MicroRNA-Triggered Programmable DNA-Encoded Pre-PROTACs for Cell-Selective and Controlled Protein Degradation.

Proteolysis-targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on-demand protein degradation. Here, we developed a miRNA-initiated assembled pre-PROTAC (miRiaTAC) platform that enables the on-demand activation and termination of target degradation in a cell type-specific manner. Using miRNA-21 as a model, we engineered DNA hairpins labeled with JQ-1 and pomalidomide and facilitated the modular assembly of DNA-encoded pre-PROTACs through a hybridization chain reaction. This configuration promoted the selective polyubiquitination and degradation of BRD4 upon miR-21 initiation, highlighting significant tumor selectivity and minimal systemic toxicity. Furthermore, the platform incorporates photolabile groups, enabling the precise optical control of pre-PROTACs during DNA assembly/disassembly, mitigating the risk of excessive protein degradation. Additionally, by introducing a secondary ligand targeting CDK6, these pre-PROTACs were used as a modular scaffold for the programmable assembly of active miRiaTACs containing two different warheads in exact stoichiometry, enabling orthogonal multitarget degradation. The integration of near-infrared light-mediated photodynamic therapy through an upconversion nanosystem further enhanced the efficacy of the platform with potent in vivo anticancer activity. We anticipate that miRiaTAC represents a significant intersection between dynamic DNA nanotechnology and PROTAC, potentially expanding the versatility of PROTAC toolkit for cancer therapy.

Ethnic sensitivity analyses of pharmacokinetics, efficacy and safety in polycythemia vera treatment with ropeginterferon alfa-2b.

Ropeginterferon alfa-2b (Ropeg) is approved for the treatment of adults with polycythemia vera (PV). This report aims to analyze the ethnic sensitivity of Ropeg for the treatment of PV, comparing the pharmacokinetics (PK), efficacy, and safety profiles across diverse ethnic groups. We conducted a relevant review of PV and analysis of data obtained from clinical studies involving Ropeg. The PK behavior of ropeg showed no significant differences between Chinese and overseas populations. Their efficacy and safety profiles were similar across the ethnic groups. The analyses indicated that the dose-exposure-response profile of Ropeg was consistent irrespective of ethnic variations. The results suggest that Ropeg exhibits a consistent PK and pharmacodynamics profile and a similar therapeutic effect across different ethnic groups, confirming its efficacy and safety in the global treatment of PV. More generally, these findings support the broader application of Ropeg in diverse patient populations and emphasize the need for an inclusive clinical practice.

Comprehensive evaluation on phenolic derivatives and antioxidant activities of diverse yellow maize varieties.

The main phenolic derivatives and antioxidant capacity of ninety-three yellow maize varieties were investigated, together with their color parameters. Sixteen phenolics were identified in the free extract by UPLC-ESI-MS/MS, N', N″-diferuloyl putrescine and N', N″-dicoumaryl spermidine were the major phenolic derivatives. Fourteen phenolic compounds were found in the bound extract, with trans-p-coumaric acid, trans- and cis-ferulic acid being the predominant phenolic acids. The orange-yellow maize varieties presented the highest total phenolic content (TPC) and total flavonoid content (TFC), along with significantly higher antioxidant potential. Correlation analysis showed that b* value (corresponding to yellow degree) was positively correlated with the total carotenoid content (TCC), phenolic content, and antioxidant capacity (p < 0.05). Through Hierarchical Clustering Analysis (HCA), the 93 maize varieties could be divided into three categories according to b* value and antioxidant activity. The heatmap visualization further underscored the component differences across various varieties, unveiling the intricate phytochemical profiles of these maize varieties.

[68Ga]Ga-LNC1007 versus 2-[18F]FDG in the evaluation of patients with metastatic differentiated thyroid cancer: a head-to-head comparative study.

