tbuckley/cabot-search huggingface dataset:
Abstract 2074: Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer
Authors: Sheeja Aravindan, Somasundaram T. Somasundaram, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan
Journal: Cancer Research (2019)

Abstract The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiotherapy-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems (Panc-1, Panc-3.27, BxPC-3, MiaPaCa-2) and a mouse model of radiation-residual disease. For residual PC studies, PC xenografts developed in nude mice were selectively exposed to clinically relevant fractionated irradiation, (2 Gy/day for 5 days per week for a total of 3 weeks), to a total dose of 30 Gy. QPCR profiling of custom archived 88 oncogenes in therapy-resilient PC cells identified a ‘shared’ activation of 40 oncogenes. SW-PD pre-treatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue-microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins (Fosb, cFos, Fra2, cMYC, MYB, NF2) and other critical architects (SELE, CD73, Cytokeratins, Col3, Decorin, and Sulf2). Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment. Citation Format: Sheeja Aravindan, Somasundaram T. Somasundaram, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2074.
Abstract MP72: Geographic and Demographic Patterns of Rheumatic Heart Disease in Western Kenya
Authors: Rebecca Lumsden, Constantine Akwanalo, Wendy P O’Meara, Gerald S Bloomfield
Journal: Circulation (2016)

Introduction: Rheumatic heart disease (RHD) remains a leading cause of cardiovascular mortality in sub-Saharan Africa. Identifying geographic “hot spots” and high risk populations are crucial for the development of RHD prevention and screening strategies in high burden areas. Objectives: We aimed to identify demographic patterns and geographic variation in RHD prevalence in western Kenya. Methods: We conducted a retrospective chart review of all patients &lt;50 years old (n=937) attending adult cardiology clinic at a national referral hospital in western Kenya. Demographic information, residential location and cardiac history were collected. We mapped the spatial distribution of cardiac disease rates and analyzed the effect of distance from the hospital on RHD status using multivariable logistic regression. Results: Two-thirds (64%) of all patients &lt;50 years old had RHD. RHD patients were younger (26 vs. 33 years, p&lt;0.001) and more often female (69% vs. 59%, p=0.002) than non-RHD patients. Patients of Nilote ethnicity had over twice the odds of RHD than non-Nilotes (OR 2.5, 95%CI 1.7-3.7). Global clustering of disease rates exists within 200km of the hospital with significant clustering of the RHD and non-RHD rate difference seen surrounding the hospital in the (Moran’s I: 0.3, p=0.001) (Figure). Clustering was attenuated after controlling for age, gender, ethnicity and distance from the hospital. There was an interaction between ethnicity and distance to the hospital such that the odds of RHD increased with further distance for Nilotes, but the odds of RHD in non-Nilotes decreased with further distance. Conclusion: Most adult cardiology patients treated at a national referral hospital in western Kenya have RHD. Young females of Nilote ethnicity are commonly affected. Ethnicity and distance to the hospital interdependently affect the odds of RHD, and geographic clustering of disease rates may reflect this relationship. Future studies in this area should consider the impact of ethnic predisposition to RHD.
Abstract 4231: Association between age of first full-term pregnancy and subsequent breast cancer risk
Authors: Neha Tabassum
Journal: Cancer Research (2019)

Abstract Introduction Amongst the various risk factors for breast cancer (BC), age at first full-term pregnancy is still a complex problem. Early first full-term pregnancy (before 25 years of age) is believed to confer protection towards the development of BC after menopause compared to the risk in nulliparous women but is also correlated with a transient increase in the risk of developing BC soon after pregnancy. On the other hand, a late first pregnancy (after 35 years of age) is believed to increase the risk of developing breast cancer after menopause, equating or increasing the risk compared to nulliparous women. Material and Methods In our project, currently, we aim to do a pilot study with 4 fresh frozen normal samples of nulliparous and early-and late-parous women from Komen tissue bank (USA) and to create a mathematical model to determine how rates of both drivers and passengers mutations are affected by pregnancy and how the risk can be determined in parous and nulliparous women. We plan to measure low-frequency mutations from fresh frozen normal breast samples from patients with different reproductive stages using both Whole Genome Sequencing in this pilot group,and later on to expand the findings with Exome Sequencing on the remaining cohort of 55 normal samples. Results and Discussions We are currently in the process of analysing the data from the whole genome sequencing and whilst we do this, we are also collecting DNA from laser-capture microdissected epithelial and stromal cells, for the remaining samples. Bioinformatics tools are used to eliminate germline mutations from the stroma and to determine where the mutations are located within the genome, and how their frequency changes within the sample cohort. Conclusion While this study is aimed to understand the scientific basis of breast cancer and therefore it is not clinically applicable in the immediate future, understanding the cancer risk associated with age of pregnancy will provide future patients, in particular from at-risk categories, with an informed choice when deciding to plan a pregnancy and a surveillance programme could also be implemented to closely monitor any changes in the breast after a late pregnancy and improve early detection. Furthermore, we could hypothesise that in the long-term future, with the wider application of mammary ductoscopy, breast samples could be analysed in the clinic to calculate the mutation rate of the patient and identify individual risk. This risk stratification along with available predictors such as the ‘Gail model’ could be applied in breast cancer surveillance programmes. Note: This abstract was not presented at the meeting. Citation Format: Neha Tabassum. Association between age of first full-term pregnancy and subsequent breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4231.
Abstract 1612: The effect of docosahexaenoic acid on androgen-dependent and androgen-independent prostate tumors in combination with abiraterone and enzalutamide
Authors: Andrew R. Cooper, Irvin V. Ma, Andy Shao, Prem Kumar, Ronald S. Pardini
Journal: Cancer Research (2019)

