tbuckley/cabot-search huggingface dataset:
Abstract 5796: Therapeutic effects of statins against lung adenocarcinoma via mutant p53 mediated apoptosis
Authors: Cheng-wei Chou, Ching-Heng Lin, Tzu-Hung Hsiao, Chia-Chien Lo, Chih-Ying Hsieh, Cheng-Chung Huang, Yuh-Pyng Sher
Journal: Cancer Research (2020)

Abstract Introduction The p53 gene is well known as an important tumor suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumor effects of statins via inhibition of the mevalonate pathway. However, the cancer prevention and protection effects of statinsin population-based studies are controversial. Previous population-based studies have shown protective effects of statins in advanced lung cancer patients; however, the effects in early lung cancer patients are unclear. Methods We investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database retrospectively, mainly focusing on early-stage lung cancer. Cell viability, lipid raft changes, and motile activity from simvastatin-treated cell lines were examined to determine the effect of simvastatin under different p53 mutations. Apoptotic pathways and autophagy in lung cancer cells treated with simvastatin were analyzed using a western blot assay. Results Statin treatments reduced the 5-year mortality (odds ratio, 0.43; 95% confidence interval [CI], 0.37-0.49;P&amp;lt; 0.001) in this population-based study. Simvastatin inhibited cell growth, especially in mutant p53 lung cancer cell lines. Significantly higher levels of cellular apoptosis and decreased lipid rafts were shown in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased activity of the caspase-dependent apoptotic pathway in lung cancer cells containing mutant p53. In addition, simvastatin reduced migration in cells with a mutated p53 gene. Conclusion This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Simvastatin induced cellular apoptosis and regulated lipid raft content; further, motile activity was reduced in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits. Citation Format: Cheng-wei Chou, Ching-Heng Lin, Tzu-Hung Hsiao, Chia-Chien Lo, Chih-Ying Hsieh, Cheng-Chung Huang, Yuh-Pyng Sher. Therapeutic effects of statins against lung adenocarcinoma via mutant p53 mediated apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5796.
Abstract 2343: The incidence of BRAF mutation in non-small cell lung cancers is low in Korean patients
Authors: Ahrong Kim, Hyo Yeong Ahn, Chang Hun Lee, Young Dae Kim, Min Ki Lee, Yeon Joo Jeong, So Jeong Lee
Journal: Cancer Research (2020)

Abstract Introduction: BRAF mutation is present in about 8% of all cancer. Oncogenic activity of BRAF V600E mutation was established in lung cancers. Dabrafenib and trametinib combination therapy is preferred first line therapy for advanced or metastatic lung cancer with BRAF V600E mutation. However, there is only little basic knowledge of BRAF mutational status among Korean population. In this study, BRAF mutation, particularly BRAF V600E mutational status was explored among Korean non-small cell lung cancer patients. The clinical and pathologic characteristics of BRAF V600E mutation in non-small cell lung cancers were also investigated. Materials and Methods: The final cohort was 378 cases of primary non-small cell lung cancers. Fromalin-fixed paraffin embedded (FFPE) tissue blocks were used. PNA-mediated clamping PCR for BRAF V600, BRAF V600E real-time PCR and immunohistochemistry for mutation specific monoclonal antibody of Ventana VE1 were performed on all 378 cases of non-small cell lung cancers. For positive cases, direct sequencing was performed for validation. Results: BRAF V600 mutation was detected in five cases using PNA clamping method among 378 non-small cell carcinoma cases. By using BRAF real-time PCR, a BRAF V600E mutation was detected in 3 patients among total 378 cohort. There were 2 discordant cases between PNA clamping and real-time PCR. On immunohistochemistry, 3 patients showed positive staining for tumor cytoplasm and all positive cases also had positive results in real-time PCR. Direct Sanger sequencing was done in 5 cases that had any positive results for 3 methods. The results of Sanger sequencing was the same with those of real-time PCR and immunohistochemistry. Direct sequencing using PAN PCR product was performed on 2 negative cases for validation. On sequencing using PNA clamping PCR product, all cases showed mutation for BRAF gene other than V600E genotype. Finally, there were 3 cases (0.8%) of BRAF V600E mutation and 2 cases of BRAF mutation (0.5%) other than V600E genotype. Among BRAF mutated patients, there were 2 never smokers and 3 ever smokers. All patients harboring BRAF mutation had no concomitant EGFR or ALK aberrations. Conclusion: BRAF mutation incidence is relatively lower than that of Western data set and similar to that of Japanese report. Immunohistochemistry for Ventana VE1 antibody can be a useful screening method to detect BRAF V600E mutation. Citation Format: Ahrong Kim, Hyo Yeong Ahn, Chang Hun Lee, Young Dae Kim, Min Ki Lee, Yeon Joo Jeong, So Jeong Lee. The incidence of BRAF mutation in non-small cell lung cancers is low in Korean patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2343.
Abstract 575: Disulfiram plus copper synergizes with etoposide for the treatment of Merkel cell carcinoma
Authors: Natasha Tremayne Hill, Tara Gelb, Dan Urban, Tyler Kellenberger, Matthew Hall, Isaac Brownell
Journal: Cancer Research (2020)

