The combination of SHP099 inhibits the malignant biological behavior of L-OHP/5-FU-resistant colorectal cancer cells by regulating energy metabolism reprogramming.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC. METHODS: HT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 106 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells. RESULTS: Compared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC. CONCLUSION: The combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.

Circ_0001671 regulates prostate cancer progression through miR-27b-3p/BLM axis.

Prostate cancer (PCa) ranks as the second most prevalent cancer among males globally. However, the exact mechanisms underlying its progression remain inadequately elucidated. The present study sought to investigate the role and underlying molecular mechanism of hsa_circ_0001671 (circ_0001671) in the pathogenic behavior of PCa cells. Guided by the ceRNA theory, miR-27b-3p was employed to identify circRNAs that could potentially regulate Bloom Syndrome Protein (BLM). A series of experimental approaches including bioinformatics, luciferase assays, Fluorescent In Situ Hybridization (FISH), RNA-pulldown, and RNA Immunoprecipitation (RIP) were utilized to validate the miRNA sponge function of circ_0001671. Divergent primer PCR, RNase R treatments, and Sanger sequencing were conducted for the identification of circ_0001671. Quantitative RT-PCR and Western blot analyses were performed to validate gene expression levels. Both in vitro and in vivo experiments were conducted to assess the functional role of circ_0001671 in PCa cells.It was observed that the expression levels of circ_0001671 and BLM were significantly elevated in PCa tissues and cell lines, whereas miR-27b-3p showed decreased expression. Circ_0001671 was found to promote cellular proliferation, migration, and invasion, while inhibiting apoptosis. In vivo assays confirmed that circ_0001671 facilitated tumor growth. Further mechanistic studies revealed that circ_0001671 acted as a competing endogenous RNA (ceRNA) for BLM by sponging miR-27b-3p. The oncogenic role of circ_0001671 in PCa was shown to be modulated through the miR-27b-3p/BLM axis. In conclusion, circ_0001671 exerts an oncogenic effect in prostate cancer through the regulation of BLM by sponging miR-27b-3p, thus suggesting a novel molecular target for the treatment of PCa.

Effect of acupuncture timing on functional impairment at 6 months post-onset in patients with first-ever stroke: a prospective cohort study. / é’ˆåˆºæ—¶æœºå¯¹é¦–æ¬¡ä¸­é£Žæ‚£è€ å‘ç— åŽ6ä¸ªæœˆåŠŸèƒ½éšœç¢çš„å½±å“ï¼šå‰çž»æ€§é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: To observe the effect of acupuncture intervention in the acute phase on functional impairment at 6 months post-onset in patients with first-ever stroke, and provide evidence for selecting optimal acupuncture timing in the real-world setting. METHODS: A total of 601 patients with first-ever stroke were divided into an acute intervention group (onset within 14 days, 256 cases) and a non-acute intervention group (onset between 15 and 90 days, 345 cases) based on whether they received acupuncture treatment in the acute phase. The assessments were conducted at baseline and 6 months post-onset, including modified Rankin scale (mRS) score, total number of acupuncture sessions, total number of combined therapies (moxibustion, cupping, tuina and rehabilitation treatment), recurrence, death events and disability. Logistic regression analysis was used to analyze the association between acupuncture timing and the risk of disability at 6 months post-onset. The mRS transition method was employed to assess the effect of acupuncture timing on functional improvement at 6 months post-onset. RESULTS: Without adjusting for confounding factors, compared with the non-acute intervention group, the patients in the acute intervention group had reduced risk of disability at 6 months post-onset (OR=0.434, 95%CI: 0.309-0.609, P=0.000). After adjusting for variables i.e. severity of illness, number of acupuncture sessions, and number of cupping sessions, compared with the non-acute intervention group, the patients in the acute intervention group had reduced risk of disability at 6 months post-onset (OR=0.588, 95%CI: 0.388-0.890, P=0.012). After adjusting for all confounding factors, including severity of illness, number of acupuncture sessions, number of cupping sessions, gender, smoking and drinking history, comorbidities, and diagnosis, compared with the non-acute intervention group, the patients in the acute intervention group continued to have a reduced risk of disability at 6 months post-onset (OR=0.629, 95%CI: 0.408-0.971, P=0.036). Both groups showed an overall shift towards lower mRS scores at 6 months post-onset compared to baseline, with a more significant shift towards lower scores in the acute intervention group than the non-acute intervention group. CONCLUSIONS: In the real-world setting, acupuncture intervention in the acute phase in patients with first-ever stroke, compared to acupuncture intervention after the acute phase, reduces the risk of disability at 6 months post-onset and improves functional status.

