Classification, detection, and segmentation performance of image-based AI in intracranial aneurysm: a systematic review.

BACKGROUND: The detection and management of intracranial aneurysms (IAs) are vital to prevent life-threatening complications like subarachnoid hemorrhage (SAH). Artificial Intelligence (AI) can analyze medical images, like CTA or MRA, spotting nuances possibly overlooked by humans. Early detection facilitates timely interventions and improved outcomes. Moreover, AI algorithms offer quantitative data on aneurysm attributes, aiding in long-term monitoring and assessing rupture risks. METHODS: We screened four databases (PubMed, Web of Science, IEEE and Scopus) for studies using artificial intelligence algorithms to identify IA. Based on algorithmic methodologies, we categorized them into classification, segmentation, detection and combined, and then their merits and shortcomings are compared. Subsequently, we elucidate potential challenges that contemporary algorithms might encounter within real-world clinical diagnostic contexts. Then we outline prospective research trajectories and underscore key concerns in this evolving field. RESULTS: Forty-seven studies of IA recognition based on AI were included based on search and screening criteria. The retrospective results represent that current studies can identify IA in different modal images and predict their risk of rupture and blockage. In clinical diagnosis, AI can effectively improve the diagnostic accuracy of IA and reduce missed detection and false positives. CONCLUSIONS: The AI algorithm can detect unobtrusive IA more accurately in communicating arteries and cavernous sinus arteries to avoid further expansion. In addition, analyzing aneurysm rupture and blockage before and after surgery can help doctors plan treatment and reduce the uncertainties in the treatment process.

CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.

Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts in vitro and in vivo. Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.

Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Coexisting RET/PTC and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targets in Thyroid Cancer.

PURPOSE: To investigate the role of coexisting RET/PTC rearrangement and TERT promoter mutation in the prognosis and therapeutic targeting in papillary thyroid cancer (PTC). METHODS: A total of 669 PTC patients with complete clinical follow-up and genetic data were pooled from thyroid cancer datasets TCGA, MSK MetTropism, and MSK-IMPACT, from whom 163 patients (112 women and 47 men, 4 unknown) with wild-type BRAF/RAS were identified, with median age (IQR) of 46.00 (33.00, 61.00) years and median follow-up time (IQR) of 16.13 (8.09, 27.91) months for comparative genotype cohort analysis of mortality. RESULTS: There was a significant concurrence index between RET/PTC and TERT promoter mutations, being 2.040 (95% CI 1.110-3.747, P = 0.023). Mortality occurred in 5/100 (5%) patients harboring neither mutation, 2/18 (11.1%) patients harboring TERT promoter mutation alone, 0/31 (0%) patients harboring RET/PTC alone, and 7/14 (50%) patients harboring both genetic alterations, corresponding to HRs (95% CI) of 1 (Reference), 2.469 (0.405-14.02), 3.296e-09 (0-inf), and 9.019 (2.635-30.87), respectively, which remained essentially unchanged after adjustment for patient race, sex, and age. Similar results were observed with BRAF/RAS and TERT promoter mutations. Mechanistically, RET/PTC used the MAP kinase pathway to upregulate the mutated TERT, but not the wild-type TERT, and, correspondingly, targeting RET and MEK could suppress mutated TERT but not the wild-type TERT. CONCLUSION: Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.

CircPRDM5 inhibits the proliferation, migration, invasion, and glucose metabolism of gastric cancer cells by reducing GCNT4 expression in a miR-485-3p-dependent manner.

