bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5779: The association of instrument assisted deliveries and the development of childhood brain tumors: A matched case control study
Authors: Yeh Karen , Hansen Johnni , Heck Julia E. 
Published: September 2020

Abstract
Background: Pediatric brain tumors are the second most common type of childhood cancer and have the highest mortality rate among all pediatric cancer types. New information on potentially preventative measures would be of great value. Previous studies have suggested that instrument-assisted delivery (forceps and vacuum) may be associated with an increased risk for childhood brain tumors. The goal of this study was to determine if there was an association of exposure to instrument-assisted deliveries with childhood brain tumors in Denmark. We additionally examined risk with emergency or planned cesarean section.
Methods: This was a matched case-control study with childhood brain tumor cases in Denmark diagnosed from 1978-2013. Cases were identified from the Danish Cancer Registry. Birth outcomes, maternal procedures and covariates were obtained from the Danish Medical Births Register and the nationwide Hospital Register. A total of 3,698 brain tumor cases were recruited and 25 controls were matched to each case based on child's sex and birth year (N=89,554). We used conditional logistic regression to determine associations of delivery instruments types with various childhood brain tumors.
Results: Compared to children birthed by spontaneous vaginal delivery, children who later developed ependymomas (N=136) had a greater likelihood of having been delivered by vacuum assisted deliveries (OR=1.69, 95% CI 1.01-2.83). An overall increased risk for cesarean section with any CNS tumor (OR= 1.20, 95% CI 1.06-1.36) dropped to 1.10 when we limited the age range to 4 or older (N=1,087). This suggests no clear increased risk for cancer with cesarean section, as there is a possibility that the CNS tumor was present before birth and influenced a larger head size, thus requiring a cesarean section. Planned cesarean and emergency cesarean section were not related to risk increases. While the use of forceps was rare in this population (1.2% in controls), we could not confirm previously reported associations with astrocytoma (OR=0.84), though there was a weak increase for ependymoma with wide confidence intervals (OR=2.69, 95% CI 0.77, 9.38).
Conclusions: Based on objective data, the findings in our study suggest that there might be an association between vacuum assisted deliveries and ependymomas. Our data did not support a strong association of childhood brain tumors with cesarean sections.
Citation Format: Karen Yeh, Johnni Hansen, Julia E. Heck. The association of instrument assisted deliveries and the development of childhood brain tumors: A matched case control study [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 5779.
Abstract 5811: Combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors in breast cancer via RB-independent pathway
Authors: Pandey Kamal 
Published: September 2020

Abstract
Objective: FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) are widely used to treat metastatic hormone receptor-positive (HR+) breast cancer. Despite the excellent disease control with CDK4/6 inhibitors, acquired resistance emerges in almost all cases. The strategies to combat the resistance are not yet defined. We investigated therapeutic strategies as well as mechanisms of resistance to CDK4/6 inhibitors in breast cancer.
Methods: Palbociclib resistant cells (MCF7-PR and T47D-PR) were generated from the parental MCF and T47D cell lines by treating them with gradually increasing concentration of palbociclib for over 9 months. Cell viability assay, cell cycle, and western blot were performed to confirm the acquired resistance. Microarray analyses were carried out to identify altered gene expression. We validated the overexpressed genes by qRT-PCR and western blot and further confirmed the significant inhibition by CDK2 siRNA in combination with palbociclib both in vitro and in vivo.
Results: Palbociclib-resistant MCF7 and T47D cells had about 10 fold higher half maximal inhibitory concentration (IC50), compared with parental cells. Morphological changes and alteration in EMT markers were observed in resistant cells. Loss of RB and overexpression of cyclin E1 confirmed that the cells gained resistance. Overexpression of C-MYC was observed in resistant cells compared to sensitive counterparts. Furthermore, from analysis of pleural effusion samples from HR+ breast cancer patients, we confirmed again that loss of RB and overexpression of cyclin E are significantly correlated with resistance to CDK4/6 inhibitors. Mechanistically, we found that, cyclin E-CDK2 mediated phosphorylation of C-MYC was responsible for suppressing C-MYC induced senescence. To overcome CDK4/6 inhibitor resistance, combined inhibition of CDK2 and CDK4/6 showed a synergistic effect in palbociclib-resistant in vitro and in vivo model. Further, combination-treated group showed significantly higher β-galactosidase expression compared to no- treatment control or palbociclib alone treated group.
Conclusion: The synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcame acquired resistance to CDK4/6 inhibitors via RB-independent pathway, that is, suppressing C-MYC. These findings could pave the way for the development of next generation CDK2 inhibitor in CDK4/6 inhibitor-resistant breast cancer, which is characterized by overexpressed cyclin E and C-MYC.
Keywords: CDK4/6, hormone receptor-positive breast cancer, drug resistance
Citation Format: Kamal Pandey. Combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors in breast cancer via RB-independent pathway [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 5811.
Abstract 5828: Effect of Roscovitine and mifepristone in luminal breast cancer cells
Authors: Vottero Lucía , Lanari Claudia , Fabris Victoria T. 
Published: September 2020

