Identification of the synonymous variant c.3141G > A in TNRC6B gene that altered RNA splicing by minigene assay.

BACKGROUND: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene. METHOD: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing. RESULT: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic. CONCLUSION: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants' benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases.

Serum high-density lipoprotein cholesterol levels predict early recurrence and prognosis of intrahepatic cholangiocarcinoma after surgical resection.

Introduction: Dysregulation in lipid metabolism contributes to the occurrence and development of various cancers. The connection between changes in lipid metabolism and the development of intrahepatic cholangiocarcinoma remains uncertain. Our objective was to investigate the significance of blood lipid levels in patients with intrahepatic cholangiocarcinoma who have undergone surgery. Methods: Ninety-seven ICC patients who underwent surgery were retrospectively enrolled. After 92.2 months of follow-up, the Kaplan-Meier analysis and Cox proportional hazard model were used to calculate overall survival and recurrence-free survival. Results: The median age of this cohort was 56 years, and 79 (81.4 %) of them were male. Eighty-eight (90.7 %) patients presented with tumor recurrence and 73 (75.3 %) died. In multivariate analyses, high-density lipoprotein cholesterol level (<0.91 vs. ≥ 0.91 mmol/L, hazard ratio [HR] = 2.55; 95 % CI: 1.38-4.71), lymph node metastasis (Yes vs. No, HR = 2.58; 95 % CI: 1.28-5.19), etiology factor (chronic HBV infection vs. others, HR = 0.5; 95 % CI: 0.28-0.88) and multiple tumor lesions (Yes vs. No, HR = 1.85; 95 % CI: 1.01-3.39) were independent predictors of overall survival. However, only high-density lipoprotein cholesterol level (HR = 1.86; 95 % CI: 1.19-2.92) emerged as the independent factor for recurrence-free survival. High-density lipoprotein cholesterol level (HR = 2.07; 95 % CI: 1.26-3.41), etiology factor (HR = 0.49; 95 % CI: 0.29-0.84), and multiple tumor lesions (HR = 2.00; 95 % CI: 1.14-3.51) were independent predictors of early recurrence. For patients who did not experience the spread of cancer to the lymph nodes, there was a significant correlation between the level of high-density lipoprotein cholesterol and their overall survival, recurrence-free survival, and early recurrence. For patients with low pre-operation high-density lipoprotein cholesterol levels, high post-operation high-density lipoprotein cholesterol levels were associated with better prognosis. Conclusions: Low serum high-density lipoprotein cholesterol level might serve as a sign of poor clinical outcomes (overall survival and recurrence-free survival) and early recurrence among intrahepatic cholangiocarcinoma patients. Strengthening the monitoring and intervention of intrahepatic cholangiocarcinoma patients with poor prognosis might be critical for improving the prognosis.

Indium Promotes Direct Sulfonamidation of Unactivated Alcohols.

An improved protocol has been developed for the direct sulfonamidation of unactivated alkyl alcohols using In(OTf)3 as a Lewis acid catalyst. Although the established methods using Lewis or Brønsted acids have been well-studied for the direct functionalization of alcohols, their substrate scope mainly focuses on the π-activated alcohols. In this reaction, unactivated aliphatic alcohols were evaluated and afforded the desired sulfonamide products with good to excellent yields.

Proteomic and Transcriptomic Analyses Provide New Insights into the Mechanism Underlying Lipid Deterioration in Pecan Kernels during Storage.

Pecan nuts are rich in lipids that tend to deteriorate during storage. Tandem mass-tag-based quantitative proteomics and transcriptomics were used to investigate the changes in the protein and gene profiles of stored pecan kernels for the first time. Our previous lipidomic data were jointly analyzed to elucidate the coordinated changes in lipid molecules and related proteins/genes. The mechanism underlying lipid deterioration in pecan kernels during storage was revealed by multiomics analyses. Lipid metabolism-related pathways were activated during pecan storage. Phospholipases, triacylglycerol lipases, lipoxygenases, and oil body-related proteins/genes were highly expressed during storage, revealing their involvement in lipid deterioration. These data provide rich information and will be valuable for future genetic or chemical research to alleviate lipid deterioration in pecans.

Interpretable machine learning-based clinical prediction model for predicting lymph node metastasis in patients with intrahepatic cholangiocarcinoma.