Circular RNA (circRNA) plays a key part in the pathological process of gastric cancer (GC). The study is organized to analyze the function of circPRDM5 in GC cell tumor properties. Expression levels of circPRDM5, miR-485-3p, glucosaminyl (N-acetyl) transferase 4 (GCNT4), ki67, E-cadherin, N-cadherin, and hexokinase 2 (HK2) were analyzed by quantitative real-time polymerase chain reaction (PCR), Western blotting or immunohistochemistry assay. Cell proliferation was assessed by cell colony formation assay and 5-ethynyl-2'-deoxyuridine assay. Cell migration and invasion were investigated by transwell assay. Glycolysis was evaluated by the Seahorse XF Glycolysis Stress Test Kit. Dual-luciferase reporter assay and RNA pull-down assay were performed to identify the associations among circPRDM5, miR-485-3p, and GCNT4. Xenograft mouse model assay was conducted to determine the effects of circPRDM5 on tumor formation in vivo. CircPRDM5 and GCNT4 expression were downregulated, while miR-485-3p expression was upregulated in GC tissues and cells when compared with paracancerous tissues or human gastric epithelial cells. CircPRDM5 overexpression inhibited proliferation, migration, invasion, and glucose metabolism of GC cells; however, circPRDM5 depletion had the opposite effects. CircPRDM5 repressed tumor properties of GC cells in vivo. MiR-485-3p restoration relieved circPRDM5-induced effects in GC cells. GCNT4 overexpression remitted the promoting effects of miR-485-3p mimics on GC cell malignancy. CircPRDM5 acted as a sponge for miR-485-3p, and GCNT4 was identified as a target gene of miR-485-3p. Moreover, circPRDM5 regulated GCNT4 expression by interacting with miR-485-3p.CircPRDM5 acted as a miR-485-3p sponge to inhibit GC progression by increasing GCNT4 expression, proving a potential target for GC therapy.

Copy number variants landscape of multiple cancers and clinical applications based on NGS gene panel.

BACKGROUND: The rapid adoption of next-generation sequencing in clinical oncology has enabled detection of molecular biomarkers which are shared between multiple tumour types. Intra-tumour heterogeneity is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the tumour-related copy number variants (CNVs), as key regulators of cancer origination, development, and progression, across various types of cancers are poorly understood. METHODS: We performed pan-cancer CNV analysis of cancer-related genes in 15 types of cancers including 1438 cancerous patients by next-generation sequencing using a commercially available pan-cancer panel (Onco PanScan™). Downstream bioinformatics analysis was performed in order to detect CNVs, cluster analysis of the found CNVs, and comparison of the frequency of gained CNVs between different types of cancers. LASSO analysis was used for identification of the most important CNVs. RESULTS: We also identified 523 CNVs among which 16 CNVs were common while 22 CNVs were caner-specific CNVs. Meanwhile, FAM58A was most commonly found in all studied cancers in this study and significant differences were found in FAM58A between female and male patients (p = .001). Common CNVs, such as FOXA1, NFKBIA, HEY1, MECOM, CHD7, AGO2, were mutated in 6.79%, 8.45%, 7.51%, 6.43%, 7.59%, 8.16% of tumours, while most of these mutations have proven roles in positive regulation of transcription from RNA polymerase II promoter. 11 features including sex, DIS3, EPHB1, ERBB2, FLT1, HCK, KEAP1, MYD88, PARP3, TBX3, and TOP2A were found as the key features for classification of cancers using CNVs. CONCLUSION: The 16 common CNVs between cancers can be used to identify the target of pan-cancer drug design and targeted therapies. Additionally, 22 caner-specific CNVs can be used as unique diagnostic markers for each cancer type.

[Early Efficacy Observation of Pomalidomide-based Regimen in the Treatment of High-risk Multiple Myeloma].

OBJECTIVE: To investigate the efficacy and safety of pomalidomide based regimen in the treatment of high-risk multiple myeloma (MM). METHODS: Clinical data of 27 high-risk MM patients treated in Shanxi Bethune Hospital from January 2021 to December 2022 were retrospectively analyzed. All patients were treated with pomadomide based regimen for at least 2 consecutive cycles, and the early therapeutic effect and safety were observed. RESULTS: Overall remission rate (ORR) was 63.0%(17/27 cases) and deep remission rate was 22.2%(6/27 cases) after 2 cycles of treatment; ORR was 90.5%(19/21 cases) and deep remission rate was 66.7%(14/21 cases) after 4 cycles of treatment. Both ORR and deep remission rate were significantly higher after 4 cycles of treatment than 2 cycles (P=0.044, P=0.003). Beyond that, in the newly diagnosed and relapsed refractory MM groups, ORR after 2 cycles of treatment were 75%(9/12 cases) and 60%(9/15 cases), and deep remission rates were 25%(3/12 cases) and 20%(3/15 cases), respectively; ORR after 4 cycles of treatment were 100%(9/9 cases) and 83.3%(10/12 cases), and deep remission rates were 77.8%(7/9 cases) and 58.3%(7/12 cases), respectively, while there was no significant difference in remission rates between the two groups (P>0.05). In the group of creatinine ≥177 µmol/L, the serum creatinine level was significantly decreased after 2 cycles of treatment compared with that pre-treatment (P=0.001). The 1q21 amplified subgroup accounted for the largest proportion (21/27 cases), ORR was 66.7%(14/21 cases) and deep remission rate was 23.8%(5/21 cases) after 2 cycles of treatment, ORR was 88.9%(16/18 cases) and deep remission rate was 66.7%(12/18 cases) after 4 cycles of treatment. In all the symptoms, the most common adverse reactions were pulmonary infection in 9 cases and hematological adverse reactions of grade 1-2 in 8 cases. CONCLUSION: The pomalidomide-based treatment regimen has good early curative effect on the newly diagnosed and relapsed refractory high-risk MM, and also benefits to the high-risk cytogenetic MM, or MM with renal impairment. Therefore, this treatment regimen showed a good safety, and the long-term curative effect needs to be further assessed by more clinical data.

