tbuckley/cabot-search huggingface dataset:
Abstract 3773: Investigating the tumor-host evolutionary arms race as a possible strategy for cancer therapy
Authors: Arig A. Ibrahim Hashim, Dominique Abrahams, Kim Luddy, Robert Gillies, Christina L. Richards, Joel Brown, Robert Gatenby
Journal: Cancer Research (2019)

Abstract As first proposed by Cairns and Nowell more than 60 years ago, cancer is a Darwinian process so that cancer progression and resistance to therapy are governed by natural selection and eco-evolutionary dynamics. This creates an “evolutionary arms race” between the cancer cells and the tumor suppressor mechanisms of the host. To mechanistically investigate these dynamics we have conducted an experiment in which we selected for resistance to growth of implanted Lewis lung (mouse) cancer tumor (LL/2-Luc-M38) cells in immuno-deficient (SCID) mice and immuno-competent (C57BL/6). At each round a fixed numbers of LL/2-Luc-M38 cells were implanted in 10 male SCID and 10 male C57BL/6 mice. Tumor growth was measured and the two animals that exhibited the slowest tumor growth were bred and their male progeny were used as host in the subsequent round. After 12 generations, the tumors grew at approximately 1/10th the rate compared their initial generation. We observed that the hosts evolved cancer suppression through two general strategies. The evolved SCID mice suppressed tumor growth via mechanical restriction with increased in collagen deposition in and around the tumor. In contrast BL/6 mice enhance their immunologic response. We investigated the molecular properties of tumor cells growing in the different cohorts suing microarray. We identified genes significantly different in their expression of cancer cells harvested at different days following injection in Wild Type and Evolved SCID and BL/6 mice using Principle component analysis (PCA) method. The genes were functionally classified based on Gene Ontology and the majority was found to be related to integrin binding, cell adhesion molecular binding, and extra cellular matrix (ECM) binding in SCID mice with collagen, type XII, alpha (Col12a1) being the significantly decreased (results validated with RT-PCR (**p=0.009)). However, in BL/6 mice Molecular studies, contrary to expectation, did not show significant changes in expression of immune-related genes. Rather we found a decrease in expression of genes associated with the angiogenesis and ATP production as well as increased expression of genes regulating EMT. Thus, our results highly suggest that the counter adaptive strategies deployed by the cancer cells in response to the host suppressive mechanisms is host dependent and can be a possible target for therapy. Citation Format: Arig A. Ibrahim Hashim, Dominique Abrahams, Kim Luddy, Robert Gillies, Christina L. Richards, Joel Brown, Robert Gatenby. Investigating the tumor-host evolutionary arms race as a possible strategy for cancer therapy [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 3773.
Doctors can lead case to change Northern Ireland’s highly restrictive abortion laws
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The trusted voices of doctors and medical staff are the key to changing abortion laws to give women in Northern Ireland choice, according to a panel of experts.

The panel—which met in Belfast on 23 June to discuss access to safe abortions—shared their experiences of caring for women and seeing the impact of restrictive abortion laws.

In Northern Ireland, women can only have an abortion under exceptional circumstances, such as if the pregnancy poses a serious risk to their life. Women who undergo an abortion outside of these circumstances can face life in prison.

Emma Campbell, co-chair of the campaign group Alliance for Choice, said Department of Health guidelines on abortion in Northern Ireland, published in 2013, had left doctors in a “sticky situation” because the guidelines interpreted the law in a more conservative way than was previously practised.