Abstract Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with limited treatment options. Currently two immunotherapies are approved for the treatment of MCC, the PD-L1 inhibitor avelumab and the PD-1 inhibitor pembrolizumab. Unfortunately, these treatments only have durable benefit for less than half of patients that can be treated with immunotherapy. Therefore, new and effective treatments are needed for MCC. To address this, we conducted a high-throughput drug screening of ~4,000 small molecules. Our drug screen identified disulfiram (DSF), an aldehyde dehydrogenase inhibitor used in the treatment of alcoholism, as an agent that selectively reduced MCC cell viability. Recent studies suggest that DSF complexed with copper can have anti-cancer effects. Consistent with this, the addition copper at physiological levels increased the potency of DSF in MCC cells lines. Next, we demonstrated that disulfiram combined with copper synergized with the topoisomerase II inhibitor etoposide, lowering the effective dose of etoposide required to reduce MCC cell viability. Mechanistically, combining DSF, copper and etoposide was cytotoxic but did not induce apoptosis in MCC cell lines. This combination increased the formation of double stranded DNA breaks while disulfiram plus copper induced autophagy, which could mechanistically be an indication of immunogenic cell death signaling. Taken together, our data suggest that disulfiram combined with copper and etoposide could be repurposed for the effective treatment of advanced MCC. One strong advantage of this combination is that all agents can be given orally and at dosages with minimal adverse effects. Citation Format: Natasha Tremayne Hill, Tara Gelb, Dan Urban, Tyler Kellenberger, Matthew Hall, Isaac Brownell. Disulfiram plus copper synergizes with etoposide for the treatment of Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 575.
Abstract 5070: LIN28A-mediated repression of Let-7a is involved in resistin-induced STAT3 upregulation in breast cancer cells and supports growth and stemness properties
Authors: Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Haseeb Zubair, Ajay P. Singh, Seema Singh
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and continues to be the second leading cause of cancer-related death in women in the United States. Dysregulation of Let-7 family microRNAs is observed in BC and associated with disease pathogenesis. Previously, we reported a significant increase in serum levels of resistin in BC patients as compared to the healthy individuals. Moreover, this increase was significantly greater in BC patients of African American background as compared to those of European descent. We also demonstrated that treatment of BC cells with resistin promoted their growth, aggressiveness, stemness and chemoresistance by inducing the expression and activation of STAT3. Here we present data to show that resistin induces STAT3 expression in BC cells in a LIN28A and Let-7a-dependent manner. Treatment of BC cells with resistin led to the most significant decrease in the expression of Let-7a among other Let-7 family members. Furthermore, resistin treatment also induced the expression of LIN28A at both transcript and protein levels and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity and sphere-forming ability of BC cells. Restoration of Let-7a suppressed the expression of several genes associated with growth, survival and stemness. Ingenuity Pathway Analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. Immunoblot analysis confirmed that Let-7a restoration dramatically suppressed basal as well as resistin-induced STAT3 expression. STAT3 regulation by Let-7a was further confirmed 3'UTR-reporter assay. Taken together, our findings demonstrate a novel resistin/LIN28A/Let-7a/STAT3 signaling axis regulating the growth and stemness phenotypes of BC cells. Citation Format: Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Haseeb Zubair, Ajay P. Singh, Seema Singh. LIN28A-mediated repression of Let-7a is involved in resistin-induced STAT3 upregulation in breast cancer cells and supports growth and stemness properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5070.
Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8
Authors: Zhao J. Lyu, Ying Wang, Jin L. Huang, Miao Chen, Sha Y. Wu, Qian Yan, Yu Zhang, Ying Tang, Chen Jiang, Lei Li, Yi Z. Jia, Yu C. Liu, Hong B. Mei, Feng Wang, Ren H. Li, Ya C. Chen, Xiang Lin, Zhi M. Cai, Xin Y. Guan
Journal: Molecular Therapy (2020)

