tbuckley/cabot-search huggingface dataset:
Survival analysis for patients with cancer in Gaza applying for Israeli permits to exit the Gaza Strip for health care: a retrospective cohort study of patients from 2008 to 2017
Authors: Benjamin Bouquet, Francesco Barone-Adesi, Mohamed Lafi, Kathryn Quanstrom, Federica Riccardi, Henry V Doctor, Walaa Shehada, Juliana Nassar, Sali Issawi, Mahmoud Daher, Gerald Rockenschaub, Arash Rashidian
Journal: The Lancet (2021)
Abstract 3053: Armed oncolytic virus for treatment of pediatric diffuse intrinsic pontine glioma
Authors: Sumit Gupta, Virginia Laspidea, Juan Fueyo, Oren Becher, Teresa Nguyen, Dong Ho Shin, Hong Jiang, Sagar Sohoni, Xuejun Fan, Yanhua Yi, Joy Gumin, Frederick Lang, Candelaria Gomez-Manzano, Marta M. Alonso
Journal: Cancer Research (2021)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of pediatric death by brain tumors with a median survival of only 9 months, in spite of the current standard of therapy which includes radiation. The purpose of our study is to explore the use of oncolytic adenoviruses as a new therapeutic modality. Our group is leading a phase I clinical trial in naive DIPGs treated with the oncolytic adenovirus Delta-24-RGD, also named DNX-2401 (NCT03178032), which results are still pending. Of interest, clinical trials using Delta-24-RGD in adult gliomas resulted in encouraging results with long-term survivors and the presence of a strong anti-tumor immunity. In this study, we aim to test the effect of armed Delta-24-RGD with immune costimulatory ligands such as GITRL (Delta-24-GREAT) and OX-40L (Delta-24-RGDOX or DNX-2440) for the treatment of DIPGs. We used a panel of murine DIPG cell lines (NP53 and XFMA) to test the effect of these armed-oncolytic adenoviruses. Infectivity assay using an Ad-RGD-GFP vector and flow cytometry showed the expression of the ectopic GFP in more than 80% of the NP53 cells (50 MOIs) and XFMA cells (30 MOIs). Consistent results were obtained using flow cytometry and western blot to detect the expression of the ectopic ligands GITRL and OX-40L in these cultures. These cells were semipermissive for viral replication as assessed by the detection of the viral structural protein hexon in western blot analysis. Preliminary in vivo data using immunocompetent mice models where DIPG cells have been implanted into the pons showed a dose-dependent effect and the generation of immune memory. Our results suggest that oncolytic adenoviruses expressing positive immunocheckpoints might prove be a new effective modality for treating DIPG and hence, increase survival in children suffering this dismal disease. Citation Format: Sumit Gupta, Virginia Laspidea, Juan Fueyo, Oren Becher, Teresa Nguyen, Dong Ho Shin, Hong Jiang, Sagar Sohoni, Xuejun Fan, Yanhua Yi, Joy Gumin, Frederick Lang, Candelaria Gomez-Manzano, Marta M. Alonso. Armed oncolytic virus for treatment of pediatric diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3053.
Abstract 2388: p73 - lncRNA Fer1l4 axis plays a critical role in suppression of cancer cell migration, invasion and metastasis in a p73-dependent manner via inhibition of miR-1273g-3p
Authors: Apoorva Uboveja, Yatendra Kumar Satija, Fouzia Siraj, Chanchal Bareja, Daman Saluja
Journal: Cancer Research (2021)

