tbuckley/cabot-search huggingface dataset:
Abstract 4225: Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses
Authors: Carsten Krieg, Luis Cardenas, Silvia Guglietta, John Wrangle, Mark Rubinstein, Mark Robinson
Journal: Cancer Research (2019)

Abstract Checkpoint inhibitors have significantly accelerated cancer treatment but still a majority of patients do not respond. Biomarker driven patient stratification early to the right immunotherapeutic might enhance response and patient survival. Here we used high-dimensional mass cytometry (CyTOF) combined with machine-learning bioinformatics for the in-depth characterization of immune responses before and during anti-PD-1 immunotherapy. CyTOF allows us to monitor protein expression of 34 markers on a single cell while running 20 samples simultaneously. The analysis is data driven, can be adapted to high throughput approaches and can model arbitrary trial designs such as batch effects and paired designs and is quantitative over millions of events. Using CyTOF as a precision medicine tool we could predict response to anti-PD-1 using liquid blood biopsies. Biobanked peripheral blood mononuclear cells (PBMCs) from 51 patients with stage IV melanoma before and after 12 weeks of anti-PD-1 therapy was analyzed. We observed a clear T cell response on therapy. The most evident difference in responders before therapy was an enhanced frequency of CD14+ CD16+HLA-DRhi classical monocytes. We validated our results using conventional flow and found a clear correlation of enhanced monocyte frequencies before therapy initiation with clinical response such as lower hazard and extended progression-free and overall survival. In a second study we used CyTOF to monitor immune response in 21 non small cell lung cancer (NSCLC) patients that initially responded and then progressed under anti-PD-1 to a novel combination immunotherapy of anti-PD-1 plus an IL-15 super-agonist (ALT-803). In this phase Ib clinical study a response in the CD8+ T cell compartment was observed. Unexpected our high dimensional unbiased analysis was able to detect and characterize a strong expansion of innate tumor-reactive effector NK cells starting around day 4 of therapy. Taken together, our unbiased artificial intelligence driven immune workflow might support patient selection prior to therapy, and serve as a novel tool for precision medicine to select the right drug combination and identify new drug-able cell populations. Citation Format: Carsten Krieg, Luis Cardenas, Silvia Guglietta, John Wrangle, Mark Rubinstein, Mark Robinson. Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses [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 4225.
Abstract 13117: Impaired Diastolic Adaptation to Acute Volume Overload in the Hypertrophic Rat Heart
Authors: Ana L Pires, Daniel Moreira-Gonçalves, Cláudia Moura, Ricardo Ladeiras-Lopes, Cristina Sena, Raquel Seica, Adelino Leite-Moreira
Journal: Circulation (2011)

In the present study we investigated diastolic adaptation to stretch in the intact heart and if it is preserved in the hypertrophic heart. Seven week old Wistar-Han male rats underwent: moderate tr...
Late infectious complications in hematopoietic cell transplantation survivors.
Authors: Eric Jessen Chow, Kara Cushing-Haugen, Michael Boeckh, Paul Carpenter, Mary Flowers, Stephanie Lee, Wendy M. Leisenring, Beth Mueller, Joshua A. Hill, Aimee Foord
Journal: Journal of Clinical Oncology (2019)

7046 Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p &lt; 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p &lt; 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p &lt; 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.
Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor
Authors: Pengxing He, Shenghui Niu, Shuai Wang, Xiaojing Shi, Siqi Feng, Linna Du, Xuyang Zhang, Zhilu Ma, Bin Yu, Hongmin Liu
Journal: Acta Pharmaceutica Sinica B (2019)

EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of WS-157 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. WS-157 showed excellent inhibitory activities against EGFR (IC50 = 0.81 nmol/L), EGFR[d746−750] (IC50 = 1.2 nmol/L) and EGFR[L858R] (IC50 = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo, and could be used for the development of anti-lung cancer agent targeting EGFR.
Abstract 3659: Alyref is a novel binding partner and co-factor for MYCN-driven oncogenesis in neuroblastoma
Authors: Zsuzsanna Nagy, Maxwell Kanikevich, Jessica Koach, Chelsea Mayoh, Daniel Carter, Tao Liu, Yanhua Du, Cizhong Jiang, Michelle Haber, Murray Norris, Belamy Cheung, Glenn Marshall
Journal: Cancer Research (2019)