She said: “Until 2013 there were around 80 legal abortions performed in Northern Ireland each year, and last year it was around 12. The interpretation, in terms of mental health, was that the woman will need to have been sectioned or have had at least two psychotic episodes. That is a high bar. Or it will have to be a condition which would mean her pregnancy would kill …
Abstract 1448: Lymphangiogenesis-inducing whole-cell vaccine against melanoma promotes broad tumor-specific T cell immunity and effective tumor control
Authors: Maria Stella Sasso, Sylvie Hauert, Priscilla S. Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz
Journal: Cancer Research (2019)

Abstract We recently reported that the growth of lymphatic vessels (lymphangiogenesis) in mouse melanomas dramatically enhances the efficacy of immunotherapy by promoting immune cell infiltration and broadening the anti-tumor T cell repertoire (Fankhauser et al, Sci. Trans. Med. 2017). Correlative evidence supporting such ‘lymphangiogenic potentiation’ was also seen in human melanoma patients, suggesting a possible immunotherapeutic use of the pro-lymphangiogenic growth factor VEGFC. On the other hand, tumor lymphangiogenesis is known to promote cancer cell dissemination and metastasis, raising concerns about the possibility of manipulating lymphatic vessels directly within the tumor site as a treatment strategy for cancer immunotherapy. Here, we sought to manipulate and exploit the immune-promoting functions of lymphatics remotely from the tumor by developing a lymphangiogenesis-inducing cancer vaccine that mimics the microenvironment of a lymphangiogenic tumor. Whole-cell vaccines were formulated using lethally irradiated B16F10 or B16F10-OVA mouse melanoma cells, either mock-transduced or genetically modified to overexpress VEGFC, and combined with topically retained immune adjuvants (ctrl-vax and VEGFC-vax, respectively). Upon intradermal injection, VEGFC-vax induced extensive local lymphatic growth and stimulated increased lymphatic transport from the vaccine site to the draining lymph nodes. Consistently with our previous study, VEGFC induced CCL21 upregulation and local recruitment of CCR7+ naïve T cells, which could undergo in situ priming in the vaccine site. Compared to ctrl-vax, VEGFC-vax elicited a robust T cell response directed against multiple mouse melanoma antigens, as assessed by ex vivo antigen stimulation and IFNγ ELISPOT. In a prophylactic vaccine setting, VEGFC-vax induced stronger tumor-specific T cell immunity and greater protection from tumor challenge compared to both ctrl-vax as well as a GM-CSF-secreting whole-cell vaccine. Overall this study provides a proof of concept for the use of VEGFC in cancer vaccines and characterizes a whole-cell lymphangiogenesis-inducing vaccine formulation with potential for clinical translation. Citation Format: Maria Stella Sasso, Sylvie Hauert, Priscilla S. Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz. Lymphangiogenesis-inducing whole-cell vaccine against melanoma promotes broad tumor-specific T cell immunity and effective tumor control [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 1448.
Abstract 3251: Fibroblast activation protein (FAP)-selective delivery of CD40 agonistic DARPin®molecule for tumor-localized immune activation
Authors: Nicolo Rigamonti, Anja Schlegel, Sophie Barsin, Jonas Schwestermann, Susanne Mangold, Yvonne Kaufmann, Christof Zitt, Niina Veitonmäki, Victor Levitsky, Clara Metz
Journal: Cancer Research (2019)

