[In vitro expression and functional analyses of the mutants p.R243Q, p.R241C and p.Y356X of the human phenylalanine hydroxylase]. / äººè‹¯ä¸™æ°¨é ¸ç¾ŸåŒ–é ¶çªå˜ä½“p.R243Q、p.R241C和p.Y356Xçš„ä½“å¤–è¡¨è¾¾åŠåŠŸèƒ½ç ”ç©¶.

OBJECTIVES: To study the in vitro expression of three phenylalanine hydroxylase (PAH) mutants (p.R243Q, p.R241C, and p.Y356X) and determine their pathogenicity. METHODS: Bioinformatics techniques were used to predict the impact of PAH mutants on the structure and function of PAH protein. Corresponding mutant plasmids of PAH were constructed and expressed in HEK293T cells. Quantitative reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the three PAH mutants, and their protein levels were assessed using Western blot and enzyme-linked immunosorbent assay. RESULTS: Bioinformatics analysis predicted that all three mutants were pathogenic. The mRNA expression levels of the p.R243Q and p.R241C mutants in HEK293T cells were similar to the mRNA expression level of the wild-type control (P>0.05), while the mRNA expression level of the p.Y356X mutant significantly decreased (P<0.05). The PAH protein expression levels of all three mutants were significantly reduced compared to the wild-type control (P<0.05). The extracellular concentration of PAH protein was reduced in the p.R241C and p.Y356X mutants compared to the wild-type control (P<0.05), while there was no significant difference between the p.R243Q mutant and the wild type control (P>0.05). CONCLUSIONS: p.R243Q, p.R241C and p.Y356X mutants lead to reduced expression levels of PAH protein in eukaryotic cells, with p.R241C and p.Y356X mutants also affecting the function of PAH protein. These three PAH mutants are to be pathogenic.

Hypertension combined with limitations in activities of daily living and the risk for cardiovascular disease.

OBJECTIVE: The aim of present study was to evaluate the combined effect of hypertension and activities of daily living (ADL)/instrumental activities of daily living (IADL) with the risk of CVD, stroke and cardiac events. METHODS: A total of 14,083 participants aged 45 years or older from the China Health and Retirement longitudinal study were included in current study. Participants were divided into 4 groups according to hypertension and ADL/IADL status. Cox proportional hazards regression model was used to explore the associations between hypertension, ADL/IADL and new-onset CVD, stroke and cardiac events. RESULTS: During the 7-year follow-up, a total of 2,324 respondents experienced CVD (including 783 stroke and 1,740 cardiac events). Individuals with limitations in ADL alone, or with hypertension alone, or with both limitations in ADL and hypertension were associated with increased risk of CVD, with the adjusted hazard ratios (95% confidence intervals) were 1.17(1.00-1.35), 1.36(1.24-1.49) and 1.44(1.23-1.68), respectively. Those with limitations in ADL and hypertension also had higher risk of stroke (hazard ratios = 1.64; 1.26-2.14) and cardiac events (hazard ratios = 1.37; 1.14-1.64). Similarly, individuals with both limitations in IADL and hypertension were associated with increased risk of CVD (hazard ratios = 1.34; 1.15-1.57), stroke (hazard ratios = 1.50; 1.17-1.95) and cardiac events (hazard ratios = 1.27; 1.06-1.53). CONCLUSION: Hypertension and limitations in ADL/IADL jointly increased the risk of CVD, stroke and cardiac events.

Promoting Ruddlesden-Popper Perovskite Formation by Tailoring Spacer Intramolecular Interaction for Efficient and Stable Solar Cells.

Low-dimensional Ruddlesden-Popper phase (LDRP) perovskites are widely studied in the field of photovoltaics due to their tunable energy-band properties, enhanced photostability, and improved environmental stability compared to the 3D perovskites. However, the insulating spacers with weak intramolecular interaction used in LDRP materials limit the out-of-plane charge transport, leading to poor device performance of LDRP perovskite solar cells (PSCs). Here, a functional ligand, 3-guanidinopropanoic acid (GPA), which is capable of forming strong intramolecular hydrogen bonds through the carboxylic acid group, is employed as an organic spacer for LDRP PSCs. Owing to the strong interaction between GPA molecules, high-quality LDRP (GPA)2 (MA)n-1 Pbn I3n+1 film with promoted formation of n = 5 phase, improved crystallinity, preferential vertical growth orientations, reduced trap-state density, and prolonged carrier lifetime is achieved using GPAI as the dimensionality regulator compared to butylamine hydroiodide (BAI). As a result, GPA-based LDRP PSC exhibits a champion power conversion efficiency of 18.16% that is much superior to the BA-based LDRP PSC (15.43%). Importantly, the optimized GPA-based LDRP PSCs without encapsulation show enhanced illumination, thermal, storage, and humidity stability compared to BA-based ones. This work provides new insights into producing high n value LDRP films and their efficient and stable PSCs.

