Modified lentiviral globin gene therapy for pediatric ß0/ß0 transfusion-dependent ß-thalassemia: A single-center, single-arm pilot trial.

ß0/ß0 thalassemia is the most severe type of transfusion-dependent ß-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a ß-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in ß0/ß0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5 months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22 months. The treatment extended the lifespan of red blood cells by over 42 days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all ß-thalassemia.

Triptolide inhibits intrahepatic cholangiocarcinoma growth by suppressing glycolysis via the AKT/mTOR pathway.

BACKGROUND: High levels of glycolysis supply large quantities of energy and biological macromolecular raw materials for cell proliferation. Triptolide (TP) is a kind of epoxy diterpene lactone extracted from the roots, flowers, leaves, or grains of the Celastraceae plant, Tripterygium wilfordii. TP has multiple biological activities, including anti-inflammatory, immunologic suppression, and anti-cancer effects. Nevertheless, it is little known regarding its anti-intrahepatic cholangiocarcinoma (ICC) growth, and the mechanism still require exploration. PURPOSE: This research explored the effect of TP on ICC growth and investigated whether TP inhibits glycolysis via the AKT/mTOR pathway. METHODS: Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8), clonogenic assay, and flow cytometry. The underlying molecular mechanism was identified by determining glucose consumption, ATP production, lactate production, hexokinase (HK) and pyruvate kinase (PK) activity, and Western blot analysis. A rapid ICC model of AKT/YapS127A oncogene coactivation in mice was used to clarify the effect of TP treatment on tumor growth and glycolysis. RESULTS: The results showed that TP treatment significantly inhibited ICC cell proliferation and glycolysis in a dose- and time-dependent manner(P < 0.05). Further analysis suggested that TP suppressed ICC cell glycolysis by targeting AKT/mTOR signaling. Additionally, we found that TP inhibits tumor growth and glycolysis in AKT/YapS127A mice(P < 0.05). CONCLUSION: Taken together, we revealed that TP suppressed ICC growth by suppressing glycolysis via the AKT/mTOR pathway and may provide a potential therapeutic target for ICC treatment.

Integrated multi-omics profiling yields a clinically relevant molecular classification for esophageal squamous cell carcinoma.

Integrated molecular analysis of human cancer has yielded molecular classification for precise management of cancer patients. Here, we analyzed the whole genomic, epigenomic, transcriptomic, and proteomic data of 155 esophageal squamous cell carcinomas (ESCCs). Multi-omics analysis led to the classification of ESCCs into four subtypes: cell cycle pathway activation, NRF2 oncogenic activation, immune suppression (IS), and immune modulation (IM). IS and IM cases were highly immune infiltrated but differed in the type and distribution of immune cells. IM cases showed better response to immune checkpoint blockade therapy than other subtypes in a clinical trial. We further developed a classifier with 28 features to identify the IM subtype, which predicted anti-PD-1 therapy response with 85.7% sensitivity and 90% specificity. These results emphasize the clinical value of unbiased molecular classification based on multi-omics data and have the potential to further improve the understanding and treatment of ESCC.

Metabolomics profiling of AKT/c-Met-induced hepatocellular carcinogenesis and the inhibitory effect of Cucurbitacin B in mice.

Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Clinical aggressiveness, resistance to traditional therapy, and a high mortality rate are all features of this disease. Our previous studies have shown that co-activation of AKT and c-Met induces HCC development, which is the malignant biological feature of human HCC. Cucurbitacin B (CuB), a naturally occurring tetracyclic triterpenoid compound with potential antitumor activity. However, the metabolic mechanism of AKT/c-Met-induced Hepatocellular Carcinogenesis and CuB in HCC remains unclear. In this study, we established an HCC mouse model by hydrodynamically transfecting active AKT and c-Met proto-oncogenes. Based on the results of hematoxylin-eosin (H&E), oil red O (ORO) staining, and immunohistochemistry (IHC), HCC progression was divided into two stages: the early stage of HCC (3 weeks after AKT/c-Met injection) and the formative stage of HCC (6 weeks after AKT/c-Met injection), and the therapeutic effect of CuB was evaluated. Through UPLC-Q-TOF-MS/MS metabolomics, a total of 26 distinct metabolites were found in the early stage of HCC for serum samples, while in the formative stage of HCC, 36 distinct metabolites were found in serum samples, and 13 different metabolites were detected in liver samples. 33 metabolites in serum samples and 11 in live samples were affected by CuB administration. Additionally, metabolic pathways and western blotting analysis revealed that CuB influences lipid metabolism, amino acid metabolism, and glucose metabolism by altering the AKT/mTORC1 signaling pathway, hence decreasing tumor progression. This study provides a metabolic basis for the early diagnosis, therapy, and prognosis of HCC and the clinical application of CuB in HCC.