Lung Carcinoma
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2021 ◽  
Xingjun Meng ◽  
Zhihui Cao ◽  
Renfeng Liu ◽  
Kai Zheng ◽  
Shuai Ding ◽  

Abstract It is widely accepted that tumor metastasis is the dominant factor leading to cancer-related death. Tumor metastasis is mediated by cell invasion, blood circulation and lymphatic circulation. Paclitaxel, as a common anti-tumor drug and a mitotic inhibitor, promotes microtubule assembly and inhibits microtubule depolymerization. In addition, ticagrelor, an anti-platelet drug, is used to treat acute coronary syndrome. An increasing numbers of studies have reported that platelets can facilitate tumor metastasis. Therefore, inhibiting the effects of platelets can serve as a novel therapeutic strategy for cancer. To explore the effect of anti-tumor and anti-platelet drugs on tumor progression, the murine melanoma cell line, B16F10, and Lewis Lung carcinoma (LLC) cells were treated with paclitaxel and/or ticagrelor. Interestingly, the results demonstrated that paclitaxel and ticagrelor could not only suppress the proliferation, migration and invasion of B16F10 and LLC cells, but they could also prevent tumor metastasis to the lungs. Furthermore, the inhibitory effect of paclitaxel and ticagrelor was more apparent when both drugs were used in combination. Collectively, the current study demonstrated that the combination of paclitaxel and ticagrelor could be considered as a potential anti-tumor therapy approach.

2022 ◽  
Vol 46 (2) ◽  
pp. 417-431
LI PAN ◽  

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2082
Yuyong Zhou ◽  
Karen A. Gammeltoft ◽  
Andrea Galli ◽  
Anna Offersgaard ◽  
Ulrik Fahnøe ◽  

We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.

Materials ◽  
2021 ◽  
Vol 14 (20) ◽  
pp. 6114
Iryna Horak ◽  
Svitlana Prylutska ◽  
Iryna Krysiuk ◽  
Serhii Luhovskyi ◽  
Oleksii Hrabovsky ◽  

Effective targeting of metastasis is considered the main problem in cancer therapy. The development of herbal alkaloid Berberine (Ber)-based anticancer drugs is limited due to Ber’ low effective concentration, poor membrane permeability, and short plasma half-life. To overcome these limitations, we used Ber noncovalently bound to C60 fullerene (C60). The complexation between C60 and Ber molecules was evidenced with computer simulation. The aim of the present study was to estimate the effect of the free Ber and C60-Ber nanocomplex in a low Ber equivalent concentration on Lewis lung carcinoma cells (LLC) invasion potential, expression of epithelial-to-mesenchymal transition (EMT) markers in vitro, and the ability of cancer cells to form distant lung metastases in vivo in a mice model of LLC. It was shown that in contrast to free Ber its nanocomplex with C60 demonstrated significantly higher efficiency to suppress invasion potential, to downregulate the level of EMT-inducing transcription factors SNAI1, ZEB1, and TWIST1, to unblock expression of epithelial marker E-cadherin, and to repress cancer stem cells-like markers. More importantly, a relatively low dose of C60-Ber nanocomplex was able to suppress lung metastasis in vivo. These findings indicated that сomplexation of natural alkaloid Ber with C60 can be used as an additional therapeutic strategy against aggressive lung cancer.

2021 ◽  
Vol 11 (1) ◽  
Michael Peer ◽  
Sharbel Azzam ◽  
Arnold Cyjon ◽  
Rivka Katsnelson ◽  
Henri Hayat ◽  