Copper ions reinforced flexible carboxymethylcellulose/polyethyleneimine composite films with enhanced mechanical properties, UV-shielding performance, thermal stability, solvent resistance, and antibacterial activity.

A composite film (CMC/PEI) consisting of anionic carboxymethylcellulose (CMC) and cationic polyethyleneimine (PEI) can be easily produced through the solution casting method using self-assembly based on electrostatic interaction and hydrogen bonding. Subsequently, the resulting CMC/PEI polyelectrolyte composite film with a network structure was crosslinked with divalent Cu2+ ions through ionic and coordination bonds, resulting in a strengthened Cu(II)@CMC/PEI film. The composite film was characterized based on its structural, surface, thermal, UV protection, antibacterial, and degradation aspects. The results demonstrated this film has impressive mechanical properties, remarkable solvent resistance, good antibacterial properties, and excellent UV-shielding performance by completely blocking ultraviolet light with wavelengths below 360 nm. These properties can be attributed to the presence of Cu2+ ions and PEI in the film. This work is valuable for the development of novel UV-shielding materials and should contribute to the design of carboxymethylcellulose composite films with desirable properties and exceptional performance.

Transcriptomics in Rare Minnow (Gobiocypris rarus) towards Attenuated and Virulent Grass Carp Reovirus Genotype II Infection.

Grass carp reovirus genotype Ⅱ (GCRV Ⅱ) causes a variety of fish hemorrhagic disease, which seriously affects the sustainable development of grass carp aquaculture in China. Rare minnow (Gobiocypris rarus) is an ideal model fish to study the pathogenesis of GCRV Ⅱ. To investigate the involved molecular responses against the GCRV Ⅱ infection, we performed comparative transcriptomic analysis in the spleen and liver of rare minnow injected with virulent strain DY197 and attenuated strain QJ205. Results showed that the virulent DY197 strain induced more differently expressed genes (DEGs) than the attenuated QJ205 strain, and tissue-specific responses were induced. In the spleen, the attenuated and virulent strains induced different DEGs; the attenuated QJ205 infection activated steroid synthesis pathway that involved in membrane formation; however, virulent DY197 infection activated innate immunity and apoptosis related pathways while suppressing cell proliferation and migration related pathways that are important for damage tissue repair, as well as hemorrhage related pathways. In the liver, the attenuated and virulent strains infection induced similar DEGs; both strains infection activated immunity and apoptosis related pathways but suppressed metabolism-related pathways; virulent DY197 infection especially activated protein digestion and absorption-related pathways and suppressed steroid synthesis pathway. To conclude, virulent strain infection especially induced tissue-specific alterations and caused severe suppression of hemorrhage-related pathways in spleen. Our findings will contribute to better understanding of the interactions between host and GCRV II.

Deep Learner System Based on Focal Color Retinal Fundus Images to Assist in Diagnosis.

Retinal diseases are a serious and widespread ophthalmic disease that seriously affects patients' vision and quality of life. With the aging of the population and the change in lifestyle, the incidence rate of retinal diseases has increased year by year. However, traditional diagnostic methods often require experienced doctors to analyze and judge fundus images, which carries the risk of subjectivity and misdiagnosis. This paper will analyze an intelligent medical system based on focal retinal image-aided diagnosis and use a convolutional neural network (CNN) to recognize, classify, and detect hard exudates (HEs) in fundus images (FIs). The research results indicate that under the same other conditions, the accuracy, recall, and precision of the system in diagnosing five types of patients with pathological changes under color retinal FIs range from 86.4% to 98.6%. Under conventional retinopathy FIs, the accuracy, recall, and accuracy of the system in diagnosing five types of patients ranged from 70.1% to 85%. The results show that the application of focus color retinal FIs in the intelligent medical system has high accuracy and reliability for the early detection and diagnosis of diabetic retinopathy and has important clinical applications.