Application research of radiomics in colorectal cancer: A bibliometric study.

BACKGROUND: Radiomics has shown great potential in the clinical field of colorectal cancer (CRC). However, few bibliometric studies have systematically analyzed existing research in this field. The purpose of this study is to understand the current research status and future development directions of CRC. METHODS: Search the English documents on the application of radiomics in the field of CRC research included in the Web of Science Core Collection from its establishment to October 2023. VOSviewer and CiteSpace software were used to conduct bibliometric and visual analysis of online publications related to countries/regions, authors, journals, references, and keywords in this field. RESULTS: A total of 735 relevant documents published from Web of Science Core Collection to October 2023 were retrieved, and a total of 419 documents were obtained based on the screening criteria, including 376 articles and 43 reviews. The number of publications is increasing year by year. Among them, China publishes the most relevant documents (n = 238), which is much higher than Italy (n = 69) and the United States (n = 63). Tian Jie is the author with the most publications and citations (n = 17, citations = 2128), GE Healthcare is the most productive institution (n = 26), Frontiers in Oncology is the journal with the most publications (n = 60), and European Radiology is the most cited journal (n = 776). Hot spots for the application of radiomics in CRC include magnetic resonance, neoadjuvant chemoradiotherapy, survival, texture analysis, and machine learning. These directions are the current hot spots for the application of radiomics research in CRC and may be the direction of continued development in the future. CONCLUSION: Through bibliometric analysis, the application of radiomics in CRC has been increasing year by year. The application of radiomics improves the accuracy of preoperative diagnosis, prediction, and prognosis of CRC. The results of bibliometrics analysis provide a valuable reference for the research direction of radiomics. However, radiomics still faces many challenges in the future, such as the single nature of the data source which may affect the comprehensiveness of the results. Future studies can further expand the data sources and build a multicenter public database to more comprehensively reflect the research status and development trend of CRC radiomics.

HIST3H2A promotes the progression of prostate cancer through inhibiting cell necroptosis.

In recent years, there has been an increase in the incidence and mortality rates of prostate cancer (PCa). However, the specific molecular mechanisms underlying its occurrence and development remain unclear, necessitating the identification of new therapeutic targets. Through bioinformatics analysis, we discovered a previously unstudied differential gene called HIST3H2A in prostate cancer. Our study revealed that HIST3H2A is highly expressed in PCa tissues, as confirmed by analysis of both the GEO and UALCAN databases. Further analysis using the KEGG database demonstrated that HIST3H2A regulates the pathway of programmed necroptosis in cells. Additionally, we observed significant up-regulation of HIST3H2A in PCa tissues and cell lines. HIST3H2A was found to regulate cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process in tumors. Notably, HIST3H2A's role in regulating programmed necroptosis in prostate cancer cells differs from its role in apoptosis. In vitro and in vivo experiments collectively support the key role of HIST3H2A in promoting the development of prostate cancer, highlighting its potential as a therapeutic target for patients with PCa.

Efficacy of ScopeGuide-Assisted Training in Enhancing Colonoscopy Competence and Reducing Patient Discomfort.

