bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 574: In vitro TTFields enhance the response to temozolomide or radiation in GBM cells from a newly diagnosed patient
Authors: Michelhaugh Sharon K. , Mittal Sandeep 
Published: September 2020

Abstract
Background: Tumor treating fields (TTFields) are FDA-approved for treatment of newly diagnosed and recurrent glioblastoma and are typically initiated after patients have undergone surgical resection, temozolomide, (TMZ) and radiotherapy. In this study, GBM cells generated from a tumor resected from a newly diagnosed glioblastoma patient were treated in vitro with TTFields ± TMZ or treated with in vitro TTFields followed by irradiation to determine if TTFields alter the response to the standard-of-care treatment modalities.
Methods: Single-cell suspensions generated from tumor tissue obtained from a newly diagnosed patient were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. For the TMZ experiment, cells were plated on plastic coverslips (1 × 104cells/coverslip; n=4-6/group) and incubated overnight. TTFields (200 kHz; field intensity of ~1.6 V/cm). were applied with or without 50 µM TMZ for 5 days, followed by the XTT proliferation assay. For the radiation experiment, cells were plated on plastic coverslips (5 × 104cells/coverslip; n=3/group) and incubated overnight. TTFields (200 kHz; field intensity of ~1.6 V/cm). were applied for 3 days followed by irradiation with 0, 2, 4, or 6 Gy. Cells were harvested and plated to assess clonogenic potential. After 3 days, cells were stained with crystal violet and plates were scanned to determine cell counts. Data were analyzed by one-way ANOVA with Tukey's post-hoc test.
Results: In the TTFields/TMZ experiment, control XTT values were 0.665 ± 0.052, TMZ only were 0.480±0.024, TTFields only were 0.550±0.080 and TTFields + TMZ were 0.164 ± 0.062 (mean ± SD; ANOVA p&lt;0.0001). In the TTFields/radiation experiment, there was no statistical difference in cell counts across the radiation doses in the control cells. In the TTFields treated groups, the mean cell counts were 62146, 53324, 41070 and 28680 in the control, 2 Gy, 4Gy, and 6 Gy groups (ANOVA p=0.002).
Conclusions: In GBM cells generated from a newly diagnosed patient's tumor. TTFields application in combination with TMZ reduced cell proliferation by 75%, compared to only 20-30% for either treatment alone. Also, TTFields application prior to radiation significantly reduced cell counts. These results suggest that newly diagnosed patients would benefit from TTFields therapy earlier in the course of treatment.
Citation Format: Sharon K. Michelhaugh, Sandeep Mittal. In vitro TTFields enhance the response to temozolomide or radiation in GBM cells from a newly diagnosed patient [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 574.
Abstract 5761: Trends and regional distribution pattern of female lung cancer in China from 1992 to 2016
Authors: Ni Xue , Zhang Bei , Xu Ning , Zeng Xinying , Wang Qiang 
Published: September 2020

Abstract
Background: The risk factors of female lung cancer in China are still unclear. The growing trend of lung cancer in Chinese women has become a global concern of public health. This study aims to explore the secular trends and regional distribution of female lung cancer in China.
Method: The results of global burden of disease (GBD 2016) and the world standard population database (WHO 2000-2025) were used to extract age- sex- and province-specific incidence, mortality, and years of life lost due to premature death (YLL) for this report. The Joinpoint regression analysis was applied to fit the secular female lung cancer trends of age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and YLL rate for China and its 33 provincial administrative regions in 1992-2016.
Result: From 1992 to 2016, the secular trend of female lung cancer incidence in China rose upward and the trend of mortality or rate of YLL fell down. The average annual percent change (AAPC) of the ASIR, ASMR, and YLL rate were 0.7 (95%CI: 0.6,0.8%), -0.3% (95%CI: -0.5, -0.2%), and -0.7 (95%CI: -0.8, -0.6%) respectively. However, the secular trends among 33 provincial units are inconsistent. There were 5 regional patterns of joint trends in ASIR, ASMR, and YLL rate among 33 provinces, autonomous regions, and municipalities.
Conclusion: The regional pattern of the trends of female lung cancer in China suggested that the prevention and control of female lung cancer should be taken with targeted regional interventions.
Citation Format: Xue Ni, Bei Zhang, Ning Xu, Xinying Zeng, Qiang Wang. Trends and regional distribution pattern of female lung cancer in China from 1992 to 2016 [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 5761.
Abstract 5767: Multiple primary cancer from a retrospective population-based cancer registry, 1991 through 2015
Authors: Tanjak Pariyada , Thiengtrong Benjarat , Thamapala Kanokporn , Gerdsuriwong Tippawan , Songjang Cholticha , Rattanakumnerd Aem-on , Acharayothin Onchira , Karakate Supatee , Thamnongdee Nongnard , Therasakvichya Suwanit , Laiteerapong Somsri , Chinswangwatanakul Vitoon 
Published: September 2020