PURPOSE: This head-to-head comparison study aimed to compare the performance of [68Ga]Ga-FAPI-RGD (LNC1007) and 2-[18F]FDG PET/CT in the evaluation of patients with metastatic differentiated thyroid cancer (mDTC). METHODS: Ten unexplained hyperthyroglobulinemia (UHTg) patients and 20 patients with definite metastatic lesions of thyroid cancer (DmDTC) were enrolled in the study. All patients underwent both [68Ga]Ga-LNC1007 and 2-[18F]FDG PET/CT within 1 week. The final diagnosis was based on histopathological results and a comprehensive evaluation of laboratory tests and multimodal imaging characteristics. RESULTS: In patients with UHTg, [68Ga]Ga-LNC1007 PET/CT detected more metastatic lymph nodes (LNs) (17 vs. 15, P = 0.317) and lung lesions (2 vs. 0) than 2-[18F]FDG. In patients with DmDTC, [68Ga]Ga-LNC1007 PET/CT also detected more true positive lesions than 2-[18F]FDG (Total: 133 vs. 103, LN: 20 vs. 15, lung: 18 vs. 10, bone: 87 vs.73). [68Ga]Ga-LNC1007 PET/CT demonstrated significantly higher SUVmax (Total: 6.30 vs. 3.84, LN: 8.28 vs. 4.82, Lung: 3.31 vs. 1.49, Bone: 5.73 vs. 3.87, all P < 0.05) and TBR (Total: 6.92 vs. 4.93, LN: 6.48 vs. 4.16, Lung: 5.16 vs. 2.57, Bone: 7.22 vs. 5.41, all P < 0.05) in true positive lesions compared to 2-[18F]FDG. Specifically, the sensitivity of [68Ga]Ga-LNC1007 PET/CT was higher than that of 2-[18F]FDG in detecting lung and bone metastases (94.7% vs. 52.6% and 100% vs. 83.9%, all P < 0.05). [68Ga]Ga-LNC1007 PET/CT exhibited better specificity and accuracy in diagnosing LNs (96.9% vs. 66.7% and 96.3% vs. 68.5%, all P < 0.05). However, the specificity of [68Ga]Ga-LNC1007 for bone metastasis was inferior to 2-[18F]FDG (15.4% vs. 88.5%, P < 0.05). CONCLUSION: Compared with 2-[18F]FDG, [68Ga]Ga-LNC1007 PET/CT could detect more metastatic lesions, with higher SUVmax and TBR, in patients with mDTC. [68Ga]Ga-LNC1007 had better accuracy in the diagnosis of LN and lung metastasis. Trial registration ClinicalTrials.gov NCT05515783. Registered 01 May 2022. URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05515783.

Self-Assembly-Activated Engineered Magnetic Biohybrids Loaded with Phosphotriesterase for Sustainable Decontamination and Detection of Organophosphorus Pesticides.

Phosphotriesterase (PTE) biodegradation of organophosphorus pesticides (OPs) is an efficient and environmentally friendly method. However, the instability and nonreusability of free PTE become the key factors restricting its practical application. In this study, a novel cross-linked magnetic hybrid nanoflower (CLMNF) was prepared. Molecular dynamics (MD) simulations were performed to further investigate the enhanced catalytic efficiency of the enzymes. The recovery rate of enzyme activity was 298% due to the large specific surface area and metal ion activation effect. More importantly, the immobilization scheme greatly improved the stability and reuse performance of the catalyst and simplified the recovery operation. CLMNFs retained 90.32% relative activity after 5 consecutive cycles and maintained 84.8% relative activity after 30 days at 25 °C. It has a good practical application prospect in the degradation and detection of OPs. Consequently, the immobilized enzyme as a biocatalyst has the characteristics of high efficiency, stability, safety, and easy separation, establishing the key step in a biodetoxification system to control organophosphorus contamination in food and the environment.

Photoactivable CRISPR for Biosensing and Cancer Therapy.

Photoactivable CRISPR technology represents a transformative approach in the field of genome editing, offering unprecedented control over gene editing with high spatial and temporal precision. By harnessing the power of light to modulate the activity of CRISPR components, this innovative strategy enables precise regulation of Cas proteins, guide RNAs, and ribonucleoprotein complexes. Recent advancements in optical control methodologies, including the development of photoactivable nanocarriers, have significantly expanded the potential applications of CRISPR in biomedical fields. This Concept highlights the latest developments in designing photoactivable CRISPR systems and their promising applications in biosensing and cancer therapy. Additionally, the remaining challenges and future trends are also discussed. It is expected that the photoactivable CRISPR would facilitate translating more precise gene therapies into clinical use.