Development of a droplet digital PCR assay for the sensitive detection of iridovirus in Andrias davidianus.

Chinese giant salamander iridovirus (GSIV) is the first known and causative viral pathogen in Andrias davidianus. Developing a sensitive, accurate and specific assay to detect GSIV in samples is essential to prevent the further spread of the pathogen. In this study, we established a droplet digital PCR (ddPCR) assay that targeted the mcp gene of GSIV, enabling rapid and quantitative detection of the virus. We determined that the optimal annealing temperature, primer concentration and probe concentration were 57.1°C, 50 nM and 500 nM, respectively. We analysed the specificity and sensitivity of the ddPCR assay and found that five common aquatic animal viruses, including Cyprinid herpesvirus 2 (CyHV-2), infectious spleen and kidney necrosis virus (ISKNV), Koi herpesvirus (KHV) and Carp Edema Virus (CEV) displayed negative results based on this GSIV ddPCR assay. The assay can detect GSIV with the lowest detection limit of 3.7 copies per reaction. To evaluate the sensitivity and accuracy of the ddPCR assay, we tested different infected tissue samples with both the ddPCR and TaqMan real-time PCR assays. Our results showed that the ddPCR assay detected GSIV in all samples with 100% positivity, while the TaqMan real-time PCR assay detected GSIV in only 82.1% of samples. The established ddPCR method provided several advantages in detecting GISV, including high sensitivity, high precision and absolute quantification, making it a powerful tool for detection of possible and potential GSIV infection, even in samples with low viral load.

Chinese giant salamander Bcl-w: An inhibitory role in iridovirus-induced mitochondrial apoptosis and virus replication.

B-cell lymphoma-2 (BCL-2) superfamily molecules play crucial roles in mitochondrial apoptosis induced by Chinese giant salamander iridovirus (GSIV). As an anti-apoptotic molecule in the BCL-2 family, the molecular mechanism of Bcl-w during GSIV infection remains unknown. In this study, we characterized for the first time an amphibian Bcl-w from Chinese giant salamander Andrias davidianus (AdBcl-w), and its function and regulatory mechanism during GSIV infection were investigated. AdBcl-w possesses the conserved structural features of Bcl-w and shares 35-54% sequence identities with other Bcl-w. mRNA expression of AdBcl-w was most abundant in liver and muscle. The AdBcl-w mRNA expression was regulated during GSIV infection. Western blotting assays revealed that the level of Bcl-w protein was downregulated markedly as the infection progresses. Confocal microscopy showed that overexpressed AdBcl-w was translocated to the mitochondria after infection with GSIV. Flow cytometry analysis demonstrated that compared with control, the apoptotic progress in cells transfected with AdBcl-w was reduced while that in cells transfected with AdBcl-w siRNA was enhanced. The number of virus major capsid protein gene copies was lower and protein synthesis was reduced in AdBcl-w overexpressing cells. In addition, AdBcl-w could bind directly to the pro-apoptotic molecule AdBak, while this interaction was weakened with GSIV infection. Moreover, p53 level was reduced and the mRNA expression levels of crucial regulatory molecules in the p53 pathway were regulated in AdBcl-w overexpressing cells during GSIV infection. These results suggested that AdBcl-w inhibit GSIV replication by regulating the virus induced mitochondrial apoptosis.

Real-world treatment patterns and outcomes of pyrotinib-based therapy in patients with HER2-positive advanced breast cancer (PRETTY): A nationwide, prospective, observational study.

Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for treating HER2-positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real-world data of pyrotinib-based therapy in this population. Patients from 61 sites across China were included. Pyrotinib-based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real-world progression-free survival (rwPFS). Of 1129 patients, pyrotinib-based therapy was prescribed as first-, second- and third- or later-line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3-15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2-24.9) months in the first-line setting, followed by 14.4 (95% CI, 12.9-15.3) months in the second-line setting. Patients with third- or later-line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4-11.8) months. Patients with trastuzumab- or trastuzumab-pertuzumab-treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first-line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib-based therapy shows promising effectiveness in the first-, as well as second- and later-line treatment, with acceptable tolerability. Further investigations regarding front-line use or novel combinations of pyrotinib might facilitate to maximize its anti-tumor potential.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated. METHODS: Through analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. RESULTS: We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. CONCLUSIONS: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Efficient and Stable ß-CsPbI3 Solar Cells through Solvent Engineering with Methylamine Acetate Ionic Liquid.

