RNA adenosine modifications related to prognosis and immune infiltration in osteosarcoma.

BACKGROUND: RNA adenosine modifications, which are primarily mediated by "writer" enzymes (RMWs), play a key role in epigenetic regulation in various biological processes, including tumorigenesis. However, the expression and prognostic role of these genes in osteosarcoma (OS) remain unclear. METHODS: Univariate and multivariate Cox analyses were used to construct the RMW signature for OS using Target datasets. RMW expression in OS tissue was detected by qPCR analysis. Xcell and GSVA were used to determine the relationship between RMWs and immune infiltration. The DGIdb and CMap databases were used for drug prediction. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS. RESULTS: A 3-RMW (CSTF2, ADAR and WTAP) prognostic signature in OS was constructed using the Target dataset and verified using GEO datasets and 63 independent OS tissues via qPCR analysis. High-risk OS patients had poor overall survival, and the prognostic signature was an independent prognostic factor for OS. Functional studies showed that tumour-, metabolism-, cell cycle- and immune-related pathways were related to high risk. Next, we found that RMW-derived high-risk patients exhibited increased infiltration of M2 macrophages and cDCs. Furthermore, we predicted the potential drugs for OS using the DGIdb and CMap databases. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS by repressing cell growth and inducing cell cycle arrest at the G1 phase. CONCLUSION: The 3-RWM-based prognostic signature established in this study is a novel gene signature associated with immune infiltration, and strophanthidin was identified as a candidate therapy for OS by repressing OS cell growth and the cell cycle.

Kinetic 18F-FDG PET/CT imaging of hepatocellular carcinoma: a dual input four-compartment model.

BACKGROUND: The endoplasmic reticulum plays an important role in glucose metabolism and has not been explored in the kinetic estimation of hepatocellular carcinoma (HCC) via 18F-fluoro-2-deoxy-D-glucose PET/CT. METHODS: A dual-input four-compartment (4C) model, regarding endoplasmic reticulum was preliminarily used for kinetic estimation to differentiate 28 tumours from background liver tissue from 24 patients with HCC. Moreover, parameter images of the 4C model were generated from one patient with negative findings on conventional metabolic PET/CT. RESULTS: Compared to the dual-input three-compartment (3C) model, the 4C model has better fitting quality, a close transport rate constant (K1) and a dephosphorylation rate constant (k6/k4), and a different removal rate constant (k2) and phosphorylation rate constant (k3) in HCC and background liver tissue. The K1, k2, k3, and hepatic arterial perfusion index (HPI) from the 4C model and k3, HPI, and volume fraction of blood (Vb) from the 3C model were significantly different between HCC and background liver tissues (all P < 0.05). Meanwhile, the 4C model yielded additional kinetic parameters for differentiating HCC. The diagnostic performance of the top ten genes from the most to least common was HPI(4C), Vb(3C), HPI(3C), SUVmax, k5(4C), k3(3C), k2(4C), v(4C), K1(4C) and Vb(4C). Moreover, a patient who showed negative findings on conventional metabolic PET/CT had positive parameter images in the 4C model. CONCLUSIONS: The 4C model with the endoplasmic reticulum performed better than the 3C model and produced additional useful parameters in kinetic estimation for differentiating HCC from background liver tissue.

Varespladib mitigates acute liver injury via suppression of excessive mitophagy on Naja atra envenomed mice by inhibiting PLA2.