Abstract Standard treatments for prostate cancer typically involve androgen deprivation therapy (ADT). In later stages of prostate cancer, the tumor typically evolves to become insensitive to ADT, otherwise known as castration-resistant prostate cancer (CRPC). Despite being hormone-insensitive, CRPC has been shown to respond to both abiraterone and enzalutamide. Although both treatments deprive the tumor of androgens, they both display different mechanisms of action. Abiraterone inhibits androgen production, and enzalutamide acts by interrupting the binding of androgens to the androgen receptor. Studies in our laboratory have shown that docosahexaenoic acid (DHA; C22:6, n-3), a long chain omega-3 polyunsaturated fatty acid (PUFA), inhibits tumorigenesis in both androgen-dependent (LNCaP) and androgen-independent (PC-3, DU145) prostate cancer cell lines in culture. Moreover, in vivo studies with n-3 supplementation have been shown to significantly reduce PC-3 and DU145 tumor growth compared to corn oil diets rich in linoleic acid (C18:2, n-6). With evidence suggesting that n-3 PUFA dietary supplementation can inhibit tumorigenesis in CRPC, this study investigated the efficacy of DHA in combination with both abiraterone and enzalutamide in a subset of prostate tumor phenotypes in vitro. PC-3 and LNCaP cell viability were reduced with DHA in combination with either enzalutamide or abiraterone compared to primary treatments of each. These results suggest that DHA enrichment can augment abiraterone and/or enzalutamide therapy with androgen-dependent and androgen-independent prostate tumors in vitro. The results of this study provide preliminary evidence of the effectiveness of nutritional supplementation in conjunction with cancer therapeutics, and it will serve as a prelude to a pilot clinical trial evaluating the effects of nutritional supplementation with high levels of omega-3 fatty acids on enzalutamide inhibition of CRPC. Citation Format: Andrew R. Cooper, Irvin V. Ma, Andy Shao, Prem Kumar, Ronald S. Pardini. The effect of docosahexaenoic acid on androgen-dependent and androgen-independent prostate tumors in combination with abiraterone and enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1612.
Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models
Authors: Julie Ross, Marissa Rashkovan, Jennifer Fraszczak, Charles Joly-Beauparlant, Charles Vadnais, René Winkler, Arnaud Droit, Christian Kosan, Tarik Möröy
Journal: Cancer Research (2019)

Abstract Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer that mainly affects children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage lead to health problems later in life, underlining the need for improved therapies. MYC is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy. We show that ablation of the function of the BTB/POZ domain factor Zbtb17 (Miz-1), an important cofactor of c-Myc, significantly delayed T- and B-ALL/lymphoma in mice and interfered with the oncogenic transcriptional activity of c-Myc. Leukemic cells that still emerged in this system activated DNA replication pathways that could be targeted by current chemotherapeutic drugs such as cytarabine. Acute ablation of the Miz-1 POZ domain enhanced the effect of cytarabine treatment. The combined treatment was effective in both Eμ-Myc and Notch ICN-driven leukemia models and prolonged survival of tumor-bearing animals by accelerating apoptosis of leukemic cells. These observations suggest that targeting MIZ-1 could render current ALL chemotherapies more effective, with a better outcome for patients. Significance: Ablation of the POZ domain of Miz-1 perturbs its interaction with c-MYC and delays the generation of T- and B-cell leukemias and lymphomas.
Abstract 425: Development and validation of liquid biopsy assay for copy number loss in cancers
Authors: Simo Zhang, Feng Xie, Amy Chang, Zhixin Zhao, Carlos Montesinos, Xiaohong Wang, Kemin Zhou, Shidong Jia, Jianjun Yu, Pan Du
Journal: Cancer Research (2019)