CsPbI3, an all-inorganic perovskite material with suitable band gap and excellent thermal stability, has garnered significant attention for its potential in perovskite solar cells (PSCs). However, CsPbI3 is susceptible to phase changes from photoactive to photoinactive in humid environments. Hence, it is crucial to achieve controllable growth of CsPbI3 perovskite thin films with the desired ß-crystal phase and compact morphology for efficient and stable PSCs. Herein, MAAc was used as a solvent for the CsPbI3 precursor to fabricate ß-CsPbI3 perovskite. An intermediate compound of CsxMA1-xPbIxAc3-x was initially formed in the MAAc solution, and during annealing, the MA+ and Ac- ions were replaced by Cs+ and I- ions, respectively. Furthermore, the incorporation of strong C═O···Pb coordination stabilized the black-phase ß-CsPbI3 and facilitated the growth of crystals with a narrow vertical orientation and large grain size. As a result, the PSCs with an efficiency of 18.9% and improved stability (less than 10% decay after 2000 h of storage in N2 and less than 30% decay after 500 h of storage in humid air without any encapsulation) were achieved.

SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor.

Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.

Nonstructural protein NS17 of grass carp reovirus Honghu strain promotes virus infection by mediating cell-cell fusion and apoptosis.

Fusion-associated small transmembrane (FAST) proteins can promote cell fusion, alter membrane permeability and trigger apoptosis to promote virus proliferation in orthoreoviruses. However, it is unknown whether FAST proteins perform these functions in aquareoviruses (AqRVs). Non-structural protein 17 (NS17) carried by grass carp reovirus Honghu strain (GCRV-HH196) belongs to the FAST protein family, and we preliminarily explored its relevance to virus infection. NS17 has similar domains to FAST protein NS16 of GCRV-873, comprising a transmembrane domain, a polybasic cluster, a hydrophobic patch and a polyproline motif. It was observed in the cytoplasm and the cell membrane. Overexpression of NS17 enhanced the efficiency of cell-cell fusion induced by GCRV-HH196 and promoted virus replication. Overexpression of NS17 also led to DNA fragmentation and reactive oxygen species (ROS) accumulation, and it triggered apoptosis. The findings illuminate the functions of NS17 in GCRV infection, and provide a reference for the development of novel antiviral strategies.

Pharmacokinetics and Bioequivalence of 2 Nifedipine Controlled-Release Tablets: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

The aim of this study was to evaluate the bioequivalence of generic nifedipine controlled-release tablet compared to branded product under fasting and fed conditions. A randomized, single-dose, 2-period, crossover study with a 7-day washout period was performed in 84 healthy Chinese volunteers (fasting cohort, n = 42; fed cohort, n = 42). In each study period, volunteers were assigned to receive a single oral dose of the generic or reference product (30 mg). Blood samples were collected before dosing and up to 72 hours after administration. The plasma concentration of nifedipine was determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained using a noncompartmental model and log-transformed pharmacokinetic parameters (maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity) were used to evaluate bioequivalence. The results showed that the 90% confidence interval for the geometric mean ratio of pharmacokinetic parameters of the test and reference products ranged from 80.0% to 125.0% in both the fasting and fed cohorts, meeting the criteria for bioequivalence. No serious adverse events were reported throughout the study and no adverse events led to withdrawal from the study. Food effects were found in both the test and reference products, with mean maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity increased by 23.7%, 20.7%, and 20.5%, respectively, for the test product and 35.2%, 13.4%, and 14.7% for the reference product after a high-fat and high-calorie breakfast.

Multi-objective optimization of mechanical ventilation with the aid of purifiers in two scenarios: Regular operation and mitigating the spread of respiratory infectious diseases.

