bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4227: Safety of dendtritic cell and cytokine-induced killer(DC-CIK) cell based immunotherapy in patients with solid tumor: A large retrospective study in China
Authors: Wang Shuo , Ren Jun 
Published: September 2020

Abstract
Background: Adoptive T cell therapy especially cytokine-induced killer cell and dendric cell treatment (DC-CIK) alone or combined with chemotherapy had significantly improved patient survival time. Although some side effects studies were briefly reported in some articles. However, systematic assessment of the adverse side effects for DC-CIK therapy, especially combined with chemotherapy has not been reported.
Patients and Methods: Totally 1099 consecutive patients (2054 trail cycles) enrolled in DC-CIK treatment trials at Beijing Shijitian hospital between August 2012 and August 2018 were retrospectively reviewed, and applying Common Terminology Criteria for Adverse Events version 4.0 [CTCAE v4.0] standards to definite adverse effects (AE).
Result: The 370 patients (34%)/ 815 cycles enrolled in our trail combined with chemotherapy. In total, there were 548(cases)/870(cycles) had AEs. The AE class mainly composed of Neurological 34 cycles (4%), Musculoskeletal 28 cycles (3%), Immunopathies 5 cycles(1%), Hematological 521 cycles(60%), General disorders and Administration site conditions 224 cycles(26%), Gastrointestinal 209 cycles(24%), Skin 15 cycles(2%), Metabolism and Nutrition disorders 119 cycles(14%). AE class of the Gastrointestinal (vomiting P=0.025), Nutrition disorders (anorexia P=0.016) and Hematological (anemia P&lt;0.0001, leukopenia P&lt;0.0001) appears in the DC-CIK treatment were mainly correlated with combined with chemotherapy. Multiple logistic regression analysis suggests that no matter whether DC-CIK was combined with chemotherapy, multi-line treatment was more prone to nausea, anorexia, fatigue, anemia and leukopenia than the first-line treatment. However, correlation analysis verified that increasing cycles of only DC-CIK treatment could reduce the incidence rate of fatigue (P=0.001), anorexia (P&lt;0.0001) and anxiety (P=0.01).
Conclusion: Most of the adverse side effects that occur during autologous DC-CIK treatment were associated with combined or previously applied chemotherapeutic treatment, which also indicates that autologous DC-CIK anti-tumor therapy was safe. At the same time, the application of DC-CIK alone treatment could also reduce the occurrence rate of some side effects.
Citation Format: Shuo Wang, Jun Ren. Safety of dendtritic cell and cytokine-induced killer(DC-CIK) cell based immunotherapy in patients with solid tumor: A large retrospective study in China [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 4227.
Abstract 4283: Assessment of the tumor mutational burden in a large cohort of Chinese advanced pan-cancer patients
Authors: Liu Ping , Cui Longgang , Cai Shangli 
Published: September 2020

Abstract
Background: Immunotherapy have led to a paradigm shift in cancer treatment, while only a small subset of patients can benefit from the treatment. Recent studies have revealed that tumor mutational burden (TMB) is positively correlated with immunotherapy, however, by far, limited data are available for Chinese tumor patients.
Methods: We retrospectively assessed the TMB value with a validated 381-cancer-gene panel across 7,822 patients with advanced cancers, including gastric cancer (n= 457), gallbladder cancer (n=608), colorectal cancer (n=785), breast cancer (n=263), Hepatocellular carcinoma (n=904) and lung cancer (n=2135), Renal cell carcinoma (n=346), Liver cancer (904), NSCLC (2135), Melanoma (110), Ovarian cancer (177), Pancreatic cancer (363), Gastric carcinoma (457), Urinary tract cancer (166) and others.
Results: A highest 20% of TMB in each histology was selected as the cut-point. Based on our analysis, the highest and the lowest TMB level was observed in endometrial cancer and RCC, respectively. More specifically, the TMB cut-point was 10.5 for biliary tumor, 9.7 for breast cancer, 15.2 for endometrial cancer, 12.1 for CRC, 49.8 for endometrial cancer, 12.1 for oesophageal cancer, 11.1 for head and neck carcinoma, 7.3 for RCC, 10.1 for HCC, 14.5 for NSCLC, 8.9 for melanoma, 8.1 for ovarian cancer, 7.4 for pancreatic cancer, 11.3 for GC, and 20.1 for urinary tract cancer. Consistent results were observed when the median TMB was applied in the analysis.
Conclusion: This is the first study focusing on the distribution of TMB value in a large cohort of Chinese cancer patients. The results showed the varying distributions of TMB across histology and suggested that a high TMB status may not assigned by one universal cut-point across different cancer types. Our findings have provide clues to guide the treatment strategy in clinical practice and shed lights on the future trial design.
Citation Format: Ping Liu, Longgang Cui, Shangli Cai. Assessment of the tumor mutational burden in a large cohort of Chinese advanced pan-cancer 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 4283.
Abstract 4289: Detection of germline large genomic rearrangements in BRCA1/2 genes by a capture-based NGS panel reveals its contribution to Chinese patients with solid tumors
Authors: Li Jing , Yang Bo , Huang Kefei , Liu Changhao , Dong Hua , Wang Jie , Li Fugen , Lin Zhong-qiu 
Published: September 2020