OBJECTIVE: Prediction of lymph node metastasis (LNM) for intrahepatic cholangiocarcinoma (ICC) is critical for the treatment regimen and prognosis. We aim to develop and validate machine learning (ML)-based predictive models for LNM in patients with ICC. METHODS: A total of 345 patients with clinicopathological characteristics confirmed ICC from Jan 2007 to Jan 2019 were enrolled. The predictors of LNM were identified by the least absolute shrinkage and selection operator (LASSO) and logistic analysis. The selected variables were used for developing prediction models for LNM by six ML algorithms, including Logistic regression (LR), Gradient boosting machine (GBM), Extreme gradient boosting (XGB), Random Forest (RF), Decision tree (DT), Multilayer perceptron (MLP). We applied 10-fold cross validation as internal validation and calculated the average of the areas under the receiver operating characteristic (ROC) curve to measure the performance of all models. A feature selection approach was applied to identify importance of predictors in each model. The heat map was used to investigate the correlation of features. Finally, we established a web calculator using the best-performing model. RESULTS: In multivariate logistic regression analysis, factors including alcoholic liver disease (ALD), smoking, boundary, diameter, and white blood cell (WBC) were identified as independent predictors for LNM in patients with ICC. In internal validation, the average values of AUC of six models ranged from 0.820 to 0.908. The XGB model was identified as the best model, the average AUC was 0.908. Finally, we established a web calculator by XGB model, which was useful for clinicians to calculate the likelihood of LNM. CONCLUSION: The proposed ML-based predicted models had a good performance to predict LNM of patients with ICC. XGB performed best. A web calculator based on the ML algorithm showed promise in assisting clinicians to predict LNM and developed individualized medical plans.

Single-cell transcriptome analysis profiling lymphatic invasion-related TME in colorectal cancer.

Lymphatic invasion (LI) is extremely aggressive and induces worse prognosis among patients with colorectal cancer (CRC). Thus, it is critical to characterize the cellular and molecular mechanisms underlying LI in order to establish novel and efficacious therapeutic targets that enhance the prognosis of CRC patients. RNA-seq data, clinical and survival information of colon adenocarcinoma (COAD) patients were obtained from the TCGA database. In addition, three scRNA-seq datasets of CRC patients were acquired from the GEO database. Data analyses were conducted with the R packages. We assessed the tumor microenvironment (TME) differences between LI+ and LI- based scRNA-seq data, LI+ cells exhibited augmented abundance of immunosuppression and invasive subset. Marked extracellular matrix network activation was also observed in LI+ cells within SPP1+ macrophages. We revealed that an immunosuppressive and pro-angiogenic TME strongly enhanced LI, as was evidenced by the CD4+ Tregs, CD8+ GZMK+, SPP1+ macrophages, e-myCAFs, and w-myCAFs subcluster infiltrations. Furthermore, we identified potential LI targets that influenced tumor development, metastasis, and immunotherapeutic response. Finally, a novel LIRS model was established based on the expression of 14 LI-related signatures, and in the two testing cohorts, LIRS was also proved to have accurate prognostic predictive ability. In this report, we provided a valuable resource and extensive insights into the LI of CRC. Our conclusions can potentially benefit the establishment of highly efficacious therapeutic targets as well as diagnostic biomarkers that improve patient outcomes.

Boosting the reversibility of Zn anodes via synergistic cation-anion interface adsorption with addition of multifunctional potassium polyacrylate.

Rechargeable aqueous Zn batteries have the edge in resource reserve, cost, energy and conversion efficiency due to the inherent features of metal Zn anodes. However, the application of Zn-based batteries is being seriously hindered by Zn dendrites and water-induced side-reactions. Here, potassium polyacrylate (K-PAM) is proposed as the electrolyte additive to form a synergistic cation-anion interface on Zn surface. The carboxyl anions and K+ cations are preferentially adsorbed on the Zn surface due to the intrinsic surfactant characteristics, which could homogenize Zn plating and suppress parasitic reactions. The synergistic regulation of K-PAM additive endows the ZnZn symmetric cells with excellent cyclic durability of 1250 h at 1 mA cm-2, which is significantly better than the polyacrylic acid additive only with carboxyl anions. Moreover, trace K-PAM addition into traditional ZnSO4 electrolyte endows the ZnCu batteries with a considerable average Coulombic efficiency of 99.2 %. Additionally, higher capacity retention and excellent cycling stability of ZnVO2 cells further mark K-PAM as a potentially impressive aqueous electrolyte additive for high-performance Zn-based batteries. This work will provide a promising method for the synergistic regulation with cations and anions of electrolyte additives to improve the stability and reversibility of Zn anodes.

