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Cancer Medicine Jun 2024Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore,...
AIM
Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs.
METHODS
This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed.
RESULTS
The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039).
CONCLUSIONS
DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.
Topics: Humans; Carcinoma, Hepatocellular; Male; Liver Neoplasms; Female; Antibodies, Monoclonal, Humanized; Retrospective Studies; Lung Neoplasms; Aged; Middle Aged; Feasibility Studies; Hemorrhage; Bevacizumab; Antineoplastic Combined Chemotherapy Protocols; Anticoagulants; Administration, Oral; Aged, 80 and over
PubMed: 38924675
DOI: 10.1002/cam4.7430 -
Environmental Toxicology Jun 2024Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy...
Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton's tyrosine kinase (BTK) plays a pivotal role in B-cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis-HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin-resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin-resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment.
PubMed: 38924303
DOI: 10.1002/tox.24368 -
Journal of Cellular and Molecular... Jun 2024IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH...
IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH databases. Different algorithms and R packages are used to perform various analyses. Here, in our comprehensive study on IL33 in HCC, we observed its differential expression across cancers, implicating its role in cancer development. The single-cell analysis highlighted its primary expression in endothelial cells, unveiling correlations within the HCC microenvironment. Also, the expression level of IL33 was correlated with patients survival, emphasizing its potential prognostic value. Biological enrichment analyses revealed associations with stem cell division, angiogenesis, and inflammatory response. IL33's impact on the immune microenvironment showcased correlations with diverse immune cells. Genomic features and drug sensitivity analyses provided insights into IL33's broader implications. In a pan-cancer context, IL33 emerged as a potential tumour-inhibitor, influencing immune-related molecules. This study significantly advances our understanding of IL33 in cancer biology. IL33 exhibited differential expression across cancers, particularly in endothelial cells within the HCC microenvironment. IL33 is correlated with the survival of HCC patients, indicating potential prognostic value and highlighting its broader implications in cancer biology.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Tumor Microenvironment; Prognosis; Gene Expression Regulation, Neoplastic; Interleukin-33; Biomarkers, Tumor
PubMed: 38923705
DOI: 10.1111/jcmm.18468 -
Cancer Medicine Jun 2024HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish...
OBJECTIVES
HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation.
MATERIALS AND METHODS
In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS).
RESULTS
In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490).
CONCLUSIONS
In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib.
Topics: Humans; Female; Retrospective Studies; Male; Middle Aged; Aged; Lung Neoplasms; Receptor, ErbB-2; Mutation; Acrylamides; Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Progression-Free Survival; Adult; Aminoquinolines; Immune Checkpoint Inhibitors; Bevacizumab; Aged, 80 and over
PubMed: 38923311
DOI: 10.1002/cam4.7335 -
Journal of Neuroinflammation Jun 2024The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for...
The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.
Topics: Nucleotidyltransferases; Membrane Proteins; Animals; Humans; Mice; Neuroinflammatory Diseases; Mice, Inbred C57BL; Choroidal Neovascularization; Signal Transduction; Mice, Knockout; Diabetic Retinopathy
PubMed: 38918759
DOI: 10.1186/s12974-024-03155-y -
Scientific Reports Jun 2024Natural killer (NK) cells play a key role in defense against Salmonella infections during the early phase of infection. Our previous work showed that the...
Natural killer (NK) cells play a key role in defense against Salmonella infections during the early phase of infection. Our previous work showed that the excretory/secretory products of Ascaris suum repressed NK activity in vitro. Here, we asked if NK cell functionality was influenced in domestic pigs during coinfection with Ascaris and Salmonella enterica serotype Typhimurium. Ascaris coinfection completely abolished the IL-12 and IL-18 driven elevation of IFN-γ production seen in CD16 + CD8α + perforin + NK cells of Salmonella single-infected pigs. Furthermore, Ascaris coinfection prohibited the Salmonella-driven rise in NK perforin levels and CD107a surface expression. In line with impaired effector functions, NK cells from Ascaris-single and coinfected pigs displayed elevated expression of the inhibitory KLRA1 and NKG2A receptors genes, contrasting with the higher expression of the activating NKp46 and NKp30 receptors in NK cells during Salmonella single infection. These differences were accompanied by the highly significant upregulation of T-bet protein expression in NK cells from Ascaris-single and Ascaris/Salmonella coinfected pigs. Together, our data strongly indicate a profound repression of NK functionality by an Ascaris infection which may hinder infected individuals from adequately responding to a concurrent bacterial infection.
Topics: Animals; Killer Cells, Natural; Ascariasis; Coinfection; Swine; Swine Diseases; Salmonella Infections, Animal; Salmonella typhimurium; Ascaris suum; Interferon-gamma; Perforin; Interleukin-12; T-Box Domain Proteins; Interleukin-18
PubMed: 38918457
DOI: 10.1038/s41598-024-64497-4 -
Nature Cancer Jun 2024Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations... (Review)
Review
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future.
Topics: Humans; Neovascularization, Pathologic; Neoplasms; Angiogenesis Inhibitors; Animals; History, 20th Century; Molecular Targeted Therapy
PubMed: 38918437
DOI: 10.1038/s43018-024-00780-7 -
Bioorganic & Medicinal Chemistry Letters Jun 2024Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination of the phthalimide moiety of...
Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination of the phthalimide moiety of immunomodulatory drugs (IMiDs) has a strong beneficial effect on the ability to inhibit angiogenesis. The neomorphic activity of E3 ligase complexes is induced by the binding of IMiDs to cereblon. We investigated that a set of eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce the degradation of neomorphic substrates (IKZF3, GSPT1, CK1α, SALL4). Hence, the antiangiogenic activity of fluorinated IMiDs was not triggered by neosubstrate degradation features. A fluorine scanning of non-traditional IMiDs of the benzamido glutarimide chemotype was performed. By measuring the endothelial cell tube formation, no angiogenesis inhibitors were identified, confirming the narrow structure-activity window of IMiD-induced antiangiogenesis.
PubMed: 38917956
DOI: 10.1016/j.bmcl.2024.129858 -
Naunyn-Schmiedeberg's Archives of... Jun 2024As a cardiovascular disease, coronary heart disease (CHD) is characterized by poor prognosis and increasing morbidity and mortality rates. Echinacoside (ECH) can...
Echinacoside activates Nrf2/PPARγ signaling pathway to modulate mitochondrial fusion-fission balance to ameliorate ox-LDL-induced dysfunction of coronary artery endothelial cells.
As a cardiovascular disease, coronary heart disease (CHD) is characterized by poor prognosis and increasing morbidity and mortality rates. Echinacoside (ECH) can protect against multiple cardiovascular diseases due to its antioxidant and anti-inflammatory properties. However, the role of ECH in CHD remains unclear. In ECH-treated human coronary artery endothelial cells (HCAECs), cell viability, NO production, endothelial nitric oxide synthase (eNOS) expression, and angiogenesis ability were detected using cell counting kit-8 (CCK-8) assay, diaminofluorescein-FM diacetate (DAF-FM DA) staining, western blot, and tube formation assay, respectively. The activities of oxidative stress markers were detected using dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay and corresponding assay kits. Cell apoptosis was detected utilizing flow cytometry and caspase3 assay. Western blot was used to detect the expressions of Nrf2/PPARγ signaling pathway- and mitochondrial dynamics-related proteins. Mitochondrial membrane potential and mitochondrial fusion and fission were detected using JC-1 staining and immunofluorescence (IF) assay. In this study, ECH was found to revive the viability, ameliorate the endothelial dysfunction, suppress oxidative stress, and inhibit the apoptosis in ox-LDL-induced HCAECs via activating Nrf2/PPARγ signaling pathway, which were all abolished following the treatment of Nrf2 inhibitor ML385. It was also identified that ECH regulated mitochondrial fusion-fission balance in ox-LDL-induced HCAECs through the activation of Nrf2/PPARγ signaling pathway. In summary, ECH activated Nrf2/PPARγ signaling pathway to regulate mitochondrial fusion-fission balance, thereby improving ox-LDL-induced dysfunction of HCAECs.
PubMed: 38916831
DOI: 10.1007/s00210-024-03233-1 -
International Ophthalmology Jun 2024To assess the effectiveness of a switch to faricimab in individuals affected by DME and previously treated with aflibercept.
PURPOSE
To assess the effectiveness of a switch to faricimab in individuals affected by DME and previously treated with aflibercept.
METHODS
In this retrospective, single-center study, DME patients previously treated with at least 3 injections of aflibercept then switched to faricimab were enrolled. Best corrected visual acuity (BCVA) and central subfield thickness (CST) were recorded at baseline, at the time of the switch and at 6 months follow-up. At transition to faricimab, patients were categorized as "good visual responders" (≥ 5 letters from baseline) or "poor visual responders" (< 5 letters), and as "good anatomical responders" (any reduction in edema compared to baseline) or "poor anatomical responders" (no reduction or worsening of edema). Changes in BCVA and CST were recorded at 6 months after the switch to faricimab.
RESULTS
100 eyes of 100 patients (61 female, 61%) were switched to faricimab after a mean of 6.8 ± 3.3 aflibercept injections. At the 6 months follow-up, only "poor visual responders" (N = 62) demonstrated a meaningful increase in BCVA (Δswitch-6M = + 5 letters; P = 0.007), coupled with a reduction in CST (Δswitch-6M = - 67.9 µm; P = 0.004); participants with "poor anatomical response" upon transitioning exhibited a significant functional gain (Δswitch-6M = + 4.5 letters; p = 0.05) but limited CST enhancements (Δswitch-6M = - 95.1 µm; p = 0.05).
CONCLUSIONS
Faricimab shows a positive impact on anatomical and functional metrics in DME cases refractory to aflibercept.
Topics: Humans; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Female; Male; Retrospective Studies; Macular Edema; Diabetic Retinopathy; Intravitreal Injections; Visual Acuity; Middle Aged; Angiogenesis Inhibitors; Tomography, Optical Coherence; Follow-Up Studies; Aged; Treatment Outcome; Drug Substitution; Vascular Endothelial Growth Factor A
PubMed: 38916818
DOI: 10.1007/s10792-024-03226-2