Abstract
Background: Germline mutations in BRCA1/2 genes have been found associate with risk to develop breast and ovarian cancer in women. Patients with these mutations are also highly sensitive to PARP inhibitors. However, current NGS-based method lacks the capability to accurately detect large genomic rearrangements (LGR) including exon level deletions and duplications.
Method: We have enhanced our capture-based NGS panel and developed an algorithm to detect LGRs in BRCA1/2 genes. We applied the method to retrospectively profile germline DNA from over 14,000 patients with solid tumors, including 367 ovarian cancers and 574 breast cancers. Samples with positive test results for exon level deletions or duplications were subsequently confirmed by MLPA.
Results: Out of the 14,000 patients, we identified 19 patients with exon level deletions (BRCA1, n = 16; BRCA2, n = 3) and 7 with duplications (BRCA1, n = 6; BRCA2, n = 1). The germline LGR events were predominantly found in ovarian and breast cancer patients with a frequency of 1.9% (7/367) in ovarian cancer and a frequency of 1.2% (7/574) in breast cancer. We also observed occasional findings in non-small cell lung cancer, colorectal cancer as well as gastric cancer. From these LGRs, BRCA1 exon 2del (n = 4), BRCA1 exon 7del (n = 4) and BRCA1 exon 17-18del (n = 3) are the most recurrent LGRs observed.
Conclusion: We here report a method to comprehensively evaluate the germline LGRs in BRCA1 and BRCA2 genes using the capture-based NGS panel. We verified the results by MLPA as an orthogonal assay and report the population frequency of LGRs occurrence in Chinese patients with solid tumors.
Citation Format: Jing Li, Bo Yang, Kefei Huang, Changhao Liu, Hua Dong, Jie Wang, Fugen Li, Zhong-qiu Lin. Detection of germline large genomic rearrangements in BRCA1/2 genes by a capture-based NGS panel reveals its contribution to Chinese patients with solid tumors [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 4289.
Abstract 432: Development of a novel engineered B2M mouse strain on B-NDG background that specifically eliminates MHC I expression while retaining normal FcRn-mediated antibody retention
Authors: An W. Frank , Gao Lan , Wang Xiaoen , Sharma Shruti , Li Kaiqi , Gao Xiqiang , Shang Chengzhang , Hu Yuting 
Published: September 2020

Abstract
Severely immunodeficient mouse strains, such as NOD.Cg-Prkdcscid Il2rg-/-, have been widely used to evaluate human immune responses, including applications in immuno-oncology in recent years. However, when human peripheral blood mononuclear cells (PBMCs) are engrafted in these mice, severe acute xenogeneic graft versus host disease (GvHD) arises due to engagement of human T cell receptors (TCRs) and murine major histocompatibility complex (MHC) I and II. GvHD shortens animal life span and results in only a brief window of evaluation of human immune cell functions in such mouse models. Efforts have been undertaken to reduce human PBMC-induced GvHD and to subsequently extend the window of human immunity assessment by eliminating mouse MHC I and MHC II. While these MHC deficient mice show few symptoms of GvHD, the use of beta-2-microglobulin (B2M) null allele in order to eliminate expression of all MHC I molecules resulted in an unintended consequence in that these mice had rapid antibody clearance. This is because B2M is also associated with neonatal Fc receptor (FcRn) and is important to FcRn-mediated in vivo antibody recycling and retention. Low half-lives of antibodies in B2M null mice render them unsuitable for antibody efficacy assessment. To overcome this undesired pharmacokinetic (PK) limitation of B2M null allele, while retaining its desired effect on eliminating MHC I expression and alleviating GvHD, we engineered a B2M knock-out strain in the background of B-NDG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/Bcgen) that was deficient in MHC I expression but not antibody retention. In present study, we describe genetic, phenotypic, pharmacokinetic, and functional characterizations of the resulting mouse strain, which we believe will be a valuable addition to the collection of severely immunodeficient mouse models that permit extended and appropriate interrogation of antibody therapeutics on human immune cells.
Citation Format: W. Frank An, Lan Gao, Xiaoen Wang, Shruti Sharma, Kaiqi Li, Xiqiang Gao, Chengzhang Shang, Yuting Hu. Development of a novel engineered B2M mouse strain on B-NDG background that specifically eliminates MHC I expression while retaining normal FcRn-mediated antibody retention [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 432.
Abstract 4361: A systematic study of the impact of estrogens and selective estrogen receptor modulators on prostate cancer cell proliferation
Authors: Lafront Camille , Germain Lucas , Weidmann Cindy , Audet-Walsh Etienne 
Published: September 2020