OBJECTIVE: In this study, we aimed to evaluate the efficacy of the Magnetic Scope Guide Assist (ScopeGuide) in enhancing the procedural competence of endoscopists and reducing patient discomfort during colonoscopy. METHODS: This was a retrospective study with 88 trainee participants. The study participants were trained on patients who underwent colonoscopy without anesthesia. Both ScopeGuide-assisted training and conventional training (without ScopeGuide) were utilized for colonoscopy instruction. The outcomes of training were compared, with a particular emphasis on the competency of looping resolution. RESULTS: ScopeGuide-assisted training was superior to conventional training in multiple aspects, including looping resolution ( Z =-3.681, P <0.001), pain scores ( Z =-4.211, P <0.001), time to reach the cecum ( Z =-4.06, P <0.001), willingness to undergo repeat colonoscopy ( Z =-4.748, P <0.001), competence of positional changes ( Z =-4.079, P <0.001), and the effectiveness of assisted compression ( Z =-3.001, P =0.003). Further stratified analysis revealed that the ScopeGuide-assisted training mode was more beneficial for junior endoscopists ( P <0.05 in all parameters) but not for intermediate endoscopists ( P >0.05) and partially beneficial for senior endoscopists ( P <0.05 for all parameters except looping resolution). CONCLUSION: ScopeGuide-assisted training can significantly facilitate endoscopists in resolving loops and reducing patient pain, thereby enhancing their colonoscopy abilities.

Antiplatelet effects of the CEACAM1-derived peptide QDTT.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) restricts platelet activation via platelet collagen receptor GPVI/FcRγ-chain. In this study, screening against collagen-induced platelet aggregation was performed to identify functional CEACAM1 extracellular domain fragments. CEACAM1 fragments, including Ala-substituted peptides, were synthesized. Platelet assays were conducted on healthy donor samples for aggregation, cytotoxicity, adhesion, spreading, and secretion. Mice were used for tail bleeding and FeCl3-induced thrombosis experiments. Clot retraction was assessed using platelet-rich plasma. Extracellular segments of CEACAM1 and A1 domain-derived peptide QDTT were identified, while N, A2, and B domains showed no involvement. QDTT inhibited platelet aggregation. Ala substitution for essential amino acids (Asp139, Thr141, Tyr142, Trp144, and Trp145) in the QDTT sequence abrogated collagen-induced aggregation inhibition. QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.

What is the context? The study focuses on Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its role in platelet activation, particularly through the GPVI/FcRγ-chain pathway.The research aims to identify specific fragments of CEACAM1's extracellular domain that could restrict platelet activation, without increasing bleeding risk.What is new? The researchers identified a peptide called QDTT derived from the A1 domain of CEACAM1's extracellular segment. This peptide demonstrated the ability to inhibit platelet aggregation, secretion, and GP IIb/IIIa activation.The study also revealed that specific amino acids within the QDTT sequence were essential for its inhibitory effects on collagen-induced aggregation.What is the impact? The findings suggest that the A1 domain-derived peptide QDTT from CEACAM1 could serve as a potential basis for developing novel antiplatelet drugs. This peptide effectively limits platelet activation and aggregation without significantly prolonging bleeding time, indicating a promising approach to managing thrombosis and related disorders while minimizing bleeding risks.

Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency.

We report three heterozygous PROS1 mutations that caused type I protein S deficiency in three unrelated Chinese families. We measured protein S activity and antigen levels for all participants, screened them for mutations in the PROS1 gene. And we employed the calibrated automated thrombin generation (CAT) method to investigate thrombin generation. Numerous bioinformatics tools were utilized to analyze the conservation, pathogenicity of mutation, and spatial structure of the protein S. Phenotyping analysis indicated that all three probands exhibited simultaneous reduced levels of PS:A, TPS:Ag, and FPS:Ag. Genetic testing revealed that proband A harbored a heterozygous c.458_458delA (p.Lys153Serfs*6) mutation in exon 5, proband B carried a heterozygous c.1687C>T (p.Gln563stop) mutation in exon 14, and proband C exhibited a heterozygous c.200A>C (p.Glu67Ala) mutation in exon 2. Bioinformatic analysis predicted that the p.Lys153Serfs*6 frameshift mutation and the p.Gln563stop nonsense mutation in the protein S were classified as "disease-causing." The identification of the novel mutation p.Lys153Serfs*6 in PROS1 enriches the Human Genome Database. Our research suggests that these three mutations (p.Lys153Serfs*6, p.Gln563stop, and p.Glu67Ala) are possibly responsible for the decreased level of protein S in the three families. Furthermore, the evidence also supports the notion that individuals who are asymptomatic but have a family history of PSD can benefit from genetic analysis of the PROS1 gene.