Abstract
The cyclin dependent kinase (CDK)4/6 inhibitors have been recently approved in combination with endocrine therapy for luminal breast cancer treatment. On the other hand, the use of CDK2 inhibitors, such as Roscovitine, appears as a therapeutic alternative to overcome the acquisition of resistance to CDK4/6 inhibitors. However, there are few clinical trials using CDK2 inhibitors for breast cancer treatment. Most of the reports on the effects of Roscovitine were performed in MCF-7 or MDA-MB-231 cells. The aim of this work was to evaluate the effect of Roscovitine on cell proliferation in T47D human breast cancer cells which express both progesterone receptor (PR) isoforms PRA and PRB, and in the T47D-YA and T47D-YB cell lines expressing only PRA or PRB, respectively. We have previously demonstrated that cells overexpressing PRB showed higher levels of cyclin A as compared with those overexpressing PRA, thus we hypothesized that they would be more sensitive to CDK2 inhibitors. Roscovitine inhibited cell proliferation in a dose dependent manner similarly in both MCF-7 cells (used as positive control) and in T47D cells, with IC50 of 11.99 µM and 11.93 µM respectively. In addition, Roscovitine inhibited cell proliferation induced by estrogen treatment in both cell lines (p&lt;0.01); however the percentage of inhibition was higher in MCF-7 compared with T47D cells (70% versus 50%, respectively; p&lt;0.05). Roscovitine also inhibited cell proliferation induced by the fibroblast growth factor FGF2 in T47D cells (Roscovitine 2 µM p&lt;0.001 and 5 µM p&lt;0.05). Whereas both T47D-YA and -YB cells were similarly inhibited by Roscovitine, only in T47D-YA cells the combination of the antiprogestin mifepristone (MFP; 10 nM) and Roscovitine 1 µM in the presence of FGF2 induced a higher inhibitory effect than MFP or Roscovitine single treatments (p&lt;0.01). We conclude that CDK2 inhibitors may be an option for luminal breast cancer treatment independent of the levels of cyclin A, and that they might be used in combination with antiprogestins only in breast cancer cells overexpressing PRA isoform.
Citation Format: Lucía Vottero, Claudia Lanari, Victoria T. Fabris. Effect of Roscovitine and mifepristone in luminal breast cancer cells [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 5828.
Abstract 5833: Senescence is a central response to chemotherapy in ovarian cancer
Authors: Skulimowski Michael , Calvo-Gonzales Llilians , Cheng Shuofei , Clément Isabelle , Portelance Lise , Zhan Yu , Carmona Euridice , de Ladurantaye Manon , Lafontaine Julie , Rahimi Kurosh , Provencher Diane , Mes-Masson Anne-Marie , Rodier Francis 
Published: September 2020

Abstract
High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding the cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here, we find that more than 90% of tissue-derived primary HGSOC cultures, reflecting the original disease, retain the capacity to undergo stress-induced cellular senescence and primarily undergo therapy-induced senescence (TIS) in response to first-line carboplatin/taxol chemotherapy. HGSOC-TIS displays senescence-associated hallmarks, including a stable proliferation arrest, increased p16INK4A expression, persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting the occurrence of post-treatment TIS. Whether cell senescence induced by cancer therapy is beneficial or detrimental to treatment outcomes remains unknown. We find that patients with stronger TIS biomarkers in post-chemotherapy tissues have a more favorale 5-year survival, suggesting that the induction of senescence in HGSOC cells accounts, at least in part, for beneficial responses to treatment. Given that HGSOC cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, senescence-centric therapeutic avenues should be further explored.
Citation Format: Michael Skulimowski, Llilians Calvo-Gonzales, Shuofei Cheng, Isabelle Clément, Lise Portelance, Yu Zhan, Euridice Carmona, Manon de Ladurantaye, Julie Lafontaine, Kurosh Rahimi, Diane Provencher, Anne-Marie Mes-Masson, Francis Rodier. Senescence is a central response to chemotherapy in ovarian cancer [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 5833.
Abstract 5838: RNA methylation regulates autophagy via unfolded protein response in cancers
Authors: Subbarayalu Panneerdoss , Yadav Pooja , Rao Manjeet 
Published: September 2020