Abstract p73 is a member of the p53 tumor suppressor family and exerts its tumor suppressor functions by suppressing metastasis. It is increasingly evident that long noncoding RNAs (lncRNAs) play a significant role in tumor suppression. The present study is aimed to identify novel lncRNAs that play a role in p73-mediated suppression of metastasis in colorectal cancer cells. Transcriptome analysis was performed to detect the differentially expressed lncRNAs in presence and absence of p73. Out of these, FER1L4 lncRNA was found to be significantly induced in a p73-dependent manner. p73 binding to FER1L4 promoter was confirmed through bioinformatic analysis, luciferase reporter, ChIP and site-directed mutagenesis assays. Knockdown of FER1L4 and p73 significantly increased the invasion and migration rate of colorectal cancer cells as confirmed by wound-healing assay. Knockdown of FER1L4 decreased the expression of E-cadherin and increased the expression of prominent EMT markers such as N-cadherin, Snail, Vimentin and Fibronectin. FER1L4 causes a G2/M cell cycle arrest in a p73-dependent manner in HCT116p53-/-p73+/+ cells and upon FER1L4kd, normal cell cycle progression was observed. Annexin V/PI and TUNEL apoptosis assays revealed that FER1L4 induced apoptosis in HCT116p53-/-p73+/+ cells with increase in time-dependent treatment of etoposide and FER1L4kd inhibited apoptosis even in the presence of p73. The protein expression level of pro-apoptotic genes such as Bad, Bax, Bik, Bim, BID, Bak and PUMA decreased upon FER1L4kd and p73kd, confirming that FER1L4 plays a role in p73 mediated apoptosis and cell cycle arrest. FER1L4 also sponges the expression of miR-1273g-3p, thus inhibiting its oncogenic role. RNA-In situ hybridization (RNA-ISH) confirmed the decreased expression of p73 and FER1L4 mRNA in 30 human metastatic CRC tissues as compared to 30 human non-metastatic CRC tissues. Taken together, we provide conclusive proof that p73 exerts its anti-metastatic function by inducing the expression of lncRNA FER1L4 in response to genotoxic stress. Citation Format: Apoorva Uboveja, Yatendra Kumar Satija, Fouzia Siraj, Chanchal Bareja, Daman Saluja. p73 - lncRNA Fer1l4 axis plays a critical role in suppression of cancer cell migration, invasion and metastasis in a p73-dependent manner via inhibition of miR-1273g-3p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2388.
Abstract 178: Desmosome mutations in melanoma promote cellular proliferation and disease progression
Authors: Maayan Baron, Trey Ideker
Journal: Cancer Research (2021)

Abstract Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in the epithelia and other tissues under mechanical stress. Aberrant desmosome expression is often associated with developmental diseases leading to impaired tissue integrity. Recently, similar findings have been reported in cancer; Mutations in desmosomes genes have been observed in various cancer types including skin cancer, head and neck and lung cancer, however mostly epigenetic alterations have been used to associate desmosomes as suppressors of tumor metastasis. Here, we report that desmosomes are frequently mutated in seven cancer types. In melanoma, we find that over 70% of tumors have non-synonymous mutations in desmosomes, and that the desmosome mutational burden is associated with a strong decrease in mRNA expression levels in primary tumor samples (R = -0.23). Differential gene expression analysis and functional characterizations between mutant and wild-type tumors implicates the mutated cells in promoting cell proliferation at early stages of tumorigenesis. These results emerge uniquely from a systems-level analysis integrating multiple proteins in complexes and multiple cell types in heterogeneous tumors. Citation Format: Maayan Baron, Trey Ideker. Desmosome mutations in melanoma promote cellular proliferation and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 178.
Abstract 2076: Low OGG1 protects against the DNA damage induced by MTH1 inhibition
Authors: Laura Misiara Lincheta, Ling Zhang, Govindi Samaranayake, Nisha Sharma, Dao Nguyen, Yu-Ki Tahara, Eric Kool, Priyamvada Rai
Journal: Cancer Research (2021)

Abstract Increased metabolic activity of cancer cells due to uncontrolled proliferation, often leads to the accumulation of reactive oxygen species (ROS). High ROS can produce tumor-suppressive oxidative DNA damage either directly in the genome or through oxidation of deoxynucleotides that can then be incorporated into DNA. The human 8-oxoguanine glycosylase 1 (OGG1), a base excision repair (BER) enzyme, protects cells from the former by excising genomic 8-oxodG; MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, protects cells from the latter by degrading 8-oxo-dGTP. There has been much interest in increasing oxidative DNA damage in tumors as a therapeutic option. Accordingly, inhibitors are being developed that can target both MTH1 and 8-oxodG glycosylase 1 (OGG1) with the speculation that this co-targeting will significantly increase tumor suppression efficiency. Our lab has shown that MTH1 inhibition leads to DNA strand breaks and tumor-suppressive effects in cancers characterized by high MTH1enzymatic activity. Here we assessed whether co-inhibition of OGG1 would provide benefits in tumor-suppressive effects over MTH1 inhibition alone. We first compared OGG1 and MTH1 expression in paired normal versus tumor tissue from lung adenocarcinoma patients and found that, unlike MTH1, OGG1 tends to remain within normal range in cancerous tissue. Similarly, TCGA lung adenocarcinoma patients show minimal OGG1 elevations and a positive correlation between OGG1 and MTH1 mRNA levels even when both are low. This data suggests that tumors with low OGG1 and MTH1 are robustly represented in the tumor continuum. We then co-depleted OGG1/MTH1 in the A549 lung cancer cell line and found this co-depletion led to lower DNA strand breaks and decreased cell senescence over those caused by MTH1 depletion alone. The shMTH1-transduced cells were less sensitive to SU0268, a potent OGG1 inhibitor compared to shGFP-transduced counterparts. We also treated A549 cells with SU0383, a dual OGG1/MTH1 inhibitor. The dual-inhibitor did not consistently increase cytotoxicity either with duration or dose of treatment beyond single inhibitors or combined single MTH1 and OGG1 inhibitors. In conclusion, our findings suggest that the co-inhibition of OGG1 with MTH1 does not produce enhanced therapeutic benefit in tumor cells, and could instead diminish the tumor-inhibitory effects of MTH1 inhibition that arise from induction of DNA strand breaks and p53-induced senescence. Citation Format: Laura Misiara Lincheta, Ling Zhang, Govindi Samaranayake, Nisha Sharma, Dao Nguyen, Yu-Ki Tahara, Eric Kool, Priyamvada Rai. Low OGG1 protects against the DNA damage induced by MTH1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2076.
Abstract 2197: Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer
Authors: Dingxiao Zhang, qiang Hu, Xiaozhuo Liu, Yibing Ji, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Silvia Buonamici, Ping Zhu, Jianmin Wang, song liu, Dean Tang
Journal: Cancer Research (2021)