Urea nitrogen-to-albumin ratio predicts ventricular aneurysm formation in ST-segment elevation myocardial infarction.

AIMS: Left ventricular aneurysm (LVA) is an important complication of acute myocardial infarction. The aim of this study was to investigate the possible predictive value of blood urea nitrogen-to-albumin ratio (BAR) for the LVA formation in acute ST-segment elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: A total of 1123 consecutive patients with STEMI were prospectively enrolled. The clinical and laboratory data were compared between LVA group and non-LVA group. Multivariable logistic regression analysis was performed to assess the independent risk factors of LVA formation. Predictive power of BAR and composite variable for LVA formation were assessed using receiver operating characteristic curve. LVA was detected in 162 patients (14.4%). The BAR was significantly higher in patients with LVA [0.16 (0.13-0.19) vs. 0.13 (0.10-0.17), P < 0.001]. Multivariable logistic regression analysis revealed that left ventricular ejection fraction (LVEF) [odds ratio (OR) = 0.865, P < 0.001], culprit vessel-left anterior descending artery (LAD) (OR = 4.705, P < 0.001), and BAR (OR = 2.208, P = 0.018) were all independent predictors for LVA formation. The predictive value of BAR remained significant even after cross-validation by splitting population into training set (OR = 1.957, P = 0.034) and validation set (OR = 1.982, P = 0.039). The maximal length and width of LVA were significantly increased in patients with BAR ≥ 0.15 when compared with BAR < 0.15 (3.37 ± 1.09 vs. 2.92 ± 0.93, P = 0.01, for maximal length, and 2.20 ± 0.55 vs. 1.85 ± 0.63, P = 0.001, for maximal width). The discriminant power of BAR for LVA is 0.723, which is superior to both blood urea nitrogen (C statistic = 0.586, P < 0.001) and albumin (C statistic = 0.64, P < 0.001). The combination of BAR, LVEF, and culprit vessel-LAD could significantly increase the predictive ability (C statistic = 0.874, P < 0.001, for vs. BAR). Subgroup analysis of age, sex, hypertension, diabetes, smoking, LVEF, serum albumin, multiple-vessel disease, and Gensini score had no effect on the association between BAR and risk of LVA formation (P < 0.05 for all subgroups). CONCLUSIONS: A higher BAR was an independent predictor for LVA formation in STEMI patients with primary PCI.

Implementation of Tunneled Peripherally Inserted Central Catheters Placement in Cancer Patients: A Randomized Multicenter Study.

This study sought to evaluate the impact of the subcutaneous tunneling technique on peripherally inserted central catheter (PICC) placement. We randomized 694 patients who needed PICC placement to either the tunneled PICCs (experimental group) or the non-tunneled PICCs (control group) from August to December 2021. The cumulative frequency of complications was assessed as the primary outcome. Secondary outcomes comprised of the amount of bleeding, catheter insertion time, self-reported pain score, and one-puncture success rate. After 6 months of follow-up, the tunneled PICCs group showed a significant decrease in the frequency of total complications, especially in infection (3.0% vs. 7.1%, p = .021) and catheter-related thrombosis (3.3% vs. 8.3%, p = .008), although approximately 0.5 ml bleeding and 3.5 min time were increased. This randomized multicenter study supports the efficacy of subcutaneous tunneling technology in reducing PICC-related complications, enhancing patient comfort, and encouraging using subcutaneous tunneling technology for PICC placement.

Enhancing bowel preparation quality and tolerability in a low health literacy population in Western China: a multicenter randomized trial.