Abstract
N6-methyladenosine (m6A) RNA methylation is a dynamic, reversible and most abundant epitranscriptomic modification found on mRNA and long-non coding RNAs. M6A is regulated by methyl transferases (writes m6A), demethylases (erases m6A) and read by specific RNA binding proteins known as m6A readers that can modulate the fate of specific transcript. Recent studies have suggested that RNA methylation affects several fundamental cellular and molecular functions including mRNA splicing, stability, export, stem cell fate, circadian rhythms, DNA repair and cell survival. In addition, we and others have shown that RNA methylation plays an important role in tumor growth and progression. Here, we discovered that m6A may regulate tumorigenesis by regulating autophagy in cancer cells. Our results revealed that altering the levels of m6A methylation led to increased levels of LC3, which is a universal marker for autophagy. In addition, autophagy initiation protein ULK1 and other autophagy complex proteins including ATG5, ATG12, ATG16L1, and LAMP1 levels were significantly increased in cells with altered m6A methylation. Importantly, we discovered that change in m6A levels by altering the RNA demethylase protein induced the unfolded protein response (UPR) pathway, which is a known activator of autophagy. To understand the molecular mechanism of autophagy induction, we looked into three branches of UPR pathways and discovered that protein kinase RNA like kinase (PERK) UPR signaling pathway is highly activated in ALKBH5 depleted cancer cells and might regulate autophagy induction and cancer cell survival. In conclusion, our study is the first investigation to show that RNA methylation plays an important role in cancer growth by regulating autophagy via UPR.
Citation Format: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao. RNA methylation regulates autophagy via unfolded protein response in cancers [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 5838.
Abstract 5843: XBP1 regulates the expression of cell cycle associated genes in ERα positive breast cancer cells
Authors: Barua David , Sultana Afrin , Islam Md Nahidul , Gupta Ananya , Gupta Sanjeev 
Published: September 2020

Abstract
Estrogen receptor α (ERα)-positive breast cancer is a heterogeneous disease with distinct molecular features. Over the time of treatment, endocrine resistance develops in these types of cancers which is major challenge in recent times and finding a better treatment options against these resistant cancers is urgent. Several studies have suggested the association of XBP1 in therapy resistance in ERα-positive breast cancers. Indeed, XBP1 physically interacts with ER and activates ER-dependent transcription in a ligand-independent manner. Moreover, overexpression of XBP1 in ERα-positive breast cancer cells confers estrogen independent growth and reduced sensitivity to anti-estrogen. Despite growing evidence about the involvement of XBP1 in ERα-positive breast cancer, molecular targets of XBP1 is poorly understood. The aim of current study is to identify the XBP1-regulated targets in ERα-positive breast cancer cells. XBP1 deficient sub-clones in MCF7 cells were generated by using CRISPR-CAS9 mediated gene knockout strategy. Cell viability and anti-estrogen sensitivity were determined by MTS assay, cell proliferation was evaluated by colony formation assay, cell death was determined by flow cytometry. XBP1-regulated genes were identified by analysing transcriptomic data from control and XBP1-knockdown T47D cells (GSE49955). Relative expression of genes were analysed by qPCR. RRM2 overexpression clones were generated by transfecting RRM2 vector using nucleofector. Deficiency of XBP1 in MCF7 cells showed decreased growth and proliferation as compared to control MCF7 cells. Deletion of XBP1 in MCF7 cells demonstrated compromised E2-mediated cell growth and reduced activation of E2-dependent genes. Moreover, XBP1 deficiency in MCF7 cells increases sensitivity towards anti-estrogens including tamoxifen and fulvestrant. Expression of cell cycle associated genes RRM2, CDC6 and TOP2A were found significantly reduced in all ERα-positive breast cancer cell lines with compromised function of XBP1. RRM2, CDC6 and TOP2A have been previously reported as direct targets of XBP1 in other cell types (i.e., muscle, pancreatic β-cell, and plasma cell) and helper T-cells. Furthermore, overexpression of RRM2 in XBP1 deficient MCF7 sub-clones rescued the cell growth and proliferation same as control MCF7 clones. Therefore, this study has revealed XBP1 regulated new targets in ERα-positive breast cancer cells which could be instrumental in providing new insights for better therapeutic potential in this context.
Citation Format: David Barua, Afrin Sultana, Md Nahidul Islam, Ananya Gupta, Sanjeev Gupta. XBP1 regulates the expression of cell cycle associated genes in ERα positive breast cancer cells [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 5843.
Abstract 5857: Molecular characterization of response to interferon alpha in sensitive and resistant bladder cancer models
Authors: Osterhout Robin , Green Jennifer , McDonnell Scott , Klova Amy , Kamal Adeela 
Published: September 2020