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors. Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.
Abstract 388: Antigen-loaded Fe3O4 nanoparticles for the stimulation and tracking of dendritic cell based vaccine
Authors: Yafei Qi, Yang Du, Jie Tian, Zhengyu Jin, Yuan Li
Journal: Cancer Research (2020)

Abstract Background and purpose:Dendritic cells (DCs), as the antigen-presenting cells, play important roles in immunotherapy. The antigen uptake, cross-presentation, maturation and lymph node migration of DCs are crucial steps for immune system activation. Herein, we aim to construct a novel Fe3O4@SIINFEKL-TAT nanoparticle, which mainly consists of Fe3O4 nanosphere core and transmembrane peptide TAT on the shell, and also with the model antigen SIINFEKL peptide, a peptide of the ovalbumin (OVA) antigen. To explore the feasibility of Fe3O4@OVA-TAT to stimulate the maturation of DCs and the in vivo tracking of DCs using MRI-MPI dual-modal imaging. Methods: On the one hand, TAT peptide facilitates the uptake of the Fe3O4@OVA-TAT nanoparticles into DCs, and subsequently the OVA antigens are cross-presented to stimulate DCs maturation. On the other hand, Fe3O4 nanosphere core can function for both magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) dual-modality imaging, which can realize the in vivo dynamic tracking of DCs migration to lymph nodes. Results: The laser confocal microscope experiments confirmed that Fe3O4@OVA-TAT can be taken up through the early endosome-late endosome pathway, but the fluorescent signal of the imaging probe is located outside the lysosome after 4 h, which suggested that Fe3O4@OVA-TAT could escape lysosomal uptake and cross-present. The CD80 and CD86 flow cytometry results showed that Fe3O4@OVA-TAT, LPS, and OVA can stimulate 90%, 60%, and 40% of BMDCs to mature, respectively (p &amp;lt; 0.05). After the Fe3O4@SIINFEKL-TAT labeled DCs was injected into the mouse footpad, the MRI T2WI signal decreased and the MPI signal increased in the popliteal and inguinal lymph nodes 24 h post-injection, suggesting that our DC vaccine can efficiently migrate to the lymph node. Conclusions: Our study showed that Fe3O4@SIINFEKL-TAT nanoparticles can stimulate and trace DCs in in vivo, which pave the way for further development and precision application of DC vaccine in both preclinical and clinical settings. Citation Format: Yafei Qi, Yang Du, Jie Tian, Zhengyu Jin, Yuan Li. Antigen-loaded Fe3O4 nanoparticles for the stimulation and tracking of dendritic cell based vaccine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 388.
REPLY:
Authors: Alexander J. Kovalic, Glen Huang, Paul J. Thuluvath, Sanjaya K. Satapathy
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. We appreciate Gao et al. for their interest in our recent article on the association between elevated liver biochemistries and severe coronavirus disease 2019 (COVID‐19) infection. We would like to address their comments to further elucidate the interpretation of our findings. First, we included studies written in English. For the two studies in question (Peng and Liu), the full text and raw data were freely translated upon online viewing of these articles and therefore were included in our pooled meta‐analysis. Second, our outlined search strategy will encompass all studies reporting raw data on liver biochemistries as aspartate aminotransferase or alanine aminotransferase, which was our primary focus. Third, we recognize the significant heterogeneity across certain pooled analyses among the studies. We have listed this specifically in the Discussion section regarding limitations of this article. Fourth, we certainly recognize the limited sample size among the data available at the time of this meta‐analysis. See further discussion below as well as within our article. Fifth, as discussed in the Methods section, we chose to assess the degree of bias using the Newcastle‐Ottawa Scale, which is a well‐validated tool to assess the risk of bias across nonrandomized studies. Sixth, we did not use a designated research protocol in the formulation of this article. However, we have conducted this article according to the standards for systematic reviews and meta‐analyses and current journal guidelines. Seventh, although it is true that the current Cochrane Handbook for Systematic Reviews of Interventions states the power of the Egger's test is low when there are fewer than 10 studies, we chose to include this and corresponding funnel plots in our analysis to provide at least some barometer of publication bias. Overall, this systematic review and meta‐analysis was done early (before March 22, 2020) when almost all the COVID‐19 pandemic data originated from China. We have acknowledged the limitations of our study in the Discussion section. Limited sample size and heterogeneity of the studies are a reflection of early studies coming out of China. Despite these limitations, the external validity of this systematic review and meta‐analysis remains strong. Since our article was submitted, many other meta‐analyses have been performed and have confirmed our findings.(1‐3) We sincerely hope that more studies from Europe and North America will shed additional information on liver‐test abnormalities and COVID‐19 infections.
Abstract 5293: A molecular classification of gastric cancer in Chilean patients
Authors: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido
Journal: Cancer Research (2020)