Abstract
Background Multiple primary cancer refers to the synchronous or metachronous appearances in the same individual. The accurate approach, which distinguishes between multiple primary cancer and metastasis, is important to make an appropriate management. This study aims to systematically classify the synchronous and metachronous multiple primary cancers, and to identify multiple primary cancer from cancer metastasis.
Methods Cancer registry was compiled at the Faculty of Medicine Siriraj Hospital, Mahidol University based on guidelines from the Surveillance Epidemiology and End Results (SEER) project. Data was validated through clinical records, coded, and verified for multiple primary cancer according to International Classification of Diseases for Oncology 3rdEdition (ICD-O-3). The cancer registry for the year 1991-2015 was queried for numbers of the multiple primary cancer.
Results A total of 1,913 patients presented multiple primary cancer, accounting for 1.48% of all patients (129,216). Median age at diagnosis of the first cancer was 60. The most multiple primary cancer in female is synchronous breast cancers, diagnosed two or more histologically distinct cancer within two months. In male, the most combination is prostate, urinary tract, and gastrointestinal cancer. In addition to understanding of the connections between primary and subsequent cancer, we plan to perform panel sequencing in each primary site of multiple gastrointestinal primary cancer to access for the causal driver mutation.
Conclusion Cancer registry is a valuable approach to punctually identify and record multiple primary cancer. Further study in genetic profiles of each primary cancer may improve our understanding of multiple primary cancer for enhancing cancer management.
Citation Format: Pariyada Tanjak, Benjarat Thiengtrong, Kanokporn Thamapala, Tippawan Gerdsuriwong, Cholticha Songjang, Aem-on Rattanakumnerd, Onchira Acharayothin, Supatee Karakate, Nongnard Thamnongdee, Suwanit Therasakvichya, Somsri Laiteerapong, Vitoon Chinswangwatanakul. Multiple primary cancer from a retrospective population-based cancer registry, 1991 through 2015 [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 5767.
Abstract 5808: Examination of clinically relevant inhibitor selectivity in live cells across the CDK family
Authors: Vasta James , Wells Carrow , Corona Cesear , Wilkinson Jennifer , Zimprich Chad , Ingold Morgan , Ogno Domenic , Schwinn Marie , Machleidt Thomas , Cong Mei , Fan Frank , Huwiler Kristin , Landreman Amy , Pickett Julie E. , Huber Kilian , Robers Matthew 
Published: September 2020