Abstract Dysregulation of mRNA alternative splicing (AS) has been implicated in development and progression of hematological malignancies. How the global AS dysregulation contributes to the development and progression of solid tumors is under-studied and remains generally unclear. Here we describe the first comprehensive AS landscape in the spectrum of human prostate cancer (PCa) development, progression and therapy resistance. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention (IR) as a hallmark of PCa stemness and aggressiveness. Systematic interrogation of 274 splicing-regulatory genes (SRGs) uncovers prevalent SRG mutations associated with, mainly, copy number variations leading to mis-expression of ~68% of SRGs during PCa evolution. Consequently, we identify many SRGs as prognostic markers associated with splicing disruption and patient outcome. Interestingly, androgen receptor (AR) controls a splicing program distinct from its transcriptional regulation. The spliceosome modulator, E7107, reverses cancer aggressiveness and inhibits the growth of castration-resistant PCa (CRPC) xenograft models and of the autochthonous Hi-Myc tumors. Altogether, our studies establish aberrant AS landscape caused by dysregulated SRGs as a hallmark of PCa aggressiveness and a novel therapeutic vulnerability for CRPC. Citation Format: Dingxiao Zhang, qiang Hu, Xiaozhuo Liu, Yibing Ji, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Silvia Buonamici, Ping Zhu, Jianmin Wang, song liu, Dean Tang. Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2197.
Abstract 1477: Co-targeting c-Met and c-Src pathways to inhibit metastatic cancer cell migration and invasion
Authors: Yao Dai, Dietmar W. Siemann
Journal: Cancer Research (2021)

Abstract Overexpression of tyrosine kinases c-Src and c-Met has been shown to be highly associated with disease progression and poor clinical outcomes in many types of cancers. Although small molecule Src or Met inhibitors are being individually evaluated in clinical trials, patient data suggest that single treatment with any of these inhibitors only yield limited effects. One possibility is that redundant signaling pathways in tumor cells may allow tumor cell functions less interrupted upon inhibition of only one pathway. We therefore propose that c-Src and c-Met are two compensatory pathways that may cooperate to promote cancer metastasis. In order to delineate this hypothesis, we studied treatment effects of combining inhibitors targeting c-Src (dasatinib) and c-Met (ASLAN002) on multiple functional behaviors associated with tumor metastasis in c-Src and c-Met expressing metastatic cancer cells. Combination of Src- and Met-inhibitors was found to strongly inhibit cell colony formation by clonogenic survival assay. In a wound-healing assay, compared to either treatment alone, the combinatorial treatment exhibited greater suppression on cell motility. In addition, using a Matrigel-based Transwell assay, dasatinib plus ASLAN002 resulted in significant reduction of cell invasion in the presence or absence of HGF. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on functional behaviors associated with cancer metastasis in vitro including survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic models in vivo. Citation Format: Yao Dai, Dietmar W. Siemann. Co-targeting c-Met and c-Src pathways to inhibit metastatic cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1477.
The new platforms of health care
Authors: E. Ray Dorsey
Journal: npj Digital Medicine (2021)

For the past century, health care measurement and delivery have been centered in hospitals and clinics. That is beginning to change as health measures and increasingly care delivery are migrating to homes and mobile devices. The COVID-19 pandemic has only accelerated this transition. While increasing access to care and improving convenience, this move toward platforms operated by for-profit firms raises concerns about privacy, equity, and duty that will have to be addressed. In addition, this change in measuring health and delivering health care will create opportunities for educators to expand the settings for training, researchers to conduct studies at enormous scale, payors to embrace lower-cost clinical settings, and patients to make their voices heard.
Unchanged negative prostate mpMRI during active surveillance, is it still necessary to biopsy and follow-up?
Authors: H.B. Luiting, A.S. Rannikko, C.H. Bangma, E.R. Boevé, A. Semjonow, F. Staerman, K.H. Tully, R. Valdagni, M.J. Roobol
Journal: European Urology (2021)
Abstract 3198: In vitro exhausted T cell assays
Authors: Thibaut J. Janss, Juliette Lamy, Johan Arnold, Sofie Pattijn
Journal: Cancer Research (2021)