Trifarotene alleviates skin photoaging injury by inhibition of JNK/c-Jun/MMPs.

Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 µmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.

The effect of tamoxifen as an adjuvant therapy for breast cancer on apolipoproteins and lipoprotein(a) concentrations in women: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Tamoxifen has been used in the management of breast cancer. The available evidence on the effect of tamoxifen on lipoprotein(a) and apolipoproteins is controversial. Hence, this meta-analysis of randomized controlled trials (RCTs) was conducted to increase the quality of evidence on the effect of tamoxifen on lipoprotein(a) and apolipoproteins. METHODS: Eligible RCTs published up to September 2023 were carefully selected following a comprehensive search. Thereafter, a meta-analysis was conducted using a random-effects model and the results were presented as the weighted mean difference (WMD) with a 95 % confidence interval (CI). RESULTS: The results from the random-effects model indicated a rise in ApoA-I (WMD: 16.24 mg/dL, 95 % CI: 5.35, 27.12, P = 0.003), and a decrease in ApoB (WMD: -9.37 mg/dL, 95 % CI: -15.16, -3.59, P = 0.001) and lipoprotein(a) (WMD: -3.24 mg/dL, 95 % CI: -5.66, -0.83, P < 0.001) concentrations following tamoxifen administration in women. Furthermore, a more pronounced decrease in ApoB (WMD: -12.86 mg/dL, 95 % CI: -19.78, -5.93, P < 0.001) and elevation in ApoA-1 levels (WMD: 51.97 mg/dL, 95 % CI: 45.89, 58.05, P < 0.001) were identified in a single study on patients with breast cancer. CONCLUSION: The current meta-analysis demonstrated an increase of ApoA-I and a decrease of ApoB and lipoprotein(a) levels after treatment with tamoxifen in women.

Hormetic responses to cadmium exposure in wheat seedlings: insights into morphological, physiological, and biochemical adaptations.

Cadmium is commonly recognized as toxic to plant growth, low-level Cd has promoting effects on growth performance, which is so-called hormesis. Although Cd toxicity in wheat has been widely investigated, knowledge of growth response to a broad range of Cd concentrations, especially extremely low concentrations, is still unknown. In this study, the morphological, physiological, and biochemical performance of wheat seedlings to a wide range of Cd concentrations (0-100 µΜ) were explored. Low Cd treatment (0.1-0.5 µM) improved wheat biomass and root development by enhancing the photosynthetic system and antioxidant system ability. Photosynthetic rate (Pn) was improved by 5.72% under lower Cd treatment (1 µΜ), but inhibited by 6.05-49.85% from 5 to 100 µΜ. Excessive Cd accumulation induced oxidative injury manifesting higher MDA content, resulting in lower photosynthetic efficiency, stunted growth, and reduction of biomass. Further, the contents of ascorbate, glutathione, non-protein thiols, and phytochelatins were improved under 5-100 µΜ Cd treatment. The ascorbate peroxidase activity in the leaf showed a hormetic dose-response characteristic. Correlation analysis and partial least squares (PLS) results indicated that antioxidant enzymes and metabolites were closely correlated with Cd tolerance and accumulation. The results of the element network, correlation analysis, and PLS showed a crucial role for exogenous Cd levels in K, Fe, Cu, and Mn uptake and accumulation. These results provided a deeper understanding of the hormetic effect of Cd in wheat, which would be beneficial for improving the quality of hazard and risk assessments.

Non-discriminating engineered masking of immuno-evasive ligands on tumour-derived extracellular vesicles enhances tumour vaccination outcomes.