Single-Electron Reduction of "Push-Pull" C-C Single Bond and Decyanation Using Tertiary Amines as the Organic Electron Donor.

Using commercially available tertiary amines as an organic electron donor (OED), the reduction of "push-pull" C-C single bond and reductive decyanation of tetrahydroisoquinolines were realized. These reactions exhibited higher reaction efficiency and better functional group tolerance compared with those of metallic reductants, and the mechanistic study indicated that a radical intermediate was involved in the reduction of the C-C single bond, which provides a new way to the OED-enabled mild reduction.

Single-nucleus RNA sequencing reveals that macrophages and smooth muscle cells promote carotid atherosclerosis progression through mitochondrial autophagy.

Carotid atherosclerotic plaques are the manifestation of atherosclerosis in the carotid arteries and can significantly increase the incidence of cerebrovascular disease. Macrophages and smooth muscle cells are crucial for their development. To reveal the mechanism of carotid atherosclerotic plaque formation, we performed single-nucleus RNA sequencing of the carotid plaque tissue and identified 11 cell types, and the macrophages were divided into 5 different macrophage subpopulations. The macrophages and smooth muscle cells in the patients with symptomatic carotid atherosclerotic plaques caused intraplaque cell death via the mitochondrial autophagic pathway, resulting in plaque instability and rupture, which in turn led to clinical cardiovascular and cerebrovascular events. The findings provide new insights into carotid atherosclerosis formation, and this may provide new directions for the prevention and treatment of carotid atherosclerosis.

CBr4 as a Mild Oxidant-Enabled Oxidation of a sp3 C-H Bond: A Facile Synthesis of the Persistent Iminium Salts of Tetrahydroisoquinolines.

Using CBr4 as a mild oxidant, the direct C-H bond oxidation of N-aryltetrahydroisoquinolines was achieved, giving a series of the corresponding iminium salts in high yields under metal- and photo-free reaction conditions. This reaction is superior in high yields and good functional group tolerance, and the late-stage derivatization showed that these iminium salts can readily be applied to the synthesis of the functionalized THIQs.

CREG1 deficiency impaired myoblast differentiation and skeletal muscle regeneration.

BACKGROUND: CREG1 (cellular repressor of E1A-stimulated genes 1) is a protein involved in cellular differentiation and homeostasis regulation. However, its role in skeletal muscle satellite cells differentiation and muscle regeneration is poorly understood. This study aimed to investigate the role of CREG1 in myogenesis and muscle regeneration. METHODS: RNA sequencing data (GSE8479) was analysed from the Gene Expression Omnibus database (GEO, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). We generated Creg1 knockdown and skeletal muscle satellite cells specific Creg1 overexpression mice mediated by adeno-associated virus serotype 9 (AAV9), skeletal muscle mature myofibre Creg1 knockout mice (myoblast/Creg1MKO), and control mice Creg1flox/flox (Creg1fl/fl) as in vivo models. The mice were injected into tibialis anterior (TA) muscle with 100 µL of 10 µM cardiotoxin to establish a muscle regeneration model. Creg1fl/fl and Creg1MKO mice were treated with AAV-sh-C-Cbl (2 × 1010 genomic copies/mouse) to silence C-Cbl in the TA muscle. 293T and C2C12 cells were transfected with plasmids using lipofectamine RNAi MAX in vitro. Mass spectrometry analyses and RNA sequencing transcriptomic assay were performed. RESULTS: We analysed the transcriptional profiles of the skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women in GSE8479 database, and the results showed that Creg1 was associated with human sarcopenia. We found that Creg1 knockdown mice regenerated less newly formed fibres in response to cardiotoxin injection (~30% reduction, P < 0.01); however, muscle satellite cells specific Creg1 overexpression mice regenerated more newly formed fibres (~20% increase, P < 0.05). AMPKa1 is known as a key mediator in the muscle regeneration process. Our results revealed that CREG1 deficiency inhibited AMPKa1 signalling through C-CBL E3-ubiquitin ligase-mediated AMPKa1 degradation (P < 0.01). C-CBL-mediated AMPKa1 ubiquitination was attributed to the K48-linked polyubiquitination of AMPKa1 at K396 and that the modification played an important role in the regulation of AMPKa1 protein stability. We also found that Creg1MKO mice regenerated less newly formed fibres compared with Creg1fl/fl mice (~30% reduction, P < 0.01). RNA-seq analysis showed that CREG1 deletion in impaired muscles led to the upregulation of inflammation and DKK3 expression. The TA muscles of Creg1MKO mice were injected with AAV-vector or AAV-shC-Cbl, silencing C-CBL (P < 0.01) in the skeletal muscles of Creg1MKO mice significantly improved muscle regeneration induced by CTX injury (P < 0.01). CONCLUSIONS: Our findings suggest that CREG1 may be a potential therapeutic target for skeletal muscle regeneration.

Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1 correlate with Crohn's disease.

To identify candidate pathogenic genes of early-stage Crohn's disease (CD) and predict potential roles of genetic factors in CD, we performed whole exome sequencing on a child with early-stage Crohn's disease (CD) and her parents (core family), found that the patient carried heterozygous variants of 4 genes: NOD2 c. 2257 C > T, IL10RA c. 301 C > T, PLA2G6 c. 2029 C > T, COL7A1 c. 3190 G > A. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1, intestinal inflammatory response is triggered, normal intestinal wall tissue damage, leading to CD phenotype.

Development and validation of a clinical prediction model for the risk of distal metastasis in intrahepatic cholangiocarcinoma: a real-world study.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant and easily metastatic bile duct tumor with poor prognosis. We aimed at studying the associated risk factors affecting distal metastasis of CCA and using nomogram to guide clinicians in predicting distal metastasis of CCA. METHODS: Based on inclusion and exclusion criteria, 345 patients with CCA were selected from the Fifth Medical Center of Chinese PLA General Hospital and were divided into distal metastases (N = 21) and non-distal metastases (N = 324). LASSO regression models were used to screen for relevant parameters and to compare basic clinical information between the two groups of patients. Risk factors for distal metastasis were identified based on the results of univariate and multivariate logistic regression analyses. The nomogram was established based on the results of multivariate logistic regression, and we drawn the corresponding correlation heat map. The predictive accuracy of the nomogram was evaluated by receiver operating characteristic (ROC) curves and calibration plots. The utility of the model in clinical applications was illustrated by applying decision curve analysis (DCA), and overall survival(OS) analysis was performed using the method of Kaplan-meier. RESULTS: This study identified 4 independent risk factors for distal metastasis of CCA, including CA199, cholesterol, hypertension and margin invasion, and developed the nomogram based on this. The result of validation showed that the model had significant accuracy for diagnosis with the area under ROC (AUC) of 0.882 (95% CI: 0.843-0.914). Calibration plots and DCA showed that the model had high clinical utility. CONCLUSIONS: This study established and validated a model of nomogram for predicting distal metastasis in patients with CCA. Based on this, it could guide clinicians to make better decisions and provide more accurate prognosis and treatment for patients with CCA.

Oxidants Controlled C-H Bond Functionalization of N-Aryltetrahydroisoquinolines: The Construction of the Quaternary Carbon Center and Cleavage of the C-N Bond.

Initiated by triarylamine radical cation salt (TBPA), the direct C-H bond functionalization of α-N-aryltetrahydroisoquinoline esters was smoothly realized, giving a series of α-hydroxylated derivatives with a quaternary carbon center in good yields. Differently, in the presence of tert-butyl nitrite (TBN), the C-N single bond was cleaved to keto esters. The mechanistic study revealed that these reactions were mediated by a similar mechanism, in which the N-nitrosation might provide a driving force to the C-N bond cleavage.

Unraveling the molecular links between benzopyrene exposure, NASH, and HCC: an integrated bioinformatics and experimental study.

Benzopyrene (B[a]P) is a well-known carcinogen that can induce chronic inflammation and fibrosis in the liver, leading to liver disease upon chronic exposure. Nonalcoholic steatohepatitis (NASH) is a chronic liver condition characterized by fat accumulation, inflammation, and fibrosis, often resulting in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the intricate connections between B[a]P exposure, NASH, and HCC. Through comprehensive bioinformatics analysis of publicly available gene expression profiles, we identified differentially expressed genes (DEGs) associated with B[a]P exposure, NASH, and liver cancer. Furthermore, network analysis revealed hub genes and protein-protein interactions, highlighting cellular metabolic dysfunction and disruption of DNA damage repair in the B[a]P-NASH-HCC process. Notably, HSPA1A and PPARGC1A emerged as significant genes in this pathway. To validate their involvement, we conducted qPCR analysis on cell lines and NASH mouse liver tissues and performed immunohistochemistry labeling in mouse and human HCC liver sections. These findings provide crucial insights into the potential regulatory mechanisms underlying benzopyrene-induced hepatotoxicity, shedding light on the pathogenesis of B[a]P-associated NASH and HCC. Moreover, our study suggests that HSPA1A and PPARGC1A could serve as promising therapeutic targets. Enhancing our understanding of their regulatory roles may facilitate the development of targeted therapies, leading to improved patient outcomes.

ceRNA Network Analysis Reveals Potential Key miRNAs and Target Genes in COVID-19-Related Chronic Obstructive Pulmonary Disease.