AbstractThe aim of this study was to identify predictors of postoperative outcome and survival of locally advanced non-small cell lung carcinoma (NSCLC) resections after neoadjuvant chemotherapy or chemoradiation. Medical records of all patients with clinical stage III potentially resectable NSCLC initially treated by neoadjuvant chemotherapy or chemoradiation followed by major pulmonary resections were retrieved from the databases of four Israeli Medical Centers between 1999 to 2019. The 124 suitable patients included, 86 males (69.4%) and 38 females (30.6%), with an average age of 64.2 years (range 37–82) and an average hospital stay of 12.6 days (range 5–123). Complete resection was achieved in 92.7% of the patients, while complete pathologic response was achieved in 35.5%. The overall readmission rate was 16.1%. The overall 5-year survival rate was 47.9%. One patient (0.8%) had local recurrence. Postoperative complications were reported in 49.2% of the patients, mainly atrial fibrillation (15.9%) and pneumonia (13.7%), empyema (10.3%), and early bronchopleural fistula (7.3%). The early in-hospital mortality rate was 6.5%, and the 6-month mortality rate was 5.6%. Pre-neoadjuvant bulky mediastinal disease (lymph nodes > 20 mm) (p = 0.034), persistent postoperative N2 disease (p = 0.016), R1 resection (p = 0.027), preoperative N2 multistation disease (p = 0.053) and postoperative stage IIIA (p = 0.001) emerged as negative predictive factors for survival. Our findings demonstrate that neoadjuvant chemotherapy or chemoradiation in locally advanced potentially resectable NSCLC, followed by major pulmonary resection, is a beneficial approach in selected cases.

eLife ◽  
2021 ◽  
Vol 10 ◽  
E Josue Ruiz ◽  
Adan Pinto-Fernandez ◽  
Andrew P Turnbull ◽  
Linxiang Lan ◽  
Thomas M Charlton ◽  

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. Here, we show that genetic inactivation of Usp28 induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN and Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

Li Cheng ◽  
Todd Creasy ◽  
Fernanda Pilataxi ◽  
Lydia Greenlees ◽  
Luis Vence ◽  

AbstractThe rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened the long-term forecast for many cancer patients. However, the specific genomic and proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We treated four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with these ICB therapies. All four tumors showed a robust increase in interferon gamma (IFN-γ) production (100–300% higher than isotype control) in both D- and D + T-treated tumors. Three of the four tumors showed additional increases in IFN-γ production with D + T compared with D (40–70%). A substantial reduction in interleukin 10 (IL-10) was also found in three of the four tumors (reduced to 4–8%) in response to D and D + T. Conventional CD4 + /CD8 + populations and T cell activation markers increased after D and D + T treatment. D and D + T upregulated multiple IPA pathways involving T cell activation. D + T resulted in additional upregulation of Th1/Th2 pathways through a different set of genes, as well as greater reduction in genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness. Our results demonstrated that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of EMT, angiogenesis, and cancer stemness warrants further evaluation in a larger set of tumors.

2021 ◽  
pp. 487-491
Aya Yamashita ◽  
Eijiro Akasaka ◽  
Hajime Nakano ◽  
Daisuke Sawamura

A 67-year-old man with non-small-cell lung carcinoma was referred to our department because of a pruritic rash on his head and upper extremities. Prior to the development of the rash, he had received 4 cycles of combination therapy with pemetrexed, carboplatin, and pembrolizumab, followed by 2 cycles of pembrolizumab monotherapy. On physical examination, violaceous scaly erythema grouped on his scalp and upper extremities. Histologically, the scalp lesions demonstrated irregular acanthosis that formed a characteristic saw-tooth appearance with hypergranulosis and typical lichenoid tissue reaction. These findings suggested that the scalp lesions were lichen planus. Two-week administration of topical corticosteroid dramatically improved the rash. Immunotherapy with pembrolizumab, an anti-PD-1 antibody, can induce T-cell activation that results in various immune-related adverse effects such as lichenoid tissue reaction. However, lichen planus is generally found on the extremities and/or oral mucosa, and unlike in this case, the scalp is rarely affected. Although the exact mechanism underlying predominant scalp involvement is unknown, the present case indicates that anti-PD-1 therapy-induced lichen planus can develop not only on the extremities and oral mucosa but also on the scalp. Interestingly, the lesions were not induced by the combination of chemotherapy and pembrolizumab; rather, they occurred soon after initiation of pembrolizumab monotherapy. In the present case, pembrolizumab-induced T-cell activation which triggered lichenoid tissue reaction may have been suppressed by chemotherapy-induced immunosuppression. Dermatologists should have a thorough knowledge of the cutaneous lesions that manifest as irAEs of anti-PD-1 therapy.

2021 ◽  
Vol 11 ◽  
Naoki Yanagawa ◽  
Noriyuki Yamada ◽  
Ryo Sugimoto ◽  
Mitsumasa Osakabe ◽  
Noriyuki Uesugi ◽  

IntroductionDNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.MethodsA total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.ResultsOnly 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.ConclusionThe frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.

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