The success of personalized cancer immunotherapy depends on the initial tumour antigenic presentation to dendritic cells and macrophages. Tumour-derived extracellular vesicles (TEVs) contain abundant tumour antigenic molecules. The presence of anti-phagocytotic signals such as cluster of differentiation 47 (CD47) on the surface of the TEVs, however, leads to evasion of the same dendritic cells and macrophages. Here we show that iron oxide hydroxide nanocomposites can successfully mask TEV surfaces and unblock phagocytosis without affecting extracellular vesicles' elicited immune goals. After internalization, the mask disintegrates in the lysosome, releasing the tumour antigenic cargo. This triggers antigen presentation and promotes dendritic cell activation and maturation and macrophage reprogramming in animal models, leading to a drastic reduction of tumour volume and metastasis, and in human malignant pleural effusion clinical samples. This straightforward masking strategy eliminates the ubiquitous anti-phagocytosis block found in clinical samples and can be applied universally across all patient-specific TEVs as tumour antigenic agents for enhanced immunotherapy.

Role of FGF21 in mediating the effect of phosphatidylcholine on GBM.

Objective: The causal relationship and mechanisms between lipids and glioblastoma (GBM) remain unclear. This study aims to investigate the independent causal relationship between liposomal phosphatidylcholine 16:0_22:6 (PC16) and GBM, and to identify the potential mediating role of the inflammatory factor-fibroblast growth factor 21(FGF21). Methods: Utilizing summary statistics from genome-wide association studies (GWAS) of lipids (179 types in 7174 Finnish individuals), GBM (243 cases and 287137 controls), and inflammatory factors (91 types in 14824 European individuals), a two-sample Mendelian Randomization (MR) approach was employed to establish the causal link between liposomal PC16 and GBM. Additionally, a two-step MR method was used to quantify the proportion of the causal effect of PC16 on GBM that is mediated by the inflammatory factor FGF21. Results: MR analyses revealed a strong causal relationship between PC16 and GBM (OR=1.72, 95% CI: 1.11-2.68, P=0.016), but no reverse causality was observed from GBM to PC16 (OR=1.01, 95% CI: 0.99-1.02, P=0.38). Mediation analysis showed a strong causal relationship between PC16 and the FGF21 (OR = 0.94, 95% CI: 0.89-0.99, P=0.018) as well as between FGF21 and GBM (OR = 0.42, 95% CI: 0.25-0.71, P=0.001), with the mediation effect accounting for 9.78% of the total effect. This suggests that the causal relationship between PC16 and GBM is likely mediated by the intermediary factor FGF21. No evidence of pleiotropy was found in the sensitivity analysis of these positive results. Conclusion: In summary, the findings of this study suggest that liposomal PC16 may increase the risk of GBM occurrence, and FGF21 may play a significant mediating role in this causal relationship.

Analyzing Risk Factors for Delayed Extubation Following Posterior Approach Surgery for Congenital Scoliosis: A Retrospective Cohort Study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Investigate the risk factors for delayed extubation after posterior approach orthopedic surgery in patients with congenital scoliosis. METHODS: The clinical data of patients who received surgery for congenital scoliosis at the First Affiliated Hospital of Xinjiang Medical University between January 2021 and July 2023 have been gathered. Patients are categorized into the usual and the delayed extubation groups, depending on the duration of tracheal intubation after surgery. The study employs univariate and multivariate logistic regression models to examine the clinical characteristics of the two cohorts and discover potential risk factors linked to delayed extubation. In addition, a prediction model is created to visually depict the significance of each risk factor in terms of weight according to the nomogram. RESULTS: A total of 119 patients (74.8% females), with a median age of 15 years, are included. A total of 32 patients, accounting for 26.9% of the sample, encountered delayed extubation. Additionally, 13 patients (10.9%) suffered perioperative complications, with pneumonia being the most prevalent. The multivariate regression analysis revealed that the number of osteotomy segments, postoperative hematocrit, postoperative Interleukin-6 levels, and weight are predictive risk factors for delayed extubation. CONCLUSIONS: Postoperative hematocrit and Interleukin-6 level, weight, and number of osteotomy segments can serve as independent risk factors for predicting delayed extubation, with combined value to assist clinicians in evaluating the risk of delayed extubation of postoperative congenital scoliosis patients, improving the success rate of extubation, and reducing postoperative treatment time in the intensive care unit.

Penicipyrrolizidinones A-C, three pyrrolizidinone alkaloids with unprecedented skeletons from the mangrove-derived fungus Penicillium sp. DM27.