Abstract CD40 is a co-stimulatory molecule belonging to the tumor necrosis factor receptor superfamily which can activate both innate and adaptive immune system, making it an interesting target for tumor immunotherapy. Systemic administration of agonistic CD40 antibodies (Ab) has shown signs of activity in cancer patients, but dose-limiting toxicity impaired the clinical efficacy. New approaches are therefore needed to increase the therapeutic index of CD40-targeting molecules and achieve better clinical outcomes. Here, we report an alternative approach designed to activate CD40 specifically in the tumor microenvironment (TME), and not systemically, in order to increase efficacy and reduce systemic toxicity. This novel approach is based on a bispecific DARPin® molecule, targeting CD40 and fibroblast activation protein (FAP) alpha, intended to induce immune activation only when clustered by binding to FAP-expressing cells in the TME. The bispecific FAP x CD40 DARPin®molecule was tested in a reporter assay and in additional cell assays using primary human 1) B cells, 2) macrophages and 3) dendritic cells. These studies demonstrated CD40 activation only in the presence of FAP-positive, but not with FAP-negative cells, confirming a mechanism of action strictly dependent on FAP-mediated cross-linking. A surrogate mouse-specific FAP x CD40 DARPin® molecule (mFAP x CD40) was generated and tested in similar in vitro assays and showed FAP-dependent activation of CD40 and comparable results as the human construct. In vivo experiments, performed in tumor-free mice, showed a comparable half-life between mFAP x CD40 and an anti-mouse CD40 Ab (clone FGK45). However, mFAP x CD40, in contrast to the FGK45 Ab, did not increase the serum level of IL-6, supporting a mode of action that is dependent on FAP-mediated crosslinking of CD40 receptor. In additional studies mFAP x CD40 was active and inhibited the growth of FAP+ tumors. There were no signs of toxicity with mFAP x CD40 in contrast to the FGK45 Ab which resulted in body weight loss. In conclusion, we have generated bispecific agonist FAP x CD40 DARPin® molecules able to activate the CD40 pathway with a targeting (FAP)-dependent mechanism of action. Citation Format: Nicolo Rigamonti, Anja Schlegel, Sophie Barsin, Jonas Schwestermann, Susanne Mangold, Yvonne Kaufmann, Christof Zitt, Niina Veitonmäki, Victor Levitsky, Clara Metz. Fibroblast activation protein (FAP)-selective delivery of CD40 agonistic DARPin®molecule for tumor-localized immune activation [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 3251.
Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.
Authors: Kirsten Fischer, Othman Al-Sawaf, Jasmin Bahlo, Anna-Maria Fink, Maneesh Tandon, Mark Dixon, Sandra Robrecht, Kathryn Humphrey, Sebastian Böttcher, Eugen Tausch, Rod Humerickhouse, Barbara Eichhorst, Clemens-Martin Wendtner, Anton W. Langerak, Karl-Anton Kreuzer, Valentin Goede, Stephan Stilgenbauer, Mehrdad Mobasher, Matthias Ritgen, Michael J. Hallek
Journal: Journal of Clinical Oncology (2019)

7502 Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score &gt;6 and/or an estimated creatinine clearance &lt;70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles (C) of standard Clb or Ven 400 mg daily in combination with G for first 6 C. Primary endpoint was PFS. MRD− in peripheral blood (PB) or bone marrow (BM) 3 months (mo) after treatment completion was a key secondary endpoint. MRD was analyzed serially from C4 every 3 mo by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10 -4 ) and by next generation sequencing (NGS; cut-offs, 10 -4 , 10 -5 ,10 -6 ). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P&lt;0.0001). MRD− by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P&lt;0.0001]) and BM (57% vs 17% [P&lt;0.0001]) 3 mo after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD− was associated with longer PFS. Higher MRD− rates were achieved early and were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 mo after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off-treatment: 19 mo). MRD− rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD− at &lt;10 -4 , 31% vs 4% at &lt;10 -6 and 35% vs 15% at ≥10 -6 –&lt;10 -5 , respectively. Conclusions: Fixed-duration VenG induced deep (&lt;10 -6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.
National data on the epidemiology of IDDM in Greece
Authors: C. Dacou-Voutetakis, K. Karavanaki, H. Tsoka-Gennatas
Journal: Diabetes Care (1995)

OBJECTIVE-To detect the incidence, geographic distribution, and seasonal variation of insulin-dependent diabetes mellitus (IDDM) in all of Greece. RESEARCH DESIGN AND METHODS--One hundred and thirty-seven children (75 boys and 62 girls) up to 14.9 years of age were diagnosed with IDDM in Greece in 1992. RESULTS--The age-adjusted incidence of IDDM in Greece in 1992 was 6.25/100,000 population (boys: 6.17/100,000; girls: 6.28/100,000). There was a significant pubertal peak. The incidence of IDDM was significantly higher in metropolitan (10.0/100,000) than in rural (4.21/100,000), semirural (7.48/100,000), or urban areas (5.36/100,000) of Athens. There was a marginal difference between rural and semirural areas. No significant seasonal variation in the incidence of IDDM was observed. CONCLUSIONS--We conclude that the incidence of IDDM in Greece is among the five lowest in Europe. An impressive clustering of cases was observed in the Athens metropolitan area compared with the rural and semirural areas, an observation that possibly underlines the importance of environmental factors (stressful situations, infections, dietary habits, and others) in the expression of IDDM.
Outcome of CML patients with de novo bleeding complications: Do they behave differently?
Authors: Rajeev Sandal, Aditya Jandial, Kundan Mishra, Gaurav Prakash, Alka Khadwal, Deepesh Lad, Neelam Varma, Pankaj Malhotra
Journal: Journal of Clinical Oncology (2019)