Abstract MYCN amplification is a poor prognostic indicator in neuroblastoma associated with high-risk disease. Therapies that directly repress the MYCN oncogenic signal in neuroblastoma are limited. We and others have shown that MYCN requires multiple cofactors to increase its protein stability in neuroblastoma cells, so that the very high MYCN levels required to drive tumourigenesis can be achieved. Here, we have identified ALYREF, a nuclear molecular chaperone protein, as a novel regulator of MYCN function in neuroblastoma. High expression of ALYREF predicted poor neuroblastoma patient survival and substantially correlated with MYCN levels in a large dataset (n=649) of human neuroblastoma tumour samples. ALYREF mRNA expression was also significantly increased in ganglia cells from the homozygous TH-MYCN neuroblastoma mouse in comparison to ganglia from wild-type littermates. Using co-immunoprecipitation and mass spectrometry, we identified ALYREF, as a direct binding partner of nuclear MYCN protein. Chromatin immunoprecipitation showed that MYCN bound the ALYREF gene promoter, and knockdown MYCN by MYCN siRNAs decreased ALYREF expression. A set of overexpression and knockdown experiments in MYCN-amplified neuroblastoma cells revealed that MYCN and ALYREF form a positive forward feedback expression loop. Overexpression of ALYREF further increased MYCN expression and protein stability in MYCN-amplified neuroblastoma cells. We found that ALYREF had a critical function in regulating the turnover of MYCN protein through transcriptional repression of the E3 protein ubiquitin ligase, NEDD4. The stabilized N-Myc oncoprotein enhanced ALYREF expression and stimulated cell growth of neuroblastoma. Additionally, we demonstrated that ALYREF plays a significant role in maintaining cell viability and proliferation of MYCN-amplified neuroblastoma cells. Taken together, our findings demonstrate a crucial role for ALYREF in regulating MYCN function and suggest that ALYREF-mediated stabilization of MYCN protein contributes to the development and progression of the disease. Thus inhibition of ALYREF activity using small molecules is a potential therapy for MYCN-amplified tumours. Citation Format: Zsuzsanna Nagy, Maxwell Kanikevich, Jessica Koach, Chelsea Mayoh, Daniel Carter, Tao Liu, Yanhua Du, Cizhong Jiang, Michelle Haber, Murray Norris, Belamy Cheung, Glenn Marshall. Alyref is a novel binding partner and co-factor for MYCN-driven oncogenesis in neuroblastoma [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 3659.
Abstract 4993: The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas
Authors: Imane Nafia, Ariel Savina, Alban Bessede, Antoine ITALIANO
Journal: Cancer Research (2019)

Abstract Background: Sarcomas are heterogenous malignant mesenchymal neoplasms known to be particularly resistant to immunotherapy, which thus calls the interest of the elucidation of related resistance mechanisms. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of patients undergoing Pembrolizumab and metronomic cyclophosphamide. The KP has already been described to favor tolerance and immune escape through the degradation of L-Tryptophan and production of a series of metabolites including L-Kynurenine. While Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP still represents an attractive therapeutic target, the exact functional role of the KP upon immunotherapy has not yet been clearly elucidated. Methods: Using a preclinical syngeneic mouse model of sarcoma based on the inoculation of murine sarcoma MCA205 cell line, we investigated the modulation of the KP upon PDL1 blockade. Besides the evaluation of tumor growth and survival, intratumoral biopsy was performed and used for further gene expression analysis by RT-qPCR. More precisely, KP enzymes- and key cytokines-encoding genes were assessed. Using the same experimental setting on satellite mice, intratumoral microdialysis was performed on day 13 post-tumor inoculation and kynurenine contents were quantified within the tumoral microenvironment. Results: PDL1 blockade, using a specific anti-PDL1 antibody (provided by Genentech), exhibited a clear anti-tumoral effect associated with an intratumoral inflammatory cytokines signature driven by Ifng, Tnfa and Il2. Interestingly, Ifng level was significantly and positively associated with response to anti-PDL1. As regards to KP enzymes, a slight upregulation of the tryptophan-degrading enzymes Ido1 and Ido2 was detected while no changes were observed for Tdo2. An increase of kynurenine-degrading enzymes, including Kmo (encoding for Kynurenine monoamine oxygenase) and Kynu (encoding for kynureninase), was also detected thereby suggesting that PDL1 blockade favors Kynurenine degradation as a possible compensatory mechanism. These results were confirmed by intratumoral microdialysis in the satellite study. Indeed, anti-PDL1 was able to decrease the Kynurenine to Tryptophan ratio(Kyn / Trp) while increasing intratumoral production of kynurenines catabolites. In conclusion, this new set of data on a preclinical sarcoma model highlights for the first time that PDL1 blockade deeply modulates the Kynurenine Pathway with an effect not exclusively associated to the upper part of the pathway and thus warrants further investigation. Citation Format: Imane Nafia, Ariel Savina, Alban Bessede, Antoine ITALIANO. The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas [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 4993.
Abstract 5030: Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages
Authors: Elham Pishali Bejestani, G. Kenneth Lloyd, Melanie Buchi, Reto Ritschard, Petra Herzig, Ramon Mohanlal, Lan Huang, James R. Tonra, Alfred Zippelius, Abhishek Kashyap
Journal: Cancer Research (2019)