BACKGROUND AND AIMS: Insufficient bowel preparation (BP) presents substantial challenges to the effectiveness of outpatient colonoscopy for colorectal cancer screening, particularly within populations characterized by low health literacy and poor adherence. METHODS: We conducted a prospective, randomized, blinded, endoscopic controlled study involving 474 colonoscopy outpatients aged 18-80 years hailing from a low health literacy population with convenient access to WeChat. These patients were subsequently randomized into three groups: the control group, WeChat group, and the automatic reminder group (ARG). All people were administered 3 L of polyethylene glycol. The Boston Bowel Preparation Scale (BBPS) score of 6 or a segmental score of 2 was used as the primary outcome to evaluate BP quality. Secondary outcomes included polyp detection rate (PDR) and adverse events, etc. RESULTS: Our findings revealed that both the WeChat group (n = 158) and ARG (n = 158) exhibited significantly higher rates of adequate BP compared to the control group (n = 158) (WeChat vs. control, 79.1% vs. 61.4%; ARG vs. control, 74.7% vs. 61.4%; p < 0.001). Furthermore, these educationally reinforced groups displayed improved BP compliance (p < 0.05). According to the Hospital Anxiety and Depression Scale (HADS), patients in the reinforced education groups exhibited lower overall anxiety levels (p = 0.001) and experienced fewer adverse reactions (p = 0.019). Compared to the control group, the PDR in the right hemi-colon was significantly greater in the WeChat group (11.4%) (2.5%), and a similar trend was observed in the ARG (7.6%). Additionally, individuals in the WeChat group reported higher levels of satisfaction with their colonoscopy experience (p = 0.043). In a multivariate analysis, adjusting for potential confounding factors, WeChat-based re-education ([OR] 1.496, 95% CI 1.154-1.939; p = 0.002)) emerged as a protective factor for achieving adequate BP. CONCLUSION: Enhanced education through WeChat can improve BP quality, and ARG applies equally to low health literacy populations.

Advances in Mesenchymal stem cells regulating macrophage polarization and treatment of sepsis-induced liver injury.

Sepsis is a syndrome of dysregulated host response caused by infection, which leads to life-threatening organ dysfunction. It is a familiar reason of death in critically ill patients. Liver injury frequently occurs in septic patients, yet the development of targeted and effective treatment strategies remains a pressing challenge. Macrophages are essential parts of immunity system. M1 macrophages drive inflammation, whereas M2 macrophages possess anti-inflammatory properties and contribute to tissue repair processes. Mesenchymal stem cells (MSCs), known for their remarkable attributes including homing capabilities, immunomodulation, anti-inflammatory effects, and tissue regeneration potential, hold promise in enhancing the prognosis of sepsis-induced liver injury by harmonizing the delicate balance of M1/M2 macrophage polarization. This review discusses the mechanisms by which MSCs regulate macrophage polarization, alongside the signaling pathways involved, providing an idea for innovative directions in the treatment of sepsis-induced liver injury.

BTN2A2, a new biomarker and therapeutic target for glioma.

BACKGROUND: Protein casein 2A2 (BTN2A2) is a costimulatory molecule first identified in antigen-presenting cells. Studies have shown the involvement of BTN2A2 in immunity. However, the exact role and the mechanism of BTN2A2 in tumors are still unclear. METHODS: First, we performed real-time PCR to measure BTN2A2 expression in glioma cell lines. Next, we performed Genes Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to understand the mechanism of BTN2A2 in glioma. Next, we used the "ESTIMATE", "ssGSEA" and "CIBERSORT" algorithms to analyze the correlation between BTN2A2 and immune cell infiltration (ICI). Finally, we performed immunohistochemistry, growth curve, transwell, and colony formation assays to determine the functions of BTN2A2 in glioma. RESULTS: Our results showed an increase in BTN2A2 expression levels in glioma tissues and cells. Next, we determined that BTN2A2 was correlated with the prognosis of patients with glioma. Then, using the ESTIMATE, ssGSEA, and CIBERSORT algorithms, we discovered that BTN2A2 was significantly associated with immune cell infiltration (ICI) in glioma. We observed an increase in BTN2A2 expression levels with an increase in the patient's tumor grade. Furthermore, BTN2A2 significantly enhanced the proliferative and migratory abilities of glioma cells. CONCLUSIONS: Our results showed a significant increase in BTN2A2 expression levels in glioma cells and tissues. Furthermore, the prognosis of patients expressing high BTN2A2 levels was poor. Moreover, BTN2A2 was correlated with progression and ICI in patients with glioma. Together, this indicates that BTN2A2 could be a therapeutic target for patients with glioma.