Abstract Objective: Incidence and mortality rates of gastric cancer (GC) are characterized by their geographical heterogeneity. In Chile, GC is the leading cause of cancer death. To date, GC patients' response to standard therapies remains limited. A molecular classification of GCs may deliver better stratifications. Herein, we obtained clinical data, protein expression and genetic profiles in a cohort of Chilean patients and present a molecular classification that correlated with overall survival (OS) rates. Methods: A total of 71 patients were included. Clinical data were obtained from medical records; protein expression was analyzed by a Tissue MicroArray. We also performed Next Generation Sequencing to assess p53 status (WT or Mut). Supervised clustering was used to generate a molecular classification. Kaplan-Meier method was used to calculate OS. Hazard ratio was calculated by Cox regression. Results: We defined 5 GC subgroups: Epstein-Barr virus+ (EBV, n=9; 13%), Microsatellite Instable (MSI, n=9; 13%), E-cadherin loss (EMT-like, n=12; 17%). The remaining patients (those MSS-/EBV-/not EMT-like) were classified either as p53 WT (n=21; 30%) or p53 Mutated (n=20; 28%). According to subgroups, 5-year survival rates were: MSI=77,8%; EBV=43.2%; p53WT=43.5%; p53Mut=25% and EMT-like=16.7%. Hazard ratios for p53Mut and EMT-like were 5.1 (IC 95%: 1.16-22.41; p=0.031) and 6.81 (IC 95%: 1.48-31.24; p=0.014), respectively against the MSI group used as reference. This association is maintained in a multivariate model using age, gender and stage. Conclusions: Our study defined 5 GC subgroups. These are associated to OS rates. EMT-like and p53Mut subgroups displayed poorer survival. Future studies should explore actionable targets in these subsets in order to improve their survival. Citation Format: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido. A molecular classification of gastric cancer in Chilean patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5293.
In preparation for a COVID-19-influenza double epidemic
Authors: Vijay Shankar Balakrishnan
Journal: The Lancet Microbe (2020)

WHO reports the worldwide circulation of influenza virus to be much lower than expected for this time of the year. With over 22 million cases and nearly 800 000 deaths due to COVID-19 reported globally at the time of writing and the northern hemisphere entering the influenza season, this low circulation of influenza virus could be matters of both reassurance and concern, warns WHO. The decreased circulation of the virus is likely largely attributable to the mandatory physical distancing and hygiene protocols implemented to curb the spread of the severe acute respiratory syndrome coronavirus 2.