Snakebite envenomation often leads to severe visceral injuries, including acute liver injury (ALI). However, the toxicity mechanism remains unclear. Moreover, varespladib can directly inhibit phospholipase A2 (PLA2) in snake venom, but its protective effect on snakebite-induced ALI and the mechanism have not been clarified. Previous studies have shown that snake venom PLA2 leads to neuron cell death via reactive oxygen species (ROS), one of the initial factors related to the mitophagy pathway. The present study group also found that ROS accumulation occurred after Naja atra envenoming. Hematoxylin and eosin (H/E) staining and immunohistochemistry (IHC) were performed to identify the expression of inflammatory factors in the liver tissue, and flow cytometry and immunofluorescence were used to detect ROS levels and mitochondrial function. Immunofluorescence and western blotting were also used for detecting mitophagy pathway-related proteins. The results showed that N. atra bite induced ALI by activating mitophagy and inducing inflammation and that varespladib had a protective effect. Collectively, these results showed the pathological mechanism of ALI caused by N. atra bite and revealed the protective effect of varespladib.

Circulating 25-hydroxyvitamin D concentration can predict bowel resection risk among individuals with inflammatory bowel disease in a longitudinal cohort with 13 years of follow-up.

BACKGROUND: Although the beneficial properties of vitamin D in anti-inflammation and immunity-modulation are promising in the management of inflammatory bowel disease (IBD), data were limited for the critical IBD prognosis. The association between serum vitamin D levels and the risk of bowel resection in individuals with IBD remains largely unknown. MATERIALS AND METHODS: We performed a longitudinal cohort study among 5474 individuals with IBD in the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] was measured using direct competitive chemiluminescent immunoassay. Bowel resection events were ascertained via national inpatient data. Multivariable-adjusted Cox proportional hazard regression was used to examine the association between serum 25(OH)D and bowel resection risk, presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate dose-response associations. RESULTS: During a mean follow-up of 13.1 years, we documented 513 incident bowel resection cases. Compared to participants with vitamin D deficiency, non-deficient participants showed a significantly reduced bowel resection risk in IBD (HR 0.72, 95% CI 0.59-0.87, P=0.001), Crohn's disease (CD, HR 0.74, 95% CI 0.56-0.98, P=0.038), and ulcerative colitis (UC, HR 0.73, 95% CI 0.57-0.95, P=0.020). When comparing extreme quintiles of 25(OH)D level, participants with IBD showed a 34% reduced risk of bowel resection (95% CI 11%-51%, P=0.007) and participants with UC showed a 46% reduced risk (95% CI 19%-64%, P=0.003), while this association was not significant in CD (HR 0.93, 95% CI 0.59-1.45, P=0.740). Linear dose-response associations were observed using the RCS curve (all P-nonlinearity>0.05). CONCLUSION: Increased serum level of 25(OH)D is independently associated with reduced bowel resection risk in IBD. This association was significant in UC but may not be stable in CD. Vitamin D deficiency is a risk factor for bowel resection in individuals with IBD, and may be an effective metric in predicting and risk-screening surgical events.

Prevalence of atypical pathogens in patients with severe pneumonia: a systematic review and meta-analysis.

OBJECTIVES: We aimed to summarise the prevalence of atypical pathogens in patients with severe pneumonia to understand the prevalence of severe pneumonia caused by atypical pathogens, improve clinical decision-making and guide antibiotic use. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Web of Science and Cochrane Library were searched through November 2022. ELIGIBILITY CRITERIA: English language studies enrolled consecutive cases of patients diagnosed with severe pneumonia, with complete aetiological analysis. DATA EXTRACTION AND SYNTHESIS: We conducted literature retrieval on PubMed, Embase, Web of Science and The Cochrane Library to estimate the prevalence of Chlamydia, Mycoplasma and Legionella in patients with severe pneumonia. After double arcsine transformation of the data, a random-effects model was used for meta-analyses to calculate the pooled prevalence of each pathogen. Meta-regression analysis was also used to explore whether the region, different diagnostic method, study population, pneumonia categories or sample size were potential sources of heterogeneity. RESULTS: We included 75 eligible studies with 18 379 cases of severe pneumonia. The overall prevalence of atypical pneumonia is 8.1% (95% CI 6.3% to 10.1%) In patients with severe pneumonia, the pooled estimated prevalence of Chlamydia, Mycoplasma and Legionella was 1.8% (95% CI 1.0% to 2.9%), 2.8% (95% CI 1.7% to 4.3%) and 4.0% (95% CI 2.8% to 5.3%), respectively. We noted significant heterogeneity in all pooled assessments. Meta-regression showed that the pneumonia category potentially influenced the prevalence rate of Chlamydia. The mean age and the diagnostic method of pathogens were likely moderators for the prevalence of Mycoplasma and Legionella, and contribute to the heterogeneity of their prevalence. CONCLUSIONS: In severe pneumonia, atypical pathogens are notable causes, especially Legionella. The diagnostic method, regional difference, sample size and other factors contribute to the heterogeneity of prevalence. The estimated prevalence and relative heterogeneity factors can help with microbiological screening, clinical treatment and future research planning. PROSPERO REGISTRATION NUMBER: CRD42022373950.

