[Research Progress in the Efficacy and Safety of ALK Inhibitors 
in the Treatment of NSCLC Brain Metastasis].

Lung cancer is one of the most lethal malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 80%-85% of all pathological types. Approximately 30%-55% of NSCLC patients develop brain metastases. It has been reported that 5%-6% of patients with brain metastases harbor anaplastic lymphoma kinase (ALK) fusion. ALK-positive NSCLC patients have shown significant therapeutic benefits after treatment with ALK inhibitors. Over the past decade, ALK inhibitors have rapidly evolved and now exist in three generations: first-generation drugs such as Crizotinib; second-generation drugs including Alectinib, Brigatinib, Ceritinib, and Ensartinib; and third-generation drugs like Lorlatinib. These drugs have exhibited varying efficacy in treating brain metastases in ALK-positive NSCLC patients. However, the numerous options available for ALK inhibition present a challenge for clinical decision-making. Therefore, this review aims to provide clinical guidance by summarizing the efficacy and safety of ALK inhibitors in treating NSCLC brain metastases.
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Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis.

Purpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib's treatment response and outcome were also explored. Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.

Selecting an Appropriate Experimental Animal Model for Cholangiocarcinoma Research.

Cholangiocarcinoma (CCA) is a highly aggressive biliary tree malignancy with intrahepatic and extra-hepatic subtypes that differ in molecular pathogeneses, epidemiology, clinical manifestations, treatment, and prognosis. The overall prognosis and patient survival remains poor because of lack of early diagnosis and effective treatments. Preclinical in vivo studies have become increasingly paramount as they are helpful not only for the study of the fundamental molecular mechanisms of CCA but also for developing novel and effective therapeutic approaches of this fatal cancer. Recent advancements in cell and molecular biology have made it possible to mimic the pathogenicity of human CCA in chemical-mechanical, infection-induced inflammatory, implantation, and genetically engineered animal models. This review is intended to help investigators understand the particular strengths and weaknesses of the currently used in vivo animal models of human CCA and their related modeling techniques to aid in the selection of the one that is the best for their research needs.

Methylselenocysteine Potentiates Etoposide-Induced Cytotoxicity by Enhancing Gap Junction Activity.

Homomeric or heteromeric connexin (Cx) hemichannels-composed gap junction (GJ) intercellular channel can mediate direct cell-to-cell communication. Accumulating studies indicate that GJs potentiate the cytotoxicity of antitumor drugs in malignant cells. Methylselenocysteine (MSC), a selenium compound from garlic, has been reported to modulate the activity of antineoplastic drugs, but the underlying mechanism remains unclear. This study investigates the efficacy of MSC on chemotherapeutic drugs-induced cytotoxicity and the relationship between this effect and the regulation of GJ function by MSC. Firstly, a doxycycline-regulated HeLa cell line expressing heteromeric Cx26/Cx32 was used as a tool. Etoposide, but not cisplatin or 5-fluorouracil, showed remarkable cytotoxicity in high-density (with GJ formation) cultures than in low-density (without GJ formation) in transformed HeLa cells. And cell density had no effect on etoposide-mediated cytotoxicity in the absence of Cx expression. MSC substantially enhanced etoposide-induced cytotoxicity, and this effect was only detected in the presence of functional GJs. Subsequently, MSC potentiated structural Cx expression as evidenced by increased dye coupling, but no alteration in Cx mRNA expression level in either transformed or primary cancer cell lines. Finally, a redox mechanism involving glutathione (GSH) was found to be related to the posttranscriptional modulation of Cx expression by MSC in HeLa cells. In conclusion, we provide the novel finding that MSC increases etoposide-mediated cytotoxicity by enhancing GJ activity, due to elevated Cx expression through a GSH-dependent posttranscriptional mechanism. More generally, the study highlights potential benefit of the combination of GJ modulators and chemotherapeutic agents in anticancer treatment.

General and Efficient Copper-Catalyzed Oxazaborolidine Complex in Transfer Hydrogenation of Isoquinolines under Mild Conditions.

A general and efficient method for copper-catalyzed transfer hydrogenation of isoquinolines with an oxazaborolidine-BH3 complex, under mild reaction conditions, is successfully developed. A broad range of isoquinolines has been reduced to the corresponding products with 61-85% yields. The method is applied to the synthesis of biologically active tetrahydrosioquinoline alkaloid (±)-norlaudanosine in 62% yield, which is the key precursor for the preparation of (±)-laudanosine, (±)-N-methyl-laudanosine, and (±)-xylopinine in one or two steps.

Chetomin, a Hsp90/HIF1α pathway inhibitor, effectively targets lung cancer stem cells and non-stem cells.