e18546 Background: Chronic myeloid leukemia (CML) is a clonal hematopoietic neoplasm. A subset of CML patients present may present with unusual bleeding manifestations. There is limited data on the incidence and outcome of such patients on treatment with imatinib. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score, site and severity of bleeding (as per WHO classification) were recorded. The treatment response, occurrence of cytopenias and need for second line TKI were analyzed. Results: Sixty-six patients (2.8%) out of 2350 adult CML patients had bleeding at diagnosis. The median age was 35 years (range 15 – 66 years); 56.1% were males. The median duration of follow up was 79 months (range 6 – 123 months). Splenomegaly and hepatomegaly was found in 89.3% and 65.1% patients, respectively. Baseline median hemoglobin was 9.5 g/dL; TLC was 151600/mm 3 and platelet count was 301000/mm 3 . Based on Sokal score, 15/66, 26/66 and 25/66 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 22/66, 36/66 and 8/66 patients belonged to low, intermediate and high risk categories, respectively. Based on WHO grading, 33/66, 30/66 and 3/66 patients had grade 1, 2 and 3 bleed, respectively. 48 patients had mucocutaneous bleeding [cutaneous 17, gum bleed 16, epistaxis 15], 4 had psoas haematoma, 7 had vaginal bleeding, 3 had ocular bleeding, 6 had GI bleed [upper GI 3, lower GI 3], 3 had hematuria. 74.2% achieved CHR at 6 weeks and 83.3% achieved MMR at 12 months with Imatinib. 18 developed cytopenias which required Imatinib interruption or dose reduction. 18 required Imatinib dose escalation for suboptimal response, 5 patients received second line TKI. Six patients progressed to advanced phase CML (AP/BC) after a median duration of 32 months (range 21 – 49 months). Bleeding manifestations resolved in all patients and there was no recurrence of bleeding on follow up. Conclusions: Bleeding is an uncommon presentation of CML. It might be a harbinger of an increased risk of cytopenias, suboptimal treatment response and disease progression on Imatinib.
Abstract 12571: Additive Value of Pulse Pressure Reserve During Exercise for Triage of Heart Failure With Reduced Ejection Fraction
Authors: Renata R Castro, Jesse Caron, Amil Shah, Bradley A Maron, Karla Sirianni, Jon Hainer, Marcelo Di Carli, Lynne W Stevenson, John D Groarke
Journal: Circulation (2018)

Introduction: Narrow pulse pressure (PP) at rest is associated with higher mortality in heart failure (HF) but the relevance of PP reserve (PPR) analyzed during exercise is unknown. Hypothesis: Low...
Abstract 4784: Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma
Authors: Huei-Yue Dai, Long-Yuan Li
Journal: Cancer Research (2019)