Abstract
Cyclin-dependent kinases (CDK) play key roles in diverse cellular functions including cell cycle control, cell proliferation, and transcriptional regulation. Due to these important roles, CDKs have been targeted for cancer therapeutic development, which has resulted in hundreds of small molecule inhibitors. However, conflicting data of CDK inhibitor potency has been reported and a rigorous comparison of inhibitor affinity and selectivity for intracellular CDKs is lacking. To address this need, we have developed a panel of cell-permeable energy transfer probes or tracers to enable comprehensive quantitation of inhibitor target occupancy and affinity for CDKs in live cells via a bioluminescent energy transfer (BRET) method. Specifically, the quantitative BRET-based capability is achieved via energy transfer from cell-permeable fluorescent tracers reversibly engaged to NanoLuc luciferase-tagged CDK proteins expressed in live cells. An untagged cyclin can be introduced into the cells at the same time as the NanoLuc-CDK, allowing for the interrogation of a specific CDK-cyclin pair. The BRET-based method can be used in equilibrium binding analysis. In addition, time-dependent target-compound occupancy (or residence time) can also be obtained with this method. We will present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of clinically-advanced CDK inhibitors and chemical probes across the CDK family. We observed unexpected intracellular activity profiles for some clinically-advanced CDK inhibitors. We further evaluated mechanisms for achieving target selectivity through target residence time under non-equilibrium cell culture conditions. This BRET-based method is broadly applicable for evaluating the occupancy, affinity, and selectivity of chemical matter for CDKs in live cells.
Citation Format: James Vasta, Carrow Wells, Cesear Corona, Jennifer Wilkinson, Chad Zimprich, Morgan Ingold, Domenic Ogno, Marie Schwinn, Thomas Machleidt, Mei Cong, Frank Fan, Kristin Huwiler, Amy Landreman, Julie E. Pickett, Kilian Huber, Matthew Robers. Examination of clinically relevant inhibitor selectivity in live cells across the CDK family [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 5808.
Abstract 5810: Fyn kinase negatively regulates telomere length in stem cells and cancer cells
Authors: Paul Souren , Le Thi My Le , Ryu Joohyun , Bae Ki Beom , Bode Ann M. , Dong Zigang 
Published: September 2020

Abstract
Telomere maintenance is on the critical biological process in stem cell, aging, and cancer. Cells maintain telomere either by Telomerase (TERT) dependent pathway or by alternative lengthening of telomere (ALT) pathway. Here we report a link between Fyn kinase expression and telomere length. Fyn deficient mouse and mouse embryonic stem cells (mESC) maintain a stable telomere length through activation of ALT pathway. Fyn deficient mice are also resistant to the aging process as compared to wild type mice. We uncover a novel molecular mechanism of telomere maintenance. Menin, an essential component of an MLL/SET1 histone methyltransferase (HMT) complex that specifically methylates 'Lys-4' of histone H3 (H3K4), is a potential phosphorylation target of Fyn. Phosphorylation of Menin facilitates SUMOylation and binding to Telomerase RNA Component (TERC). The telomere dysfunction is one pivotal reason for many genetic disorders, including telomere related diseases like dyskeratosis congenita (DC). Currently, there are no curative therapies for these diseases of telomere dysfunction. We knockout Fyn gene from DC mice model and also used 4-Amino-5-(4-chlorophenyl)-7-(dimethyl ethyl) pyrazolo[3,4-d]pyrimidine (PP2), a selective inhibitor of Fyn kinase. Our results demonstrate that Fyn could be a therapeutic target in telomere related diseases. Knockout of Fyn or inhibition of Fyn by using inhibitor improves DC phenotype in mice like bone marrow failure. Human iPSC generated from DC patient's skin fibroblast shows higher expression of p-Menin and maintains a stable telomere length when we inhibited Fyn.
Citation Format: Souren Paul, Thi My Le Le, Joohyun Ryu, Ki Beom Bae, Ann M. Bode, Zigang Dong. Fyn kinase negatively regulates telomere length in stem cells and 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 5810.
Abstract 5812: FOXD1 mediates G2/M transition in clear cell renal cell carcinoma
Authors: Bond Kyle Henry , Jaikaran Ryan , Qiu Suizhen , Oxburgh Leif 
Published: September 2020