NOD-like Receptor Signaling Pathway in Gastrointestinal Inflammatory Diseases and Cancers.

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular proteins with a central role in innate and adaptive immunity. As a member of pattern recognition receptors (PRRs), NLRs sense specific pathogen-associated molecular patterns, trigger numerous signaling pathways and lead to the secretion of various cytokines. In recent years, cumulative studies have revealed the significant impacts of NLRs in gastrointestinal (GI) inflammatory diseases and cancers. Deciphering the role and molecular mechanism of the NLR signaling pathways may provide new opportunities for the development of therapeutic strategies related to GI inflammatory diseases and GI cancers. This review presents the structures and signaling pathways of NLRs, summarizes the recent advances regarding NLR signaling in GI inflammatory diseases and GI cancers and describes comprehensive therapeutic strategies based on this signaling pathway.

Diagnostic Potential of Endometrial Cancer DNA from Pipelle, Pap-Brush, and Swab Sampling.

Endometrial cancer (EC) is a major gynecological malignancy with rising morbidity and mortality worldwide. The aim of this study was to explore a safe and readily available sample and a sensitive and effective detection method and its biomarkers for early diagnosis of EC, which is critical for patient prognosis. This study designed a panel targeting variants for EC-related genes, assessed its technical performance by comparing it with whole-exon sequencing, and explored the diagnostic potential of endometrial biopsies using the Pipelle aspirator, cervical samples using the Pap brush, and vaginal specimens using the swab from 38 EC patients and 208 women with risk factors for EC by applying targeted panel sequencing (TPS). TPS produced high-quality data (Q30 > 85% and mapping ratios > 99.35%) and was found to have strong consistency with whole-exome sequencing (WES) in detecting pathogenic mutations (92.11%), calculating homologous recombination deficiency (HRD) scores (r = 0.65), and assessing the microsatellite instability (MSI) status of EC (100%). The sensitivity of TPS in detection of EC is slightly better than that of WES (86.84% vs. 84.21%). Of the three types of samples detected using TPS, endometrial biopsy using the Pipelle aspirator had the highest sensitivity in detection of pathogenic mutations (81.87%) and the best consistency with surgical tumor specimens in MSI (85.16%). About 84% of EC patients contained pathogenic mutations in PIK3CA, PTEN, TP53, ARID1A, CTNNB1, KRAS, and MTOR, suggesting that this small gene set can achieve an excellent pathogenic mutation detection rate in Chinese EC patients. The custom panel combined with ultra-deep sequencing serves as a sensitive method for detecting genetic lesions from endometrial biopsy using the Pipelle aspirator.

Bi-Directional Pollution Characteristics and Ecological Health Risk Assessment of Heavy Metals in Soil and Crops in Wanjiang Economic Zone, Anhui Province, China.