COVID-19 and its impact on society have raised concerns about scaling up mechanical ventilation (MV) systems and the energy consequences. This paper attempted to combine MV and portable air cleaners (PACs) to achieve acceptable indoor air quality (IAQ) and energy reduction in two scenarios: regular operation and mitigating the spread of respiratory infectious diseases (RIDs). We proposed a multi-objective optimization method that combined the NSGA-II and TOPSIS techniques to determine the total equivalent ventilation rate of the MV-PAC system in both scenarios. The concentrations of PM2.5 and CO2 were primary indicators for IAQ. The modified Wells-Riley equation was adopted to predict RID transmissions. An open office with an MV-PAC system was used to demonstrate the method's applicability. Meanwhile, a field study was conducted to validate the method and evaluate occupants' perceptions of the MV-PAC system. Results showed that optimal solutions of the combined system can be obtained based on various IAQ requirements, seasons, outdoor conditions, etc. For regular operation, PACs were generally prioritized to maintain IAQ while reducing energy consumption even when outdoor PM2.5 concentration was high. MV can remain constant or be reduced at low occupancies. In RID scenarios, it is possible to mitigate transmissions when the quanta were < 48 h-1. No significant difference was found in the subjective perception of the MV and PACs. Moreover, the effects of infiltration on the optimal solution can be substantial. Nonetheless, our results suggested that an MV-PAC system can replace the MV system for offices for daily use and RID mitigation. Electronic Supplementary Material ESM: The Appendix is available in the online version of this article at 10.1007/s12273-023-0999-z.

Characteristics and expression profiles of MHC class â molecules in Carassius auratus.

Major histocompatibility complex class Ⅰ (MHC Ⅰ) molecules play a vital role in adaptive immune systems in vertebrates by presenting antigens to effector T cells. Understanding the expression profiling of MHC Ⅰ molecules in fish is essential for improving our knowledge of the relationship between microbial infection and adaptive immunity. In this study, we conducted a comprehensive analysis of MHC Ⅰ gene characteristics in Carassius auratus, an important freshwater aquaculture fish in China that is susceptible to Cyprinid herpesvirus 2 (CyHV-2) infection. We identified approximately 20 MHC Ⅰ genes discussed, including U, Z, and L lineage genes. However, only U and Z lineage proteins were identified in the kidney of Carassius auratus using high pH reversed-phase chromatography and mass spectrometry. The L lineage proteins were either not expressed or present at an extremely low level in the kidneys of Carassius auratus. We also used targeted proteomics to analyze changes in protein MHC Ⅰ molecules abundance in healthy and CyHV-2-infected Carassius auratus. We observed that five MHC Ⅰ molecules were upregulated, and Caau-UFA was downregulated in the diseased group. This study is the first to reveal the expression of MHC Ⅰ molecules at a large scale in Cyprinids, which enhances our understanding of fish adaptive immune systems.

Oral Vaccination of Largemouth Bass (Micropterus salmoides) against Largemouth Bass Ranavirus (LMBV) Using Yeast Surface Display Technology.

Largemouth bass ranavirus (LMBV) infects largemouth bass, leading to significant mortality and economic losses. There are no safe and effective drugs against this disease. Oral vaccines that directly target the intestinal mucosal immune system play an important role in resisting pathogens. Herein, the B subunit of Escherichia coli heat-labile enterotoxin (LTB, a mucosal immune adjuvant) and the LMBV main capsid protein (MCP) were expressed using Saccharomyces cerevisiae surface display technology. The yeast-prepared oral vaccines were named EBY100-OMCP and EBY100-LTB-OMCP. The candidate vaccines could resist the acidic intestinal environment. After 7 days of continuous oral immunization, indicators of innate and adaptive immunity were measured on days 1, 7, 14, 21, 28, 35, and 42. High activities of immune enzymes (T-SOD, AKP, ACP, and LZM) in serum and intestinal mucus were detected. IgM in the head kidney was significantly upregulated (EBY100-OMCP group: 3.8-fold; BY100-LTB-OMCP group: 4.3-fold). IgT was upregulated in the intestines (EBY100-OMCP group: 5.6-fold; EBY100-LTB-OMCP group: 6.7-fold). Serum neutralizing antibody titers of the two groups reached 1:85. Oral vaccination protected against LMBV infection. The relative percent survival was 52.1% (EBY100-OMCP) and 66.7% (EBY100-LTB-OMCP). Thus, EBY100-OMCP and EBY100-LTB-OMCP are promising and effective candidate vaccines against LMBV infection.

Inflammatory biomarkers in assessing severity and prognosis of immune checkpoint inhibitor-associated cardiotoxicity.

