ABSTRACT
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition and attack through various mechanisms, including the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation in specific TNBC subtypes. Consequently, targeting the JAK2/STAT3 signaling pathway emerges as a promising and precise therapeutic strategy for TNBC. The signal transduction cascade of the JAK2/STAT3 pathway predominantly involves receptor tyrosine kinases, the tyrosine kinase JAK2, and the transcription factor STAT3. Ongoing preclinical studies and clinical research are actively investigating this pathway as a potential therapeutic target for TNBC treatment. This article comprehensively reviews preclinical and clinical investigations into TNBC treatment by targeting the JAK2/STAT3 signaling pathway using small molecule compounds. The review explores the role of the JAK2/STAT3 pathway in TNBC therapeutics, evaluating the benefits and limitations of active inhibitors and proteolysis-targeting chimeras in TNBC treatment. The aim is to facilitate the development of novel small-molecule compounds that target TNBC effectively. Ultimately, this work seeks to contribute to enhancing therapeutic efficacy for patients with TNBC.
ABSTRACT
Objectives: Intravenous thrombolysis therapy (IVT) with recombinant tissue plasminogen activator has proven to be a beneficial treatment for acute ischemic stroke (AIS) patients when administered within 4.5 h after a stroke. This study aimed to investigate an available and inexpensive predictive tool for early neurological deterioration in AIS. Methods: Patients admitted to our department with acute stroke who were given IVT with recombinant tissue plasminogen activator within 4.5 h of stroke onset were included in the study. The NIH stroke scale (NIHSS) was used to assess patients' neurological state prior to IVT and for 24 h after. Early neurological deterioration was defined as occurring if the NIHSS total score increased by ≥ 4 or the NIHSS individual score increased by ≥ 2 compared to baseline. Patients were randomly assigned to training or validation cohorts. Results: Of the 266 AIS patients receiving IVT who were screened, 217 were deemed eligible for the study. Multivariate logistic regression analysis identified smoking history, NIHSS score, homocysteine level, and neutrophil to lymphocyte ratio as independent factors for predicting early neurological deterioration. ROC analysis was used to assess the quality of the resulting nomogram. The AUC for the training dataset was 0.826 (95 % CI, 0.719-0.932), and for the validation dataset was 0.887 (95 % CI, 0.763-1.000). Conclusion: The robustness of this nomogram suggests that it may be a reliable tool for evaluating the progression of AIS after IVT.
ABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.