A complicated infection by cutaneous Nocardia wallacei and pulmonary Mycobacterium abscessus in a Chinese immunocompetent patient: a case report.

Nocardiosis is an infectious disease caused by Nocardia that primarily affects immunocompromised hosts. Mycobacterium abscessus is a common opportunistic pathogen that causes disease in humans, including pulmonary and extrapulmonary infection. Nocardia spp. infection is uncommon, and infection with Nocardia wallacei and Mycobacterium abscessus is even rarer. A 59-year-old immunocompetent woman with risk factors for environmental exposure developed nocardiosis and presented to the hospital with a cough, shortness of breath, hemoptysis, and a back abscess. An enhanced computed tomography (CT) of the chest revealed partial destruction of the right lung, as well as consolidation of the right upper lobe. Rare pathogens N. wallacei and Mycobacterium abscessus were detected by metagenomic next-generation sequencing (mNGS) from abscess on the back and lung puncture tissue, respectively. She was treated with a combination of antibiotics and was finally discharged with a good prognosis. In this case, we present a patient who was successfully diagnosed with N. wallacei and Mycobacterium abscessus infection using mNGS. This importance of using mNGS in pathogen detection and the effective use of antibiotics in treating patients with long-term rare infections is highlighted in this report.

Adverse health effects of emerging contaminants on inflammatory bowel disease.

Inflammatory bowel disease (IBD) is becoming increasingly prevalent with the improvement of people's living standards in recent years, especially in urban areas. The emerging environmental contaminant is a newly-proposed concept in the progress of industrialization and modernization, referring to synthetic chemicals that were not noticed or researched before, which may lead to many chronic diseases, including IBD. The emerging contaminants mainly include microplastics, endocrine-disrupting chemicals, chemical herbicides, heavy metals, and persisting organic pollutants. In this review, we summarize the adverse health effect of these emerging contaminants on humans and their relationships with IBD. Therefore, we can better understand the impact of these new emerging contaminants on IBD, minimize their exposures, and lower the future incidence of IBD.

Fatty acids and lipid mediators in inflammatory bowel disease: from mechanism to treatment.

Inflammatory Bowel Disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Though the pathogenesis of IBD remains unclear, diet is increasingly recognized as a pivotal factor influencing its onset and progression. Fatty acids, essential components of dietary lipids, play diverse roles in IBD, ranging from anti-inflammatory and immune-regulatory functions to gut-microbiota modulation and barrier maintenance. Short-chain fatty acids (SCFAs), products of indigestible dietary fiber fermentation by gut microbiota, have strong anti-inflammatory properties and are seen as key protective factors against IBD. Among long-chain fatty acids, saturated fatty acids, trans fatty acids, and ω-6 polyunsaturated fatty acids exhibit pro-inflammatory effects, while oleic acid and ω-3 polyunsaturated fatty acids display anti-inflammatory actions. Lipid mediators derived from polyunsaturated fatty acids serve as bioactive molecules, influencing immune cell functions and offering both pro-inflammatory and anti-inflammatory benefits. Recent research has also highlighted the potential of medium- and very long-chain fatty acids in modulating inflammation, mucosal barriers, and gut microbiota in IBD. Given these insights, dietary intervention and supplementation with short-chain fatty acids are emerging as potential therapeutic strategies for IBD. This review elucidates the impact of various fatty acids and lipid mediators on IBD and delves into potential therapeutic avenues stemming from these compounds.