Abstract
The forkhead family of transcription factors are highly conserved and essential during embryonic development. There have been reports showing increased expression of forkheads in various cancers, but little is known about the role of these proteins in the disease context. Analysis of 500 clear cell renal cell carcinoma (ccRCC) transcriptomes in The Cancer Genome Database revealed that FOXD1 is overexpressed in ccRCC and correlates with poor patient outcomes (median survival FOXD1-low=2830 days; FOXD1-high=1913 days). Immunohistochemistry of 46 patient tumors showed that FOXD1 is expressed the majority of tumor cells (95% CI [50.6%, 79.4%]). To understand the biological role of FOXD1, we generated FOXD1-null variants of the 786-O ccRCC cell line. Using an in vivo xenograft model, FOXD1-null cells had smaller initiating tumor sizes (parent=71.05mm3; FOXD1-null=36.39mm3) and stunted tumor growth. In vitro, FOXD1-null lines had significantly reduced growth rates compared to the parental line, and showed increased cell size. Cell cycle analysis revealed that FOXD1-null cells had an increased number of cells in G2 compared to the parental line (parent=21.1%; FOXD1-null=37.1%). After G1 synchronization, all lines progressed through G1, S, and G2 at similar rates (parent=10 hours; FOXD1-null=10 hours). However, FOXD1-null clones spent increased time in G2 compared to the parental line (parent= 4 hours; FOXD1-null= 8 hours). Western blot analysis revealed decreased levels of Cyclin B1 and p-H3, as well as increased levels of p27 10 hours post-synchronization in FOXD1-null cells compared to the parent line. Staining with yH2AX did not indicate any significant change in the number of double strand breaks at any phase. These findings suggest that FOXD1 is a mediator of the transition between G2 and M, and that its loss initializes the G2/M checkpoint. Extrapolating back to our clinical observation, we propose that increased FOXD1 expression in tumor cells accelerates the transition between G2 and M, a point that is normally critical for survey and repair of DNA damage. This could result in greater tolerance for DNA damage, accelerating tumor evolution.
Citation Format: Kyle Henry Bond, Ryan Jaikaran, Suizhen Qiu, Leif Oxburgh. FOXD1 mediates G2/M transition in clear cell renal 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 5812.
Abstract 5814: Emergent functions of cyclin-dependent kinase 4 regulating aurora b and cenpp transcription
Authors: Lee Sung Hyun , Rodriguez Liliana R. , de Marval Paula L. Miliani , Rodriguez-Puebla Marcelo L. 
Published: September 2020

Abstract
A better understanding of the precise molecular mechanisms that control cell proliferation is crucial for the identification of novel cancer therapeutic targets. A critical molecule in this process is the Cyclin-Dependent Kinase 4 (CDK4), which regulates key aspects of the G1 to S phase transition through phosphorylation of the retinoblastoma (Rb) family of proteins. Since dysregulation of this cell cycle mechanism is a hallmark of most cancers, drugs have been developed to inhibit the kinase activity of CDK4. However, such drugs have been met with variable degrees of success and, in some cases, little efficacy. Research performed in the last few years has suggested that CDK4 have alternative targets other than the Rb proteins. Consistent with this idea, we found that CDK4 plays additional roles not related to the canonical function in the CDK-Rb axis. Here, we show that CDK4 remains attached to the chromatin fraction of Balb/MK2 keratinocytes upon the extraction of the soluble components (nucleoplasm and cytoplasm). Chromatin-immunoprecipitation (ChIP) analysis shows that CDK4 occupies the regulatory sites of genes associated with chromosomal segregation, such as Aurkb (Aurora B) and Cenpp (Centromere Protein P). Moreover, gain- and loss-of-function experiments showed that the AurkB and Cenpp promoters are regulated through CDK4 binding. In line with these findings, studies in skin carcinogenesis revealed that transgenic expression of CDK4 in mouse epidermis induces chromosome instability (CIN) and centrosome amplification (CA), two events linked to overexpression of Aurora B. Moreover, Aurora-B has a crucial role in chromosome bi-orientation and the spindle-assembly checkpoint, whereas Cenpp is required for proper kinetochore function. Remarkably, a persistent dysregulation of Aurora B has been reported in numerous human cancers. Thus, our results suggest that CDK4 plays a role in the maintenance of chromosomal stability, implying that additional functions could be inhibited by therapeutically targeting CDK4. Our conclusions are supported by previous reports showing that pharmacological inhibition of CDK4 led to delayed progression from G2 to mitosis in Rb-positive and as well as Rb-negative cells.
Citation Format: Sung Hyun Lee, Liliana R. Rodriguez, Paula L. Miliani de Marval, Marcelo L. Rodriguez-Puebla. Emergent functions of cyclin-dependent kinase 4 regulating aurora b and cenpp transcription [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 5814.
Abstract 5826: Molecular mechanism of OLIG2-CDK2 interaction in glioma cells
Authors: Saito Norihiko , Hirai Nozomi , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: September 2020