Abstract
Background:
Over 70% of patients newly diagnosed with bladder cancer will present with non-muscle invasive disease (NMIBC). The standard of care treatment to prevent recurrence and progression is tumor resection followed by Bacillus Calmette-Guerin (BCG). While this treatment regimen is effective for many patients, a significant fraction become resistant over time. Adenoviral-delivered IFNα gene therapy is emerging as a safe and efficacious treatment for BCG-refractory NMIBC. IFNα is a type 1 interferon that mediates complex tumor-immune interactions, and also has direct cytotoxic effect on tumors. While the mechanisms of IFNα have been extensively studied, it is unclear which of these mechanisms are most relevant for driving therapeutic response. It is also poorly understood why some tumors are sensitive to the direct cytotoxic effects of IFNα and others are resistant.
Methods:
Here, we investigate the molecular mechanisms of tumor-intrinsic sensitivity and resistance to IFNα. We characterized response of a panel of bladder cancer cell lines to treatment with IFNα, and performed concomitant gene expression profiling to identify molecular features and pathways associated with response and sensitivity. These features were then compared across responsive and non-responsive cancer cell line models from other tissues of origin including skin, pancreas, liver and lung.
Results/Conclusions:
Several bladder cancer models exhibited a dose-dependent cytotoxic response to IFNα treatments, while others were resistant to these effects. Genomic and mRNA features associated with IFNα sensitivity/resistance were identified. Pan-cancer cell line analysis identified conserved and putative tissue-specific differences in IFNα downstream signaling genes in resistant vs sensitive cell lines. These features are being evaluated and will inform future investigation of the mechanism of IFNα anti-tumor activity in patients.
Citation Format: Robin Osterhout, Jennifer Green, Scott McDonnell, Amy Klova, Adeela Kamal. Molecular characterization of response to interferon alpha in sensitive and resistant bladder cancer models [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 5857.
Abstract 5859: Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous cell carcinoma
Authors: Patel Nisarg A. , Vokes Natalie I. , Elmarakeby Haitham , Hanna Glenn J. , Van Allen Eliezer M. 
Published: September 2020

Abstract
Background:
Objective response rates for patients with advanced head and neck squamous cell carcinoma (HNSCC) receiving PD-1/L1 immune checkpoint inhibitors (ICI) without chemotherapy remain under 25%. Some studies suggest that HNSCC patients with human papillomavirus (HPV)-associated disease and high tumor mutational burden (TMB) derive greater benefit, although these findings do not yet guide patient selection. We hypothesized that uniform genomic analysis of a larger cohort may help place the predictive value of TMB in a broader biological context and identify more robust predictors of response.
Methods:
274 patients with biopsy-proven HNSCC treated with ICI at our institution from June 2014 to September 2018 were identified. Following targeted massively parallel sequencing, single nucleotide variant calling, and quality control measures, 127 samples were available for analysis. Clinical records were reviewed to determine radiographic response and overall survival. Responders included complete or partial responders by RECIST v1.1. Nonresponders included those with progressive or stable disease. We evaluated associations between genomic features and response using standard statistical methods.
Results:
TMB for the entire cohort was significantly higher among responders (p = 0.01, Fisher's); however, it had poor predictive power (AUROC = 0.68). Among the entire cohort, somatic mutations in NOTCH1 were enriched in responders (12/26 R, 17/101 NR, p = 0.003). After correcting for TMB, NOTCH1 remained associated with complete or partial response (p &lt; 0.05, logistic regression). After adjusting for mutations in NOTCH1, no significant difference in TMB was observed between responders and nonresponders (p &gt; 0.05, logistic regression). Among HPV-negative responders, somatic mutations in CDK12, a transcription-associated kinase whose loss is associated with genomic instability, neoantigen burden, and T cell infiltration, were enriched (3/26 R, 0/101 NR, p = 0.008, Fisher's).
Conclusion:
Through uniform genomic analysis of the largest ICI-treated HNSCC cohort to-date, we validated prior findings regarding the significance of TMB and NOTCH1 as correlates of response for ICI in HNSCC. We also show that TMB alone is insufficient as a predictor of response. We identify CDK12 as a variant with a mechanistic relationship to tumor immunology as a possible correlate of response in HPV-negative patients, which warrants further investigation.
Citation Format: Nisarg A. Patel, Natalie I. Vokes, Haitham Elmarakeby, Glenn J. Hanna, Eliezer M. Van Allen. Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous 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 5859.