Pancreatic cancer challenge in 52 Asian countries: age-centric insights and the role of modifiable risk factors (1990-2019).

Background: Pancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population. Methods: Data from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age-Period-Cohort model, and decomposition analysis to evaluate incidence trends and effects. Results: From 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY. Conclusion: With the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.

A universal and specific RNA biosensor via DNA circuit-mediated PAM-independent CRISPR/Cas12a and PolyA-rolling circle amplification.

Point of care testing (POCT) has important clinical significance for the diagnosis and prognosis evaluation of diseases. At present, the biosensor based on CRISPR/Cas12a has become a powerful diagnostic tool due to its high sensitivity. However, CRISPR/Cas12a requires PAM sequence to recognize target double strand and only can recognize specific sequence, so it is not universal. The current RNA detection techniques either lack consideration for specificity and universality, are expensive and difficult, or both. Therefore, it is crucial to create a CRISPR/Cas12a-based RNA detection system that is easy to use, cheap, specific, and universal in order to further its use in molecular diagnostics. Here, we established a DNA circuit-mediated PAM-independent CRISPR/Cas12a coupled PolyA-rolling circle amplification for RNA detection biosensor, namely DCPRBiosensor. The DCPRBiosensor not only functions as a simple, inexpensive, and highly sensitive RNA detection sensor, but it also boasts innovative specificity and universality features. More importantly, DCPRBiosensor removes the PAM restriction of CRISPR/Cas12a. The DCPRBiosensor's detection limit reached 100 aM and it had a linear relationship between 100 aM and 10 pM. We detected four piRNAs to verify the universality and stability of DCPRBiosensor. Then, we verified that DCPRBiosensor has good discrimination ability for single-base mismatch. Finally, we successfully detected piRNA in DLD-1 and HCT-116 cells and urine mixed samples within 4.5 h. In conclusion, we believe that DCPRBiosensor will have a substantial impact on both the development of CRISPR/as12a's applications and the investigation of the clinical value of piRNA.

Evolving Trends and Burden of Inflammatory Bowel Disease in Asia, 1990-2019: A Comprehensive Analysis Based on the Global Burden of Disease Study.

BACKGROUND: Asia's inflammatory bowel disease (IBD) burden has rapidly increased recently, but the epidemiological trends in Asia remain unclear. We report IBD's incidence, prevalence, mortality, and Disability-Adjusted Life Years (DALY) in 52 Asian countries from 1990 to 2019. METHODS: Data from the Global Burden of Disease 2019 were analyzed for IBD burden across 52 countries, using metrics like incidence, prevalence, mortality rates, and DALY. The epidemiological trend of IBD from 1990 to 2019 was assessed with the Joinpoint and APC methods. Decomposition and frontier analyses examined factors behind IBD case and death changes. The NORPRED forecasted Asia's morbidity and mortality trends from 2019 to 2044. RESULTS: From 1990 to 2019, The incidence and prevalence of IBD increased in Asia, while mortality and DALY decreased. East Asia had the highest increase in disease burden. IBD incidence was highest among the 30-34 age group, with prevalence peaking in the 45-49 age group. In high-income regions, IBD peak age shifted to younger groups. Decompose analysis showed population growth as the primary factor for the increasing IBD cases in Asia. NORDPRED model predicted a continued IBD burden increase in Asia over the next 25 years. CONCLUSIONS: Between 1990 and 2019, ASIR and ASPR of IBD in Asia increased, while ASMR and ASDR decreased. Due to population growth and aging, the IBD burden is expected to rise over the next 25 years, particularly in East Asia.