Abstract
Oligodendrocyte transcription factor 2 (Olig2) promotes proliferation of normal neural stem/progenitor cells and glioma cells. However, the mechanisms underlying the regulation of Olig2 remain largely unknown. Here we identified Olig2 as a critical phosphorylation target for cyclin-dependent kinase 2 (CDK2). CDK2-mediated Olig2 phosphorylation stabilizes Olig2 protein from proteasomal degradation. Phosphorylated Olig2 binds to the E-Box regions of p27 promoter and represses p27 transcription, which in turn activates CDK2 in positive feedback manner. CDK2-mediated Olig2 phosphorylation promotes cell cycle progression, cell proliferation, and tumorigenesis. Olig2 inhibition disrupted cell cycle control mechanism by decreasing CDK2 and elevating apoptosis-related molecules. Inhibition of CDK2 activity disrupted Olig2-CDK2 interactions and attenuated Olig2 protein stability. In addition, Olig2-high glioma initiating cells are highly sensitive to CDK2 inhibitor treatment, indicating that Olig2 can be a biomarker for personalized treatment for glioblastoma patients with CDK2 inhibitors. Further investigation on these mechanisms may lead to novel targeted therapy on GBMs with high Olig2 expression.
Citation Format: Norihiko Saito, Nozomi Hirai, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi. Molecular mechanism of OLIG2-CDK2 interaction in glioma 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 5826.
Abstract 5827: Alterations of telomere and SOX9 play key roles on pancreatic carcinogenesis
Authors: Matsuda Yoko , Yamakawa Keiko , Narusawa Yuko 
Published: September 2020

Abstract
The morbidity of pancreatic cancer is predicted to increase because of the growing elderly population. In this study, we analyzed alterations of telomere length and SOX9 expression to clarify the relationship between precancerous lesions (pancreatic intraepithelial neoplasia; PanIN), pancreatic cancer and aging. The incidence of PanIN in the elderly patients was 60%. The telomere, which can protect the chromosome ends, was shortened in the following order; pancreatic duct&gt;PanIN-1&gt;PanIN-2&gt;PanIN-3&gt;pancreatic cancer. The telomeres in normal duct epithelium became shorter with aging, and those in cancers were shorter than in controls, suggesting that telomere shortening occurs when histological changes are absent. SOX9, which regulates pancreatic progenitor cells, was the highest in carcinomas, followed by PanIN-3, PanIN-2, PanIN-1, and duct epithelium. SOX9 expression was positively correlated with telomere length in cancer cells. Inhibition of SOX9 using siRNA showed decrease of human telomerase reverse transcriptase (hTERT) expression and decrease of sphere formation in human pancreatic cancer cell lines. In conclusion, upregulation of SOX9 in the duct epithelium, which harbors shortened telomeres, may give rise to PanINs and pancreatic cancers.
Citation Format: Yoko Matsuda, Keiko Yamakawa, Yuko Narusawa. Alterations of telomere and SOX9 play key roles on pancreatic carcinogenesis [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 5827.