Understanding the extent of contamination, sources and various carcinogenic and non-carcinogenic risks associated with different heavy metals in soil-crop systems is crucial for the prevention of heavy metal pollution. A survey was undertaken to determine heavy metal concentrations and degree of pollution in soil-crop systems (rice, wheat, and corn) using various indices such as pollution factor (CF), geo-accumulation index (Igeo), enrichment coefficients and transfer coefficient, and to determine the source of heavy metals pollution in the Wanjiang Economic Zone, Anhui Province, China. A total of 308 pairs of soil-crop samples were collected in this study, comprising 245 pairs of soil-rice samples, 53 pairs of soil-wheat samples, and 10 pairs of soil-corn samples. The concentrations of cadmium (Cd) and nickel (Ni) in the soil of the study area exceeded the national limitation of heavy metals in the soil of China (GB 15618-2018, Soil Environmental Quality: Risk Control Standard for Soil Contamination of Agricultural Land. Ministry of Environmental Protection of China. Beijing. China). The concentrations of copper (Cu), zinc (Zn) and lead (Pb) were also above the national limits to a lesser extent. All eight heavy metals (Cd, Cu, Ni, Pb Zn, arsenic (As), chromium (Cr), and mercury (Hg)) exceeded the background values in the study area. The enrichment coefficients of rice, wheat and maize to Cd, Cu and Zn were higher than those to other elements. On the basis of Igeo, it can be indicated that the rhizosphere soil of rice was slightly polluted by Cd and Hg, while the concentrations of the other heavy metals were below the safety limits. The CF and pollution load index (PLI) indicated that the soil in the study area was heavily contaminated with heavy metals. A principal component analysis identified different sources of soil heavy metal pollution, that is, Cu, Pb, Zn and Cd from industrial sources, Cr and Ni from natural sources, and As and Hg from agricultural sources. The carcinogenic risk of heavy metals was related to the intake of crops. Residents in the study area ingest rice, wheat, and corn on a daily basis. On the basis this study, it is suggested that local governments should pay attention to the carcinogenic risk of heavy metals in rice.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

Comprehensive bioinformatics analysis of functional molecules in colorectal cancer.

Background: Colorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of cancer-related death. Numerous studies have found that aberrations in cellular molecules play an important role in the development of tumors. Studying and determining the interactions between these molecules can contribute to the diagnosis, treatment, and prognosis of tumors. Methods: The GSE151021, GSE156720, and GSE156719 data sets were analyzed to screen the differentially expressed messenger RNAs (DEmRNAs), long non-coding RNAs (DElncRNAs), and microRNAs (DEmiRNAs) in CRC. Database for Annotation, Visualization and Integrated Discovery (DAVID) and the Search Tool for the Retrieval of Interacting Genes/Proteins software were used to examine gene enrichment and the hub genes. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN was used to verify the expression of the hub genes. To analyze the overall survival (OS) of the hub genes, Kaplan-Meier plotter (KM plotter) was performed. Finally, the miRCancer database, TargetScan, and GSE156719 were used to identify the targets of the identified miRNAs. To predict the lncRNA-miRNA interactions, we used DIANA-LncBase v2 and GSE156720. Finally, the visualization protein­protein interaction (PPI), competitive endogenous RNA (ceRNA) network was constructed using Cytoscape v3.1. Results: By analyzing GSE151021 and GSE156720, 23 upregulated mRNAs and 10 downregulated mRNAs were identified as sharing the differentially expressed genes (DEGs) between CRC and adjacent tissues. Furthermore, nucleolar protein 14 (NOP14), the sonic hedgehog (SHH) signaling molecule, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), the BCL2 apoptosis regulator (BCL2), and zinc finger E-box binding homeobox 2 (ZEB2) were considered hub genes. The constructed lncRNA-miRNA-mRNA network revealed 7 intersecting miRNAs (4 upregulated and 3 downregulated), 79 lncRNAs (40 upregulated and 39 downregulated), and 5 mRNAs (3 upregulated and 2 downregulated). Finally, we determined that the dysregulation of lncRNAs, such as HCG16, CASC9, SNHG16, HAND2-AS1, and NR2F1-AS1, secluded altered the expression of several miRNAs, such as hsa-miR-193a-5p, hsa-miR-485-5p, hsa-miR-17-5p, and hsa-miR-92a-3p, and affected the occurrence and development of CRC. Conclusions: We identified a series of DElncRNAs, DEmRNAs, and DEmiRNAs in CRC that might be considered potential biomarkers in understanding the complex molecular pathways leading to CRC development.

Macrophagic Extracellular Vesicle CXCL2 Recruits and Activates the Neutrophil CXCR2/PKC/NOX4 Axis in Sepsis.