Three previously undescribed pyrrolizidinone alkaloids, penicipyrrolizidinones A and B (1 and 2), possessing an unprecedented 2-methyl-2-(oct-6-enoyl)pyrrolizidin-3-one skeleton, and penicipyrrolizidinone C (3), featuring a rare 1-alkenyl-2-methyl-pyrrolizidin-3,7-dione skeleton, together with four known pyrrolidine derivatives (4-7) were isolated from the mangrove-derived fungus Penicillium sp. DM27. Their structures were elucidated through comprehensive spectroscopic analysis, theoretical calculations of ECD spectra, and the modified Mosher's method. A plausible biosynthetic pathway for penicipyrrolizidinones A-C (1-3) was proposed. Compounds 4 and 5 exhibited moderate cytotoxicity against B16-F10 melanoma cells with IC50 values of 10.5 µM and 15.5 µM, respectively.

Branched hybridization chain reaction and tetrahedral DNA-based trivalent aptamer powered SERS sensor for ultra-highly sensitive detection of cancer-derived exosomes.

Exosomes have emerged as a promising noninvasive biomarker for early cancer diagnosis due to their ability to carry specific bioinformation related to cancer cells. However, accurate detection of trace amount of cancer-derived exosomes in complex blood remains a significant challenge. Herein, an ultra-highly sensitive SERS sensor, powered by the branched hybridization chain reaction (bHCR) and tetrahedral DNA-based trivalent aptamer (triApt-TDN), has been proposed for precise detection of cancer-derived exosomes. Taking gastric cancer SGC-7901 cells-derived exosomes as a test model, the triApt-TDNs were constructed by conjugating aptamers specific to mucin 1 (MUC1) protein with tetrahedral DNAs and subsequently immobilized on the surface of silver nanorods (AgNRs) arrays to create SERS-active sensing chips capable of specifically capturing exosomes overexpressing MUC1 proteins. The bHCR was further initiated by the trigger aptamers (tgApts) bound to exosomes, and as a result the SERS tags were assembled into AuNP network structures with abundant SERS hotspots. By optimizing the sensing conditions, the SERS sensor showed good performance in ultra-highly sensitive detection of target exosomes within 60 min detection time, with a broad response ranging of 1.44 to 1.44 × 104 particles·µL-1 and an ultralow limit of detection capable of detecting a single exosome in 2 µL sample. Furthermore, the SERS sensor exhibited good uniformity, repeatability and specificity, and capability to distinguish between gastric cancer (GC) patients and healthy controls (HC) through the detection of exosomes in clinical human serums, indicating its promising clinical potential for early diagnosis of gastric cancer.

Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR-mediated DNA damage response.

Despite active clinical trials on the use of Oleandrin alone or in combination with other drugs for the treatment of solid tumors, the potential synergistic effect of Oleandrin with radiotherapy remains unknown. This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase-mediated radiosensitization in lung cancer. Various assays, including clonogenic, Comet, immunofluorescence staining, apoptosis and Cell cycle assays, were conducted to evaluate the impact of oleandrin on radiation-induced double-strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double-strand break repair. The efficacy and toxicity of the combined therapy were assessed in a preclinical xenotransplantation model. Functionally, Oleandrin weakens the DNA damage repair ability and enhances the radiation sensitivity of lung cells. Mechanistically, Oleandrin inhibits ATM and ATR kinase activities, blocking the transmission of ATM-CHK2 and ATR-CHK1 cell cycle checkpoint signaling axes. This accelerates the passage of tumor cells through the G2 phase after radiotherapy, substantially facilitating the rapid entry of large numbers of inadequately repaired cells into mitosis and ultimately triggering mitotic catastrophe. The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.

Myc-mediated inhibition of HIF1a degradation promotes M2 macrophage polarization and impairs CD8 T cell function through lactic acid secretion in ovarian cancer.

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132-/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132-/- mice, shedding light on potential therapeutic avenues for ovarian cancer management.

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders.

Metformin combined with cisplatin reduces anticancer activity via ATM/CHK2-dependent upregulation of Rad51 pathway in ovarian cancer.

Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.

The feedback loop between MTA1 and MTA3/TRIM21 modulates stemness of breast cancer in response to estrogen.

The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Background: Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. Methods: A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. Results: A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. Conclusions: In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.