Non-small cell lung cancer (NSCLC) remains recalcitrant to effective treatment due to tumor relapse and acquired resistance. Cancer stem cells (CSCs) are believed to be one mechanism for relapse and resistance and are consequently considered promising drug targets. We report that chetomin, an active component of Chaetomium globosum, blocks heat shock protein 90/hypoxia-inducible factor 1 alpha (Hsp90/HIF1α) pathway activity. Chetomin also attenuated sphere-forming, a stem cell-like characteristic, of NSCLC CSCs (at ~ nM range) and the proliferation of non-CSCs NSCLC cultures and chemoresistant sublines (at ~ µM range). At these concentrations, chetomin exerted a marginal influence on noncancerous cells originating from several organs. Chetomin markedly decreased in vivo tumor formation in a spontaneous KrasLA1 lung cancer model, flank xenograft models, and a tumor propagation flank implanted model at doses that did not produce an observable toxicity to the animals. Chetomin blocked Hsp90/HIF1α pathway activity via inhibiting the Hsp90-HIF1α binding interaction without affecting Hsp90 or Hsp70 protein levels. This study advocates chetomin as a Hsp90/HIF1α pathway inhibitor and a potent, nontoxic NSCLC CSC-targeting molecule.

High STRN Expression Promotes HCC Invasion and Migration but Not Cell Proliferation or Apoptosis through Facilitating Epithelial-Mesenchymal Transition.

A STRN-ALK fusion protein has been recently identified as a potential therapeutic target in multiple cancers; however, the role of STRN alone in regulating the biological function of hepatocellular carcinoma (HCC) remains unclear. In this study, we firstly detected an overexpression of STRN in HCC tissues compared to that in adjacent nontumour (ANT) tissues through IHC analysis, and the expression level of this protein was positively correlated with lymph node metastasis and TNM stage. In vitro, high expression of STRN was also confirmed in different HCC cell lines, and regulation of STRN expression in Huh7 cells did not significantly affect tumour cell proliferation or apoptosis but was positively correlated with tumour cell invasion and migration capacities. Moreover, both the knockdown and overexpression of STRN in Huh7 cells can lead to cell morphological changes that are accompanied with an alteration of epithelial-mesenchymal transition (EMT) molecular markers E-cadherin and Vimentin. Finally, STRN was further proved to be negatively related to E-cadherin expression but positively related to Vimentin expression in human HCC tissue samples. Taken together, STRN is upregulated in HCC and acts as a tumour promoter regulating cell invasion and migration through facilitating the EMT process.

Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT.

Background: Oxaliplatin (OXA)-based chemotherapy is critical in the management of advanced hepatocellular carcinoma (HCC); however, acquired drug resistance has largely restricted its clinical efficacy. This study aims to explore the key mechanisms and regulatory factors determining chemosensitivity in HCC. Methods: We developed OXA-resistant (OR) HCC cells and used multiple methods, including real-time RT-PCR, Western blot, immunofluorescence, transwell invasion assay, wound-healing assay, MTT assay, gene transfection, and immunohistochemistry to achieve our goals. Results: We found that OR HCC cells showed a typical epithelial-mesenchymal transition (EMT) phenotype. Meanwhile, the expression of Cx32, a major member of the liver connexin (Cx) family, was lowly expressed in OR HCC cells. Downregulation of Cx32 in parental HCC cells led to EMT induction and thereby reduced OXA cytotoxicity, while Cx32 upregulation in OR HCC cells could reverse the EMT phenotype and partially restore chemosensitivity to OXA. Finally, in human HCC tissue samples, Cx32 was positively correlated with the expression of the EMT marker E-cadherin and negatively correlated with the expression of Vimentin. Conclusion: Our findings demonstrated that downregulation of Cx32 may be an important determinant for HCC cells to acquire EMT-related acquired drug resistance to OXA, and targeting Cx32 could be a novel strategy to overcome OXA resistance in HCC.

The circRNA circP4HB promotes NSCLC aggressiveness and metastasis by sponging miR-133a-5p.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) continues to top the list of cancer mortalities worldwide. The role of circular RNAs (circRNAs) in tumorigenesis has been increasingly appreciated, although it is relatively unexplored in NSCLC. Herein, we report on the role of circP4HB in NSCLC. METHODS: First, we evaluated circP4HB levels in patient-derived NSCLC tissue versus paired healthy samples. Next, we conducted experiments in vitro in NSCLC cell-lines and in vivo in a murine xenograft NSCLC model to assess the impact of circP4HB on epithelial-mesenchymal transition (EMT) in vitro and metastasis in vivo. The downstream impact of circP4HB on the microRNA miR-133a-5p, and its target the EMT marker vimentin, were also evaluated. RESULTS: NSCLC tumor specimens exhibited higher circP4HB levels in comparison to paired healthy lung samples and was associated with metastatic disease and poorer survival. circP4HB promoted EMT and vimentin expression in vitro and xenograft metastasis in vivo through sequestration of miR-133a-5p. CONCLUSION: circP4HB enhances EMT and metastatic disease through miR-133a-5p sequestration, leading to upregulation of vimentin. Therefore, these findings advocate targeting the circP4HB/miR-133a-5p/vimentin axis as a potential therapeutic option for NSCLC patients.