The continued spread of SARS-CoV-2 has presented unprecedented obstacles to the worldwide public health system. Especially, individuals with chronic obstructive pulmonary disease (COPD) are at a heightened risk of contracting SARS-CoV-2 infection due to their pre-existing respiratory symptoms that are not well-managed. However, the viral mechanism of affecting the expression of host genes, COPD progression, and prognosis is not clear yet.This study integrated the differential expression information of COPD patients and then calculated the correlation between mRNAs and miRNAs to construct a COPD-specific ceRNA network. The DEGs of individuals with SARS-CoV-2 infection and anticipated miRNAs and their targets were analyzed in 9 SARS-CoV-2 sequences from different geographic locations. Furthermore, combining the experimentally validated miRNAs and genes, the regulatory miRNA-mRNA relationships were identified. All the regulatory relationships were integrated into the COPD-specific network and the network modules were explored to get insight into the functional mechanism of SARS-CoV-2 infection in COPD patients.A higher proportion of DEGs compete with the same miRNA suggesting a higher expression of genes in the COPD-specific ceRNA network. Hsa-miR-21-3p is the largest connected point in the network, but the proportion of genes upregulated by hsa-miR-21-3p is low (P = 0.1406). This indicates that the regulatory relationship of competitive inhibition has little effect on has-miR-21, and the high expression pattern is a poor prognostic factor in COPD. Hsa-miR-15a-5p is the most significant miRNA with the highest proportion of DEGs. And ANXA2P3 is the only gene in the COPD ceRNA network that interferes with hsa-miR-15a-5p. In addition, we found that has-miR-1184- and has-miR-99-cored modules were significant, and genes ZDHHC18, PCGF3, and KIAA0319L interacting with them were all associated with COPD prognosis, and high expression of these genes could lead to poor prognosis in COPD.The key regulators such as miR-21, miR-15a, ANXA2P3, ZDHHC18, PCGF3, and KIAA0319L can be used as prognostic biomarkers for early intervention in COPD with SARS-CoV-2 infection.

Plasma Reference Ranges for Brain Injury Biomarkers (NfL, NfH, MCP-1, and MMP-9) in Healthy Chinese.

BACKGROUND: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard. METHODS: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics. RESULTS: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002). CONCLUSIONS: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders.

Gut mycobiome as a potential non-invasive tool in early detection of lung adenocarcinoma: a cross-sectional study.

BACKGROUND: The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis. METHODS: In total, 299 fecal samples from Beijing, Suzhou, and Hainan were collected prospectively. Using internal transcribed spacer 2 sequencing, we profiled the gut mycobiome. Five supervised machine learning algorithms were trained on fungal signatures to build an optimized prediction model for LUAD in a discovery cohort comprising 105 patients with LUAD and 61 healthy controls (HCs) from Beijing. Validation cohorts from Beijing, Suzhou, and Hainan comprising 44, 17, and 15 patients with LUAD and 26, 19, and 12 HCs, respectively, were used to evaluate efficacy. RESULTS: Fungal biodiversity and richness increased in patients with LUAD. At the phylum level, the abundance of Ascomycota decreased, while that of Basidiomycota increased in patients with LUAD. Candida and Saccharomyces were the dominant genera, with a reduction in Candida and an increase in Saccharomyces, Aspergillus, and Apiotrichum in patients with LUAD. Nineteen operational taxonomic unit markers were selected, and excellent performance in predicting LUAD was achieved (area under the curve (AUC) = 0.9350) using a random forest model with outcomes superior to those of four other algorithms. The AUCs of the Beijing, Suzhou, and Hainan validation cohorts were 0.9538, 0.9628, and 0.8833, respectively. CONCLUSIONS: For the first time, the gut fungal profiles of patients with LUAD were shown to represent potential non-invasive biomarkers for early-stage diagnosis.

Efficacy and safety of anti-PD-1 monotherapy versus anti-PD-1 antibodies plus lenvatinib in patients with advanced hepatocellular carcinoma: a real-world experience.