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Sorafenib, a multikinase inhibitor, is the first-line target therapy for patients with advanced HCC, but the response rate is low. Thus, development of more effective therapeutics for HCC is needed. Previously we have established a HCC-targeted BikDD gene therapy vector driven by a liver cancer-specific α-fetoprotein promoter/enhancer and transcriptional amplification module. Systemic administration of liposome-loaded HCC-targeted BikDD gene therapy vector effectively suppressed tumor growth and prolonged survival in multiple orthotopic HCC mouse models with no toxicity. Here, we further investigated whether combination of sorafenib with gene therapy could enhance anti-HCC activity. The results showed that combination of BikDD gene therapy with HCC targeted therapeutic agent sorafenib synergistically killed a panel of liver cancer cells but not normal cells in vitro by WST-1 assays and analysis of combination index according to the Chou and Talalay method. Moreover, a low dose of sorafenib combined with BikDD gene therapy augmented tumor inhibition and better mice survival compared with separate treatment alone in xenograft and syngeneic orthotopic HCC mouse models. These results suggest that sorafenib combined with HCC-targeted gene therapy may improve the therapeutic efficacy and may be a potential alternative therapeutics for HCC. Citation Format: Huei-Yue Dai, Long-Yuan Li. Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma [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 4784.
Abstract 4202: Identifying predictors of racial disparities in mortality among Blacks and Whites diagnosed with breast cancer in South Carolina
Authors: Oluwole Adeyemi Babatunde, Swann A. Adams, Jan M. Eberth, Tisha M. Felder, Robert Moran, Samantha Truman, Christian Alvarado, James Hebert
Journal: Cancer Research (2019)

Abstract Introduction: Mortality among White breast cancer (BrCA) patients is 7% lower in South Carolina (SC) and is 29% higher among Black BrCA patients in SC compared to the national average. The aim of this study was to identify predictors of racial disparities in mortality among Black and White BrCA patients in SC. Methods: Breast cancer cases were obtained retrospectively from the SC Central Cancer Registry, linked with administrative data from a private payor insurance and Medicaid Plan from 2002 to 2010. The main outcome variable was mortality which was operationalized by vital status and total survival time. The main exposure variable was patient race (White vs Black). Cox proportional hazard analyses were conducted to compare hazard ratios among Blacks and Whites to identify predictors of mortality. In assessing the relationship between race and mortality, we examined marital status, urbanicity, region, and Best Chance Network enrollment as potential effect modifiers. The multivariable model was stratified by the effect modifier variables and a backward elimination process was utilized to obtain the best fitting model among models with the following covariates: age, year of diagnosis, hormone-receptor status, stage, and grade. Results: A total of 2155 breast cancer patients (nWhites=1557; nBlacks= 598) were reported in the study period. Adjusting for cancer stage, the hazard ratio of mortality was 3.45 (1.64,7.25) among Black women who lived in the Low Country region of the state compared with White women who lived in the Low Country region of the state. In the other three regions of the state (Midlands, PeeDee and Upstate); there were no statistically significant differences between Blacks with Whites. Adjusting for cancer stage and grade showed that the hazard ratio of mortality was 1.53 (1.04,2.26) among Black women who lived in urban areas compared with White women who lived in urban areas. There were no differences between Blacks and Whites who lived in rural areas. Conclusions: Mortality was higher among Blacks who lived in the Low Country region of the state and among Blacks who lived in urban areas. To reduce racial disparities in survival, efforts directed at early detection and linkage to timely breast cancer treatment should be focused on black women living in the Low Country region of the state and in urban areas. Citation Format: Oluwole Adeyemi Babatunde, Swann A. Adams, Jan M. Eberth, Tisha M. Felder, Robert Moran, Samantha Truman, Christian Alvarado, James Hebert. Identifying predictors of racial disparities in mortality among Blacks and Whites diagnosed with breast cancer in South Carolina [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 4202.
Detection of Brain Activation in Unresponsive Patients with Acute Brain Injury
Authors: Jan Claassen, Kevin Doyle, Adu Matory, Caroline Couch, Kelly M. Burger, Angela Velazquez, Joshua U. Okonkwo, Jean-Rémi King, Soojin Park, Sachin Agarwal, David Roh, Murad Megjhani, Andrey Eliseyev, E. Sander Connolly, Benjamin Rohaut
Journal: New England Journal of Medicine (2019)

Brain activation in response to spoken motor commands can be detected by electroencephalography (EEG) in clinically unresponsive patients. The prevalence and prognostic importance of a dissociation between commanded motor behavior and brain activation in the first few days after brain injury are not well understood.