Abstract Introduction: Copy number loss (CNL) of tumor suppressor genes, such as PTEN, RB1 and BRCA1/2, are common and key characteristics of many cancers. However, non-invasive detection of CNL has represented a strong demand and practical challenge in the clinic. Here we report a high-sensitive liquid biopsy NGS assay coupled with a proprietary bioinformatics pipeline to profile and detect CNL using cell-free circulating DNA (cfDNA). Method: We developed PrediSeq, a proprietary liquid biopsy NGS assay to detect CNL, in addition to SNV, indels, rearrangement, and copy number gain. We leveraged unique molecular identifier (UMI) and proprietary bioinformatics algorithm to suppress background noise caused by PCR pre-amplification and sequencing steps. In-house developed bioinformatics pipeline, DeepSea, is used for ultra-sensitive detection of CNL and other genomic alterations. Reference materials, matched tissue and plasma samples were used for assay validation. Results: PrediSeq CNL assay was validated using serially diluted reference materials with known copy number status. The method was evaluated with the orthogonal whole-genome sequencing using a set of clinical plasma samples with matched tissues. About 82% of CNL calls (ATM, BRCA1, BRCA2, CDKN2A, RB1) in were confirmed between plasma PrediSeq and tissue WGS. In alignment with literature, CNL of ATM, CDKN2A, BRCA1, BRCA2, was observed in plasma samples of a cohort of Her2+, HR+, and triple-negative breast cancer patients. Similarly, we observed the dynamic changes of plasma-based CNL of BRCA2, PTEN, RB1, CDKN2A, ATM genes in patients of metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Conclusion: PrediSeq CNL assay has been successfully developed and validated to detect copy number loss in circulation, providing valuable molecular biomarkers to guide patient selection and treatment monitoring in precision oncology and clinical drug development. Citation Format: Simo Zhang, Feng Xie, Amy Chang, Zhixin Zhao, Carlos Montesinos, Xiaohong Wang, Kemin Zhou, Shidong Jia, Jianjun Yu, Pan Du. Development and validation of liquid biopsy assay for copy number loss in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 425.
The comparison between UGT1A1 single heterozygous and wild-type regarding the clinical outcomes of fixed-dose irinotecan monotherapy for advanced gastric cancer: a multicenter retrospective study
Authors: T. Ando, S. Nakano, S. Yuki, K. Sawada, T. Muranaka, Y. Kawamoto, H. Nakatsumi, H. Yoshita, K. Harada, Y. Kobayashi, T. Miyagishima, K. Hatanaka, A. Tanimoto, A. Ishiguro, T. Honda, T. Sasaki, M. Dazai, Y. Komatsu
Journal: Annals of Oncology (2019)
Borderline ovarian tumors: Long-term survival and preservation of fertility.
Authors: Natasha Gercovich, Carlos Garcia Gerardi, Ernesto Gil Deza, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2012)

e15508 Background: Borderline ovarian tumors, also called low-malignancy potential tumors, are infrequent tumors present predominantly in pre-menopause women. Their evolution after surgical treatment is generally very good. The main objective of this paper is to show the evolution of a group of borderline tumors treated at our institution. Methods: Between January 1, 2000 and January 1 , 2010, 36 patients diagnosed with ovarian borderline tumors were examined by two independent pathologists, according to the guidelines established by the USA Association of Directors of Anatomic and Surgical Pathology. These patients were followed at IOHM and comprise this paper’s study group. Results: Population Characteristics: Mean Age: 41 years (Range: 20-85). Affected Ovary (Right: 17 pts; Left: 14 pts; Both: 5 pts). Pathology: Mucinous (17 pts), Serous (16 pts), Clear, Brenner and Endometroid Cells (1 pt each). Stages: IA (24 pts), IB (5 pts), IC (2pts), IIIA (4 pts), IIIC (1 pt). Five patients presented non-invasive peritoneal implants and three presented positive peritoneal liquid. All patients were surgically treated: 28 with total anexohisterectomy (TAH) and 8 with unilateral ooforectomy. No patient was given any chemotherapy or radiotherapy treatment. Four patients did not attend follow-up consultations and were lost after 4, 6, 12 and 29 months with no evidence of disease (NED). Thirty-two patients were followed bi-annually during the first five years and annually thereafter. One patient became pregnant after the surgery. All patients are alive and NED with an average follow up of 50 months (range: 29-133). Conclusions: 1) Although half the cases in the study were under 35 years old, there were 12 tumors present in patients over 50 years of age and 1 borderline tumor present in an 85 year old patient. 2) Surgically treated ovarian borderline tumors have a high chance of being curable without the need of chemotherapy or radiotherapy. 3) Conservative surgery in young patients allows a conservation of fertility, provided they are subject to an adequate follow-up.
Abstract 2328: BiTE-T cell: A novel design for solid tumor
Authors: Feifei Luo, Yuedi Wang, Jie Liu, Yiwei Chu
Journal: Cancer Research (2019)