Background: The efficacy of anti-programmed cell death (PD)-1 monotherapy in advanced hepatocellular carcinoma (aHCC) is limited, and combination therapy with lenvatinib and pembrolizumab has shown promising results. However, comparative studies between immune monotherapies and combination therapies are lacking. Objectives: To investigate the efficacy and safety of anti-PD-1 monotherapy (PD-1) and anti-PD-1 plus lenvatinib (PD-1 + L) in patients with aHCC to guide clinical treatment decisions. Design: A retrospective study was conducted on a cohort of patients with aHCC who received either PD-1 monotherapy or PD-1 + L combination therapy between January 2018 and January 2020. Methods: The study retrospectively reviewed the medical records of 94 eligible patients with aHCC, with 39 in the PD-1 group and 55 in the PD-1 + L group. The efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety, were assessed. Results: With a median follow-up of 30.1 months, the PD-1 + L group demonstrated a significantly higher ORR (32.7% versus 10.3%, p = 0.013), better DCR (80.0% versus 53.8%, p = 0.012), longer median PFS (10.6 versus 4.4 months, p < 0.001) and longer median OS (18.4 versus 8.5 months, p = 0.013) than PD-1 group. For the responders, the efficacy of the two groups was durable (DOR was 11.6 versus 3.5 months, p = 0.009). Subgroup analyses based on prior tyrosine kinase inhibitor (TKI) treatment and the presence or absence of macrovascular tumor thrombosis or extrahepatic metastases favored the PD-1 + L group. The combination therapy was a good predictor of PFS and OS in multivariate analysis. Grade 3/4 treatment-related adverse events were more common in PD-1 + L group, with higher incidences of hypertension and hand-foot skin reactions. Conclusions: PD-1 monotherapy and PD-1 plus lenvatinib combination therapy were well-tolerated in patients with aHCC. PD-1 + L showed significantly better survival benefits than PD-1 monotherapy.

Understanding the impact of PD-1 and lenvatinib combination therapy on advanced hepatocellular carcinoma Abstract: This plain language summary provides a description of our research on the combination therapy of PD-1 and lenvatinib for advanced Hepatocellular carcinoma (aHCC). We aimed to investigate the effectiveness and safety of this treatment approach and offer insights for clinical decisions. Why was this study done? HCC is a challenging condition to treat, especially in advanced stages. We explored whether the combination of two drugs, PD-1 and lenvatinib, can offer better outcomes for patients with aHCC than PD-1 monotherapy. What did the researchers do? We conducted a retrospective study on patients diagnosed with aHCC who received PD-1 alone or PD-1 combined with lenvatinib between January 2018 and January 2020. We analysed the medical records to assess the treatment's efficacy and safety. What did the researchers find? After a median follow-up of 30.1 months, we observed significant improvements in the combination therapy group, with higher response rates, better disease control, longer progression free survival, and more extended overall survival than those in the PD-1 monotherapy group. Responders in the combination group also experienced a longer duration of response. What do the findings mean? Our results address the lack of data for real-world clinical experiences regarding anti-PD-1 monotherapy for patients with aHCC compared to immunotherapy plus lenvatinib are lacking. The combination of PD-1 and lenvatinib was more effective and offered better survival benefits for patients with aHCC than PD-1 alone. These results could provide new hope for patients with this challenging condition. Limitations: The study was conducted at a single centre with relatively few patients. Additionally, most patients had hepatitis B-associated liver cancer, which may limit the generalisability of our findings to other populations. Conclusions: PD-1 plus lenvatinib is a promising treatment option for patients with aHCC. It is well-tolerated, and its effectiveness surpasses that of PD-1 therapy alone. Our findings could potentially guide clinicians in making treatment decisions for patients with aHCC.

A single-cell atlas of West African lungfish respiratory system reveals evolutionary adaptations to terrestrialization.

The six species of lungfish possess both lungs and gills and are the closest extant relatives of tetrapods. Here, we report a single-cell transcriptome atlas of the West African lungfish (Protopterus annectens). This species manifests the most extreme form of terrestrialization, a life history strategy to survive dry periods that can last for years, characterized by dormancy and reversible adaptive changes of the gills and lungs. Our atlas highlights the cell type diversity of the West African lungfish, including gene expression consistent with phenotype changes of terrestrialization. Comparison with terrestrial tetrapods and ray-finned fishes reveals broad homology between the swim bladder and lung cell types as well as shared and idiosyncratic changes of the external gills of the West African lungfish and the internal gills of Atlantic salmon. The single-cell atlas presented here provides a valuable resource for further exploration of the respiratory system evolution in vertebrates and the diversity of lungfish terrestrialization.