Abstract
The estrogen receptors ERα and ERβ are expressed in prostate cancer (PCa) cells and are believed to act as an oncogene and a tumor suppressor, respectively, and thus to be attractive therapeutic targets. Indeed, compounds modulating the activity of these receptors already exist and are currently used to treat ERα-positive breast tumors. However, there is a lot of discrepancies regarding the efficacy of anti-estrogen treatments for the management of PCa. Several factors explain these discrepancies, including unspecific antibodies against ERβ, lack of proper estrogenic positive controls, and usage of estrogens and anti-estrogens molecules at high dosages were off-target effects are observed. Our objective was to conduct a systematic study on the impact of estrogenic and anti-estrogenic ligands on PCa cell proliferation and survival. After optimization of our cellular assay using the human breast cancer cell line MCF7, we used five of the most commonly studied human PCa cell models, namely LNCaP, 22Rv1, LAPC4, DU145, and PC3 cells. These cells were treated with nine estrogenic/anti-estrogenic compounds, including five selective estrogen receptor modulators (SERMs), with and without co-treatment with androgens for androgen receptor (AR)-positive cells. In both AR-positive and AR-negative cells, we observed no significant modulation of proliferation following modulation of ERs activity. Using both RNA-seq and Western Blots, ERs expression was mostly undetectable in these models. Our study indicate that commonly used PCa models in vitro are not appropriate models to study the estrogen signaling pathway in PCa. Yet, expression data from PCa tissues indicate a significant expression of both receptors, and indicate that usage of new PCa models or of in vivo models are required to properly study drug repurposing of anti-estrogens and SERMs for PCa treatment.
Citation Format: Camille Lafront, Lucas Germain, Cindy Weidmann, Etienne Audet-Walsh. A systematic study of the impact of estrogens and selective estrogen receptor modulators on prostate cancer cell proliferation [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 4361.
Abstract 4376: OP-1250, a complete estrogen receptor antagonist (CERAN) that shrinks estrogen receptor positive tumors and exhibits favorable pharmacokinetics
Authors: Hodges-Gallagher Leslie , Harmon Cyrus L. , Sun Richard , Myles David C. , Kushner Peter 
Published: September 2020

Abstract
Fulvestrant (FASLODEX), a Complete Estrogen Receptor ANtagonist (CERAN) is recognized as the most effective endocrine therapy for estrogen receptor positive (ER+) metastatic breast cancer. Unfortunately, fulvestrant must be injected i.m. and has poor drug exposure. Thus, an oral compound that shares fulvestrant's drug virtues with improved drug exposure might be both more effective and more convenient than fulvestrant. This realization has sparked intensive efforts to develop such a compound, however most efforts have focused on discovering novel selective estrogen receptor degraders (SERDS) most of which have also displayed agonist activities on gene expression and uterus, and are therefore are also selective estrogen receptor modulators (SERMs). We predict that CERANs that fully block the activities of estrogen receptor alpha (ERalpha) will have a clinical advantage over SERM/SERDs in shrinking breast tumors as well as preventing and treating endocrine resistance.
We have developed a small molecule, OP-1250 that, like fulvestrant, is a CERAN that completely turns off both transcriptional activation functions of ERalpha, as can be seen in a uterine cell assay, and also prevents uterine weight gain in ovariectomized mice. In addition, it blocks degrades ERalpha and blocks the proliferation of a large variety of ER+ breast cells. Using RNAseq, we found many estrogen-regulated biomarkers that are also regulated by SERM/SERDs, however CERANS such as OP-1250 and fulvestrant have no, or even an inverse effect on many such genes.
Unlike fulvestrant, OP-1250 gives high and stable oral drug exposure in multiple species. Consequentially, OP-1250 effectively shrinks ER+ tumors in multiple human tumor xenografts in mice at very low daily doses of 3 mg/kg, even in models containing activating ERalpha mutant receptors. Importantly, the pharmacokinetics and biodistribution of OP-1250 has a favorable profile that results in unusual potency of OP-1250 in vivo.
Citation Format: Leslie Hodges-Gallagher, Cyrus L. Harmon, Richard Sun, David C. Myles, Peter Kushner. OP-1250, a complete estrogen receptor antagonist (CERAN) that shrinks estrogen receptor positive tumors and exhibits favorable pharmacokinetics [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 4376.
Abstract 439: Withaferin A attenuates the induction of cardiac cachexia by ovarian cancer
Authors: Kelm Natia Q. , Straughn Alex R. , Ratajczak Mariusz Z. , Kakar Sham S. 
Published: September 2020