Sepsis is a life-threatening organ dysfunction caused by a dysfunctional host response to infection. Neutrophils play a protective role by releasing antibacterial proteins or by phagocytizing bacteria. However, excess neutrophils can induce tissue damage. Recently, a novel intercellular communication pathway involving extracellular vesicles (EVs) has garnered considerable attention. However, whether EVs secreted by macrophages mediate neutrophil recruitment to infected sites has yet to be studied. In this study, we assessed the chemotactic effect of EVs isolated from mouse Raw264.7 macrophages on mouse neutrophils and found that CXCL2 was highly expressed in these EVs. By regulating CXCL2 in Raw264.7 macrophages, we found that CXCL2 on macrophage EVs recruited neutrophils in vitro and in vivo. The CXCL2 EVs activated the CXCR2/PKC/NOX4 pathway and induced tissue damage. This study provides information regarding the mechanisms underlying neutrophil recruitment to tissues and proposes innovative strategies and targets for the treatment of sepsis.

Analysis of a Chinese Pedigree With Familial Chylomicronemia Syndrome Reveals Two Novel LPL Mutations by Whole-Exome Sequencing.

Familial chylomicronemia syndrome (FCS) is a rare monogenic autosomal recessive disease caused by loss-of-function mutations in genes involved in chylomicron breakdown through hydrolysis of triglycerides into free fatty acids. Patients are often diagnosed in early childhood with extremely high triglyceride levels and symptoms including abdominal pain, eruptive cutaneous xanthomata, hepatosplenomegaly, and significant cognitive, psychological, and social impairment. The most serious medical condition suffered by FCS patients is recurrent acute pancreatitis. Lipoprotein lipase (LPL) gene mutation accounts for majority of the known pathogenic mutations. Early diagnosis and strict low-fat diet are critical for successful management of the triglyceride concentration to lower the risk of pancreatitis. The true prevalence of FCS in China is unknown and here we report a Chinese female preterm neonate presented with an extremely high triglyceride level of 22.11 mmol/L on day 13 after birth. Clinical and laboratory workup including whole-exome sequencing revealed two novel compound heterozygous LPL mutations (c.406G > C and c.829G > C) that are co-segregated with her non-consanguineous parents, consistent with autosomal recessive inheritance. A diagnosis of FCS based on clinical, biochemical, and genetic ground was made to guide her management.

Genomic characterization of high-recurrence risk papillary thyroid carcinoma in a southern Chinese population.

BACKGROUND: The objective of this study was to investigate genetic variations and the relationships between these genetic variations and clinicopathological features of high-recurrence risk papillary thyroid carcinoma in a southern Chinese population. METHODS: One hundred sixty-eight patients of high-recurrence risk papillary thyroid carcinoma were recruited for this study from 2017 to 2018. Formalin-fixed paraffin-embedded tissue and the data of clinicopathological characteristics were all collected and analyzed from these patients. We used next-generation sequencing technology to investigate the targeted gene mutations and gene fusions of the pathology specimens. RESULTS: The frequency of candidate tumor driver gene mutation was 85.1% in 143 patients, including BRAF V600E mutation in 119 patients(70.8%), RET fusion in 13 patients(7.7%), TERT promoter mutations in 11 patients(6.5%), RAS (HRAS, NRAS, KRAS) gene mutations in 10 patients(6.0%), and other mutations involving TP53, PIK3CA, AKT1, PTEN and NTRK1. Concomitant presence of more than two genetic aberrations was seen in 27 patients (16.1%). Our study showed that BRAF V600E mutation is highly correlated with conventional PTC (p < 0.001), BRAF V600E and TERT promoter mutation duet was associated with older patient age (> 45, p = 0.003) and higher disease stage of III or IV (p = 0.002). RAS gene and BRAF V600E co-mutations were only seen in multifocal PTC (p = 0.015). CONCLUSION: In our high-recurrence risk PTC cohort, most patients had more than one driver gene aberration. Coexistence of BRAF V600E with TERT promoter mutations or with RAS mutations were significantly correlated with worse clinicopathological characteristics.

LASSO­based Cox­PH model identifies an 11­lncRNA signature for prognosis prediction in gastric cancer.