Abstract Genetically engineered T cells therapy is a promising strategy in cancer immunotherapy. Chimeric antigen receptor (CAR)-T cells therapy, as one successful strategy, has achieved the breakthrough and been approved in non-solid tumor but not solid tumor, which might be limited partially by CARs-restricted on cell surface and side effects of retrovirus. Meanwhile, bispecific T cell engager (BiTE), as another successful strategy, has been approved in non-solid tumor, the therapeutic limitation of which in solid tumor might be the short half-life of antibodies, the lack of endogenous effector T cells in patients with advanced cancer, and severe adverse effects. In this study, we developed a novel glypican-3 (GPC3)-targeting BiTE, αGPC3/CD3. These GPC3-BiTE engineered human T cells persistently produced GPC3-BiTE fusion proteins, which were released extracellularly to help both engineered T cell and bystander T cells to exhibit GPC3-specific activity. As a result, GPC3-BiTE-T cells could possess the capability of both CAR-T cells and BiTE, and even aid more than conventional CART cells in the CART-like function. In addition, GPC3+ tumor-bearing mice treated with the secretable GPC3-BiTE-T cells got a significant tumor growth inhibition and prolonged survival without observed adverse effect. Compared with control groups, more GPC3-BiTE-T cells with less PD-1 expression were detected at tumor site, which was similar to the GPC3-CART cell therapy. And the accumulation of GPC3-BiTE-T cells was positively related with the inhibition of tumor growth. Moreover, GPC3-BiTE-T cells assisted bystander T cells accumulated into tumor site in vivo, which was lack in GPC3-CART cell therapy. Thus, the novel GPC3-BiTE-T cells have the characteristics of high potency, long term and low toxicity, which might supply an attractive GPC3-targeting immunotherapy for solid tumors. Citation Format: Feifei Luo, Yuedi Wang, Jie Liu, Yiwei Chu. BiTE-T cell: A novel design for solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2328.
Prognostic implications of free cancer cells in gastric juice in gastric cancer patients who underwent surgery: a prospective cohort study
Authors: D. Manaka, S. Konishi, K. Kawaguchi, Y. Ikeda, T. Ota, R. Kudo, H. Ann, N. Sasaki, S. Hamasu, R. Nishitai
Journal: Annals of Oncology (2019)
T Cell Recruitment to the Intestinal Stem Cell Compartment Drives Immune-Mediated Intestinal Damage after Allogeneic Transplantation
Authors: Ya-Yuan Fu, Anastasiya Egorova, Catherine Sobieski, Jason Kuttiyara, Marco Calafiore, Shuichiro Takashima, Hans Clevers, Alan M. Hanash
Journal: Immunity (2019)
Alcohol excess: time for a new positive and multifaceted strategy
Authors: Michael Craig Watson, John Lloyd
Journal: BMJ (2019)

We agree with Salisbury that new measures are needed to promote sensible attitudes towards drinking and are pleased that her article took a balanced approach.1 We need a positive and multifaceted strategy that targets different settings and supports different age groups.

Much more could be done in primary care.234 Early identification and brief advice …
Managing cytokine release syndrome (CRS) and neurotoxicity with step-fractionated dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).
Authors: Nancy L. Bartlett, Laurie Helen Sehn, Sarit E. Assouline, Francesc Bosch, Catherine S. Magid Diefenbach, Ian Flinn, Jungyong Hong, Wonseog S Kim, Matthew J. Matasar, Loretta J. Nastoupil, Stephen J Schuster, Mazyar Shadman, Sung-Soo Yoon, Brendan Bender, Antonia Kwan, Wang Cunlin, Michael C. Wei, Shen Yin, Kasra Yousefi, L. Elizabeth Budde
Journal: Journal of Clinical Oncology (2019)

7518 Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]