Abstract
The purpose of this study was to investigate whether cardiac cachexia occurs in the context of ovarian cancer and whether Withaferin A could ameliorate the cachectic phenotype. We believe that treatment with Withaferin A can ameliorate cancer-induced cachexia and preserve heart function. Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Cachexia is a common syndrome in advanced cancer patients and accounts for approximately 20% of all cancer-related fatalities. Withaferin A is a steroidal lactone with anti-inflammatory properties that is known to inhibit the growth of ovarian cancer and was recently demonstrated to attenuate the skeletal muscle cachectic phenotype induced by a xenograft model of ovarian cancer. The ovarian cancer cell line A2780 was xenografted into severely immunodeficient female NSG mice via an intraperitoneal (i.p.) injection. Tumor-free control groups received an equivalent volume of sterile saline. Following an engraftment period of 8 days, tumor-free and tumor-bearing mice were treated with vehicle or Withaferin A at one of two doses (2 mg/kg or 4 mg/kg) via i.p. injections every 3 days until the end of the study (4 weeks). Bodyweight and grip strength were assessed on a weekly basis. Heart function was evaluated at the terminal week of the study by echocardiography using Vevo3100 system (FUJIFILM VisualSonics Inc.), followed by histological assessment of the heart for evidence of fibrosis and cardiomyocyte size changes. Cancer induced heart failure in female NSG mice (Systolic dysfunction: FS - 35±3.2; diastolic dysfunction: E/A - 0.45±0.12, IVRT - 22±1.2 msec) and reduced cardiac mass (normalized cardiac mass 9±1.1 (tumor-bearing, vehicle-treated) compared to 13±1.3 (tumor-free, vehicle-treated). Treatment with Withaferin A preserved systolic function in tumor-bearing mice (FS - 58±5.2), but diastolic dysfunction was only modestly improved (E/A - 0.83±0.98, IVRT -17±1.2 msec). Further, Withaferin A ameliorated the reduction in myofibrillar cross-sectional area induced by ovarian cancer. Lastly, treatment with Withaferin A ameliorated fibrotic depositions in the hearts in the tumor-bearing animals. In conclusion, ovarian cancer was shown to induce cardiac cachectic phenotype. Further, it was demonstrated that WFA treatment preserved systolic function, reduced diastolic dysfunction, and attenuated the atrophying and fibrotic effects of the xenografted tumors.
Citation Format: Natia Q. Kelm, Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar. Withaferin A attenuates the induction of cardiac cachexia by 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 439.
Abstract 4397: Pathway-based drug combinatory synergy prediction using gene expression and essentiality data
Authors: Li Jin , Wu Xue , Huo Yang , Liu Enze , Zeng Zhi , Cheng Lijun , Li Lang 
Published: September 2020

Abstract
Background: Experiment based drug combinatory synergy discovery is limited in a moderate scale. Systems biology models can substantially widen the search space, and discover novel mechanisms. While most of systems pharmacology models were designed to optimize the predictive performance for the drug combination synergy, they were limited by their lack of mechanistic interpretations. The gene essentiality data generated from RNAi screening have not been integrated into the systems pharmacology model yet.
Methods: Drug combinatory synergy data from NCI-ALMANAC was used in this research. Cancer cell line gene expression and essential score (RNAi screening from DepMap portal), drug targets and KEGG pathways were used in our systems pharmacology model. Two types of models were constructed. The first model predicts a drug combination's synergy using various pathways among various cell lines. The second model predicts various drug combinatory synergy in a cell line. Machine learning approaches, such as SVR, Ridge regression, Random forest and Logistic regulation were investigated in developing this model. Our predictive models were built upon 43 cell lines with both baseline gene expression and essential scores, 165 KEGG pathways, and 198 drug pairs who have at least synergistic drug combinatory effects in 3 or more cell lines.
Results: In predicting drug combinatory synergy from both predictive models, the mean R square was merely 0.006 using individual gene expression or essentiality data. The mean R-square increased to 0.022 when using pathways. In drug combination specific predictive model (model 1), 64 and 62 drug combinations were related to more than 10 pathways which had enriched essential and expression genes, respectively. The correlation between expression enrich pathways and essential enriched pathways is only 0.04. In the cell line specific predictive model (model 2), drug combination synergy score from 14 cell lines can be predicted with more than 150 pathways, and 5 cell lines can be predicted with less than 10 pathways.
Conclusion: Pathway-based models are more powerful than gene level-based models in predicting drug combination synergy. Gene expressions and essential genes provide much different information in predicting drug combination synergy. Drug combination synergy prediction and its related pathways are dramatically different among different cancer cell lines.
Citation Format: Jin Li, Xue Wu, Yang Huo, Enze Liu, Zhi Zeng, Lijun Cheng, Lang Li. Pathway-based drug combinatory synergy prediction using gene expression and essentiality data [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 4397.