The present study aimed to identify a long non­coding (lnc) RNAs­based signature for prognosis assessment in gastric cancer (GC) patients. By integrating gene expression data of GC and normal samples from the National Center for Biotechnology Information Gene Expression Omnibus, the EBI ArrayExpress and The Cancer Genome Atlas (TCGA) repositories, the common RNAs in Genomic Spatial Event (GSE) 65801, GSE29998, E­MTAB­1338, and TCGA set were screened and used to construct a weighted correlation network analysis (WGCNA) network for mining GC­related modules. Consensus differentially expressed RNAs (DERs) between GC and normal samples in the four datasets were screened using the MetaDE method. From the overlapped lncRNAs shared by preserved WGCNA modules and the consensus DERs, an lncRNAs signature was obtained using L1­penalized (lasso) Cox­proportional hazard (PH) model. LncRNA­mRNA networks were constructed for these signature lncRNAs, followed by functional annotation. A total of 14,824 common mRNAs and 2,869 common lncRNAs were identified in the 4 sets and 5 GC­associated WGCNA modules were preserved across all sets. MetaDE method identified 1,121 consensus DERs. A total of 50 lncRNAs were shared by preserved WGCNA modules and the consensus DERs. Subsequently, an 11­lncRNA signature was identified by LASSO­based Cox­PH model. The lncRNAs signature­based risk score could divide patients into 2 risk groups with significantly different overall survival and recurrence­free survival times. The predictive capability of this signature was verified in an independent set. These signature lncRNAs were implicated in several biological processes and pathways associated with the immune response, the inflammatory response and cell cycle control. The present study identified an 11­lncRNA signature that could predict the survival rate for GC.

Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.

AIMS: Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI). METHODS AND RESULTS: After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. CONCLUSION: Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future.

Identification of genes associated with renal cell carcinoma using gene expression profiling analysis.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and accounts for ~80% of all kidney cancer cases. However, the pathogenesis of RCC has not yet been fully elucidated. To interpret the pathogenesis of RCC at the molecular level, gene expression data and bio-informatics methods were used to identify RCC associated genes. Gene expression data was downloaded from Gene Expression Omnibus (GEO) database and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in RCC patients compared with controls. In addition, a regulatory network was constructed using the known regulatory data between transcription factors (TFs) and target genes in the University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) and the regulatory impact factor of each TF was calculated. A total of 258,0427 pairs of DCGs were identified. The regulatory network contained 1,525 pairs of regulatory associations between 126 TFs and 1,259 target genes and these genes were mainly enriched in cancer pathways, ErbB and MAPK. In the regulatory network, the 10 most strongly associated TFs were FOXC1, GATA3, ESR1, FOXL1, PATZ1, MYB, STAT5A, EGR2, EGR3 and PELP1. GATA3, ERG and MYB serve important roles in RCC while FOXC1, ESR1, FOXL1, PATZ1, STAT5A and PELP1 may be potential genes associated with RCC. In conclusion, the present study constructed a regulatory network and screened out several TFs that may be used as molecular biomarkers of RCC. However, future studies are needed to confirm the findings of the present study.

The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway.

UNLABELLED: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. AIMS: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. RESULTS: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. INNOVATION: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. CONCLUSION: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.

Sensitive detection of BRAF V600E mutation by Amplification Refractory Mutation System (ARMS)-PCR.

BACKGROUND: BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid. These mutations provide potentially valuable diagnostic, prognostic and treatment response prediction markers. A sensitive, specific, low-cost assay to detect these mutations is needed. RESULTS: To detect BRAF V600E mutation in formalin-fixed, paraffin-embedded (FFPE) tissue, we developed a method using Amplification Refractory Mutation System (ARMS)-PCR. This method was designed to amplify three products in a single reaction tube: a 200 bp common product serving as an amplification control, a 144 bp BRAF V600E specific product, and a 97 bp wild-type (wt) specific product. The sensitivity of this method was determined to be as low as 0.5% for the BRAF V600E allele in a wild-type background. This method was successfully validated in 72 thyroid tumors. It detected V600E mutation in 22 out of 33 (67%) of the conventional papillary thyroid carcinoma (PTC), 8 out of 12 (75%) of the tall-cell variant of PTC, whereas none of the 10 follicular variant of PTC showed BRAF V600E mutation. In addition, none of the 14 follicular adenomas and 3 follicular carcinomas had BRAF V600E mutation. As a comparison method, direct dideoxy sequencing found only 27 out of 30 (90%) mutations detected by ARMS-PCR method, suggesting that this ARMS-PCR method has higher sensitivity. CONCLUSIONS: Our ARMS-PCR method provides a new tool for rapid detection of BRAF V600E mutation. Our results indicate that ARMS-PCR is more sensitive than automated dideoxy sequencing in detecting low BRAF V600E allele burdens in FFPE tumor specimen. The strategy of this ARMS-PCR design may be adapted for early detection of point mutations of a variety of biomarker genes.