Faso and to assess which sociodemographic, disability, and multimorbidity factors are associated with frailty progression and mortality.
METHODS: This longitudinal, population-based study was conducted at the Nouna Health and Demographic Surveillance Systems (HDSS) site in northwestern Burkina Faso. Eligible participants were aged 40 years or older and had been primarily resident in a household within the HDSS area for at least the past 6 months before the baseline survey and were selected from the 2015 HDSS household census using a stratified random sample of adults living in unique households within the area. Participants were interviewed in their homes in 2018 (baseline), 2021 (follow-up), or both. We derived the Fried frailty score for each participant at each timepoint using data on grip strength, gait speed, self-reported weight loss, self-reported exhaustion, and physical activity, and described changes in frailty status (no frailty, pre-frailty, or frailty) between 2018 and 2021. We used multivariate regression models to assess factors (ie, sex, age, marital status, educational attainment, wealth quintile, WHO Disability Assessment Schedule (WHODAS) score, and multimorbidity) associated with frailty progression (either worsening frailty status or dying, compared with frailty status remaining the same or improving) and with mortality, and developed sequential models: unadjusted, adjusting for sociodemographic factors (sex, age, marital status, educational attainment, and wealth quintile), and adjusting for sociodemographic factors, disability, and multimorbidity.
RESULTS: Between May 25 and July 19, 2018, and between July 1 and Aug 22, 2021, 5952 individuals were invited to participate: 1709 (28·7%) did not consent, 1054 (17·8%) participated in 2018 only and were lost to follow-up, 1214 (20·4%) participated in 2021 only, and 1975 (33·2%) were included in both years or died between years. Of 1967 participants followed up with complete demographic data, 190 (9·7%) were frail or unable to complete the frailty assessment in 2018, compared with 77 (3·9%) in 2021. Between 2018 and 2021, frailty status improved in 567 (28·8%) participants and worsened in 327 (16·6%), and 101 (5·1%) participants died. The relative risk of frailty status worsening or of dying (compared with frailty impRoving or no change) increased with age and WHODAS score, whereas female sex appeared protective. After controlling for all sociodemographic factors, multimorbidity, and WHODAS score, odds of mortality were 1·07 (odds ratio 2·07, 95% CI 1·05-4·09) times higher among pre-frail individuals and 1·1 (2·21, 0·90-5·41) times higher among frail individuals than among non-frail individuals.
CONCLUSIONS: Frailty status was highly dynamic in this low-income setting and appears to be modifiable. Given the rapid increase in the numbers of older adults in low-income or middle-income countries, understanding the behaviour of frailty in these settings is of high importance for the development of policies and health systems to ensure the maintenance of health and wellbeing in ageing populations. Future work should focus on designing context-appropriate interventions to improve frailty status.
BACKGROUND: Alexander Von Humboldt Foundation, Institute for Global Innovation, University of Birmingham, and Wellcome Trust.