Abstract The need to better understand the tumor microenvironment (TME) dictates the characterization of the cell types involved, the roles they play and how they respond to treatment. To develop better cancer immunotherapies, in vitro primary immune cell bioassays offer an early assessment of their effects on the various players of the TME. Exhausted T cells were first discovered in LCMV virus infections where chronic stimulation due to remaining virus antigens leads to T cells that stop responding to stimulation and lose their functionality (cytokine secretion and cytotoxic activity). The same phenotype was afterwards found in the tumor microenvironment where a lot of T cells were found to be “anergic”. Reversing their loss of functionality as a therapeutic strategy has made the characterization of these exhausted T cells a priority. Their phenotype is currently defined by an increase in the expression of a specific set of cell surface markers such as PD-1, TIM-3 and LAG-3. As exhaustion builds, the expression of these markers increases while T cell functionality decreases. The loss of functionality is defined by a reduction in cytokine secretion, proliferation, and cytotoxic activity in the presence of an antigen. To evaluate this phenotype in more depth, transcription factors can also be monitored. For example, BLIMP-1 and BATF, which play a role in PD-1 expression, are shown to increase following exhaustion. New therapeutics that can reverse exhausted phenotype lead to a new population of T cells called reinvigorated T cells which possesses high effector activity such as cytotoxicity towards cancer cells. Using primary immune cells, in vitro bioassays were developed to better screen the potential effect of new therapeutics on exhausted T cells. Their ability to reverse the exhausted phenotype and facilitate the anti-tumour immune response can as a result be assessed early in the drug development process. Citation Format: Thibaut J. Janss, Juliette Lamy, Johan Arnold, Sofie Pattijn. In vitro exhausted T cell assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3198.
Abstract 2506: <i>Smarca4</i> inactivation promotes lineage-specific transformation and early metastatic features in the lung
Authors: Carla P. Concepcion, Sai Ma, Lindsay M. LaFave, Arjun Bhutkar, Manyuan Liu, Lydia P. DeAngelo, Jonathan Y. Kim, Isabella Del Priore, Adam J. Schoenfeld, Vinay K. Kartha, Peter M. Westcott, Francisco J. Sánchez-Rivera, Kevin Meli, Manav Gupta, Gregory J. Riely, Natasha Rekhtman, Charles M. Rudin, Carla F. Kim, Aviv Regev, Jason D. Buenrostro, Tyler Jacks
Journal: Cancer Research (2021)

Abstract SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex - via Smarca4 - acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution. Citation Format: Carla P. Concepcion, Sai Ma, Lindsay M. LaFave, Arjun Bhutkar, Manyuan Liu, Lydia P. DeAngelo, Jonathan Y. Kim, Isabella Del Priore, Adam J. Schoenfeld, Vinay K. Kartha, Peter M. Westcott, Francisco J. Sánchez-Rivera, Kevin Meli, Manav Gupta, Gregory J. Riely, Natasha Rekhtman, Charles M. Rudin, Carla F. Kim, Aviv Regev, Jason D. Buenrostro, Tyler Jacks. Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2506.
Long-term Symptoms After SARS-CoV-2 Infection in Children and Adolescents
Authors: Thomas Radtke, Agne Ulyte, Milo A. Puhan, Susi Kriemler
Journal: JAMA (2021)

Discussion | In this study, initial vaccine-elicited neutralizing antibody titers were negatively associated with age, resulting in a diminished ability to neutralize SARS-CoV-2 in vitro.Neutralizing titers against P.1 were reduced across all ages, although the magnitude of the age-dependent difference was smaller.Interim clinical trial data did not identify age as a contributing factor to overall vaccine efficacy. 1However, recent studies in vaccinated populations have found a measurable increase in COVID-19 cases among vaccinated older adults. 3,4 The data from the current study are consistent with neutralizing antibody levels playing an important role in this observation.Neutralizing antibody titers are thought to be strongly correlated with protection from infection; however, the threshold of this protection has not yet been precisely determined. 5 Future studies should specifically address whether the reduced antibody levels seen among older vaccinated individuals lead to concomitantly diminished protection.Additionally, the emerging SARS-CoV-2 variants of concern, including P. 1, B.1.1.7,and B.1.351,have been widely reported to be less well neutralized by vaccine-induced antibodies and are responsible for a majority of breakthrough infections, according to a May 2021 report. 6The compounding effects of reduced neutralizing antibody titers due to both age and the variants of concern should be considered when designing policies around booster vaccinations.Limitations of this study include the small sample size and the possibility of unrecognized infection prior to vaccination.