CBX8 promotes lung adenocarcinoma growth and metastasis through transcriptional repression of CDKN2C and SCEL.

Dysregulation of polycomb group (PcG) proteins that mediate epigenetic gene silencing contributes to tumorigenesis. As core components of the polycomb repressive complex 1 (PRC1), chromobox (CBX) proteins recognize H3K27me3 to recruit PRC1 to maintain a repressive transcriptional state. However, the individual biological functions of these CBX proteins in tumorigenesis warrant in-depth investigation. In this study, we analyzed the mRNA expression of CBX family genes across multiple cancers using The Cancer Genome Atlas data and found different expression patterns of the five CBX genes in different types of cancer. This analyses together with the result of immunohistochemistry indicated that CBX8 expression was significantly higher in lung adenocarcinoma (LUAD) tissues compared to adjacent nontumor tissues. Overexpression approaches demonstrated that CBX8 facilitated LUAD cell proliferation and migration in vitro. Consistently, CBX8 knockdown reduced LUAD cell proliferation and migration in both cell culture and mouse models. RNA sequencing combined with real-time RT-PCR assays revealed CDKN2C and SCEL as target genes of CBX8. Furthermore, chromatin immunoprecipitation assays indicated that CBX8 directly bound to the promoters of CDKN2C and SCEL to establish H2AK119ub. CBX8 depletion reduced the enrichment of H2AK119ub on CDKN2C and SCEL promoters. Moreover, depletion of CDKN2C and SCEL restored the repressed growth and invasion ability of LUAD cells caused by CBX8 knockdown. These findings demonstrate that CBX8 promotes LUAD growth and metastasis through the transcriptional repression of CDKN2C and SCEL. Our study uncovers the oncogenic role of CBX8 in LUAD progression and provides a new target for the diagnosis and therapy of LUAD.

Creation of a Prognostic Model Using Cuproptosis-Associated Long Noncoding RNAs in Hepatocellular Carcinoma.

Cuproptosis is an unusual form of cell death caused by copper accumulation in mitochondria. Cuproptosis is associated with hepatocellular carcinoma (HCC). Long noncoding RNAs (LncRNAs) have been shown to be effective prognostic biomarkers, yet the link between lncRNAs and cuproptosis remains unclear. We aimed to build a prognostic model of lncRNA risk and explore potential biomarkers of cuproptosis in HCC. Pearson correlations were used to derive lncRNAs co-expressed in cuproptosis. The model was constructed using Cox, Lasso, and multivariate Cox regressions. Kaplan-Meier survival analysis, principal components analysis, receiver operating characteristic curve, and nomogram analyses were carried out for validation. Seven lncRNAs were identified as prognostic factors. A risk model was an independent prognostic predictor. Among these seven lncRNAs, prostate cancer associated transcript 6 (PCAT6) is highly expressed in different types of cancer, activating Wnt, PI3K/Akt/mTOR, and other pathways; therefore, we performed further functional validation of PCAT6 in HCC. Reverse transcription-polymerase chain reaction results showed that PCAT6 was aberrantly highly expressed in HCC cell lines (HepG2 and Hep3B) compared to LO2 (normal hepatocytes). When its expression was knocked down, cells proliferated and migrated less. PCAT6 might be a potential biomarker for predicting prognosis in HCC.