AIMS: Inflammatory biomarkers, including CRP, the neutrophil-to-lymphocyte ratio (NLR), and the neutrophil-to-eosinophil ratio (NER), may predict outcomes in cancer. However, their value in immune checkpoint inhibitor (ICI) therapy-associated cardiotoxicity remains elusive. We aimed to characterize the relationship of inflammatory markers with severity of ICI-related cardiotoxicities (iRCs) and prognosis among patients with iRCs. METHODS: Patients who were diagnosed with iRCs between January 2019 and December 2021 were retrospectively enrolled and were dichotomized based on iRC severity into low-grade (grade 1-2) vs. high-grade (grade 3-4) groups. RESULTS: Forty-seven patients were included. The median time-to-event from first ICI infusion to onset of iRCs was 35 days (IQR: 19.0-65.5 days). When compared with respective baseline values, cardiac biomarkers and inflammatory markers were significantly elevated at onset of iRCs. Compared with low-grade iRCs, NER at iRC onset was significantly increased among patients with high-grade iRCs (Group × Time, P < 0.01). When grouped by the median NER (184.33) at iRC onset, NER ≥ 184.33 was associated with high-grade iRCs (OR: 10.77, P < 0.05) and had a 36.3% increased mortality compared to the lower NER group (HR: 2.67, P < 0.05). CONCLUSIONS: In patients who develop iRCs, NER is significantly elevated at iRC onset, and higher NER correlates with greater iRC severity and higher mortality. Larger datasets are needed to validate these findings.

Development and validation of cuproptosis-related lncRNA signatures for prognosis prediction in colorectal cancer.

BACKGROUND: Cuproptosis, a novel form of programmed cell death, plays an essential role in various cancers. However, studies of the function of cuproptosis lncRNAs (CRLs) in colorectal cancer (CRC) remain limited. Thus, this study aims to identify the cuprotosis-related lncRNAs (CRLs) in CRC and to construct the potential prognostic CRLs signature model in CRC. METHODS: First, we downloaded RNA-Seq data and clinical information of CRC patients from TCGA database and obtained the prognostic CRLs based on typical expression analysis of cuproptosis-related genes (CRGs) and univariate Cox regression. Then, we constructed a prognostic model using the Least Absolute Shrinkage and Selection Operator algorithm combined with multiple Cox regression methods (Lasso-Cox). Next, we generated Kaplan-Meier survival and receiver operating characteristic curves to estimate the performance of the prognostic model. In addition, we also analysed the relationships between risk signatures and immune infiltration, mutation, and drug sensitivity. Finally, we performed quantitative reverse transcription polymerase chain reaction (qRT -PCR) to verify the prognostic model. RESULT: Lasso-Cox analysis revealed that four CRLs, SNHG16, LENG8-AS1, LINC0225, and RPARP-AS1, were related to CRC prognosis. Receiver operating characteristic (ROC) and Kaplan-Meier analysis curves indicated that this model performs well in prognostic predictions of CRC patients. The DCA results also showed that the model included four gene signatures was better than the traditional model. In addition, GO and KEGG analyses revealed that DE-CRLs are enriched in critical signalling pathway, such as chemical carcinogenesis-DNA adducts and basal cell carcinoma. Immune infiltration analysis revealed significant differences in immune infiltration cells between the high-risk and low-risk groups. Furthermore, significant differences in somatic mutations were noted between the high-risk and low-risk groups. Finally, we also validated the expression of four CRLs in FHCs cell lines and CRC cell lines using qRT-PCR. CONCLUSION: The signature composed of SNHG16, LENG8-AS1, LINC0225, and RPARP-AS1, which has better performance in predicting colorectal cancer prognosis and are promising biomarkers for prognosis prediction of CRC.

Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Induced Interstitial Lung Disease.

Drug-induced interstitial lung disease (DILD) is the most common pulmonary adverse event of anticancer drugs. In recent years, the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents. Due to the diverse clinical manifestations and the lack of specific diagnostic criteria, DILD is difficult to diagnose and may even become fatal if not treated properly. Herein, a multidisciplinary group of experts from oncology, respiratory, imaging, pharmacology, pathology, and radiology departments in China has reached the "expert consensus on the diagnosis and treatment of anticancer DILD" after several rounds of a comprehensive investigation. This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening, diagnosis, and treatment of anticancer DILD. This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.