Heterologous prime-boost immunisation with mRNA- and AdC68-based 2019-nCoV variant vaccines induces broad-spectrum immune responses in mice.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV) variants has been associated with the transmission and pathogenicity of COVID-19. Therefore, exploring the optimal immunisation strategy to improve the broad-spectrum cross-protection ability of COVID-19 vaccines is of great significance. Herein, we assessed different heterologous prime-boost strategies with chimpanzee adenovirus vector-based COVID-19 vaccines plus Wuhan-Hu-1 (WH-1) strain (AdW) and Beta variant (AdB) and mRNA-based COVID-19 vaccines plus WH-1 strain (ARW) and Omicron (B.1.1.529) variant (ARO) in 6-week-old female BALB/c mice. AdW and AdB were administered intramuscularly or intranasally, while ARW and ARO were administered intramuscularly. Intranasal or intramuscular vaccination with AdB followed by ARO booster exhibited the highest levels of cross-reactive IgG, pseudovirus-neutralising antibody (PNAb) responses, and angiotensin-converting enzyme-2 (ACE2)-binding inhibition rates against different 2019-nCoV variants among all vaccination groups. Moreover, intranasal AdB vaccination followed by ARO induced higher levels of IgA and neutralising antibody responses against live 2019-nCoV than intramuscular AdB vaccination followed by ARO. A single dose of AdB administered intranasally or intramuscularly induced broader cross-NAb responses than AdW. Th1-biased cellular immune response was induced in all vaccination groups. Intramuscular vaccination-only groups exhibited higher levels of Th1 cytokines than intranasal vaccination-only and intranasal vaccination-containing groups. However, no obvious differences were found in the levels of Th2 cytokines between the control and all vaccination groups. Our findings provide a basis for exploring vaccination strategies against different 2019-nCoV variants to achieve high broad-spectrum immune efficacy.

Significance of cuproptosis-related lncRNA signature in LUAD prognosis and immunotherapy: A machine learning approach.

OBJECTIVE: Cuproptosis-related genes are closely related to lung adenocarcinoma (LUAD), which can be analyzed via the analysis of long noncoding RNA (lncRNA). To date, the clinical significance and function of cuproptosis-related lncRNAs are still not well elucidated. Further analysis of cuproptosis-related prognostic lncRNAs is of great significance for the treatment, diagnosis, and prognosis of LUAD. METHODS: In this study, a multiple machine learning (ML)-based computational approach was proposed for the identification of the cuproptosis-related lncRNAs signature (CRlncSig) via comprehensive analysis of cuproptosis, lncRNAs, and clinical characteristics. The proposed approach integrated multiple ML algorithms (least absolute shrinkage and selection operator regression analysis, univariate and multivariate Cox regression) to effectively identify the CRlncSig. RESULTS: Based on the proposed approach, the CRlncSig was identified from the 3450 cuproptosis-related lncRNAs, which consist of 13 lncRNAs (CDKN2A-DT, FAM66C, FAM83A-AS1, AL359232.1, FRMD6-AS1, AC027237.4, AC023090.1, AL157888.1, AL627443.3, AC026355.2, AC008957.1, AP000346.1, and GLIS2-AS1). CONCLUSIONS: The CRlncSig could well predict the prognosis of different LUAD patients, which is different from other clinical features. Moreover, the CRlncSig was proved to be an effective indicator of patient survival via functional characterization analysis, which is relevant to cancer progression and immune infiltration. Furthermore, the results of RT-PCR assay indicated that the expression level of FAM83A-AS1 and AC026355.2 in A549 and H1975 cells (LUAD) was significantly higher than that in BEAS-2B cells (normal lung epithelial).

Discovery of novel CDK2 inhibitors using multistage virtual screening and in vitro melanoma cell lines.

Cyclin-dependent kinases 2 (CDK2) is a serine/threonine-protein kinase, which plays a key role in the regulation of cell cycle and is related to the occurrence and development of melanoma. In this study, we identified potent inhibitors for CDK2 by combining a multistage virtual screening strategy with bioassay validations. The biochemical activity of compounds was validated with ADP-Glo™ Kinase assay in vitro, and the results indicated that the biochemical activity of compound 1 (C1) was better than other selected compounds. Cell viability assay showed that the minimum inhibition concentration of C1 for CDK2 was lower than 4 µM. Further functional test results showed that C1 exerted significant antiproliferative, pro-apoptosis, and anti-migration activity in melanoma cell lines (A375 cells, WM35 cells, and A875 cells). Our findings suggested that the C1, virtually screened from compound libraries, as the novel inhibitor of CDK2, may be further developed as an effective therapeutic agent in the treatment of melanoma lines.