Abstract The M2 phenotype is dominant in tumor associated macrophages (TAMs) and correlates with poor prognosis. As M1 polarized macrophages possess anti-tumor functions, in vivo reprogramming of macrophages is a promising strategy for cancer treatment. We recently demonstrated that microtubule destabilizing chemotherapeutic agents such as plinabulin induce potent dendritic cell maturation and thereby augment anti-tumor immune responses; yet the effects of plinabulin on macrophage polarization remain unknown. Here we demonstrate that plinabulin, which is currently being investigated for both its anti-tumor effect and prevention of chemotherapy-induced neutropenia in phase II/III clinical trials,induces M1 polarization of ex vivo cultured human monocyte-derived M2 macrophages. This was characterized by a reduction in the cell surface expression of M2 markers CD163 and CD206 and an increase in the expression of co-stimulatory M1 markers CD80 and CD86. Phenotypically, plinabulin-polarized human M1 macrophages secreted increasing levels of iNOS and inflammatory cytokines IL-1β, IL-6 and IL-12 while IL-10 and IL-4 secretion decreased. This suggests a functional skewing from immunosuppressive M2 to pro-inflammatory M1 macrophages upon exposure to plinabulin. Similarly, plinabulin induced the M1 polarization of murine FACS sorted F4/80+ intratumoral M2-TAMs, characterized by increased CD80 and decreased CD206 expression. Moreover, systemic treatment (i.p.) of tumor bearing mice with plinabulin led to a significant reduction in the number of tumor-infiltrating TAMs with a concomitant M1 polarization of the remaining TAMs. Indeed, plinabulin treatment of mice bearing subcutaneous MC38 colon cancer or orthotopic EMT6 breast cancer tumors significantly delayed tumor growth. This efficacy of plinabulin remained unaltered in Rag2-/- mice lacking T cells, suggesting that macrophages are required for its anti-tumor activity. These results identify targeting of TAMs by plinabulin as a promising therapeutic strategy. Testing of plinabulin in combination with other macrophage targeting drugs are currently being explored to investigate the dual effect in reprogramming the tumor immune microenvironment. Citation Format: Elham Pishali Bejestani, G. Kenneth Lloyd, Melanie Buchi, Reto Ritschard, Petra Herzig, Ramon Mohanlal, Lan Huang, James R. Tonra, Alfred Zippelius, Abhishek Kashyap. Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages [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 5030.
Abstract 3587: Targeting cancer metabolism: A novel approach for improved radiotherapy
Authors: Suchet Taori, Sarwat Naz, Janet Gamson, Askale Mathias, John Cook, James B. Mitchell
Journal: Cancer Research (2019)

Abstract One key distinguishing hallmark of cancer cells includes a deregulated cellular metabolism that can be reprogrammed to preferentially exhibit dependence on glycolysis over oxidative phosphorylation (OXPHOS) even in the presence of oxygen (commonly known as “Aerobic Glycolysis” or the Warburg Effect). The bi-directional conversion of glucose to lactate in the presence of oxygen is mainly driven by the activity of the lactate dehydrogenase enzyme (LDH), of which, its A isoform is highly overexpressed in a variety of tumors. In the present study we characterized two novel LDH inhibitors (NCI-006 and NCI-737) in combination with ionizing radiation (IR) for their anti-cancer and radio-sensitization effects across tumor types. This study primarily examined effects of this novel combination therapy in cell lines of Pancreatic (MiaPaca, Hs766T, Panc-1), Lung (H460, A549), Head and Neck (FaDU, UMSCC-1), and Prostate (DU145, PC3) origin. Our preliminary results indicated that targeting LDH in conjunction with IR can enhance radiosensitivity under both hypoxic and normoxic conditions across glycolytic tumor cell lines while not affecting non-glycolytic/normal cells (1522, skin fibroblast) in vitro. Further we established that this enhanced radiosensitivity could be attributed to reduced DNA repair as seen by enhanced expression of y-H2AX and reduced ATP generation. Our results also indicated that increased expression of lactate and glucose transporters, combined with cellular bioenergetics changes, leads to a reprogramming of cells to OXPHOS. Lastly, we found that inhibition of OXPHOS and NAD+ in conjunction with these novel LDH inhibitors promotes metabolic synthetic lethality in vitro. As cancer patients continue to receive radiation for local tumor control, we hope that future studies targeting cancer metabolic vulnerabilities in combination with IR in vivo will enhance the therapeutic ratio of radiotherapy. *The LDH inhibitors used in this study were provided by the NCI Experimental Therapeutics (NExT) Program Citation Format: Suchet Taori, Sarwat Naz, Janet Gamson, Askale Mathias, John Cook, James B. Mitchell. Targeting cancer metabolism: A novel approach for improved radiotherapy [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 3587.
B-cell lymphoma/leukaemia 10 and angiotensin II-induced kidney injury
Authors: Lajos Markó, Joon-Keun Park, Norbert Henke, Song Rong, András Balogh, Samuel Klamer, Hendrik Bartolomaeus, Nicola Wilck, Jürgen Ruland, Sofia K Forslund, Friedrich C Luft, Ralf Dechend, Dominik N Müller
Journal: Cardiovascular Research (2019)

B-cell lymphoma/leukaemia 10 (Bcl10) is a member of the CARMA-Bcl10-MALT1 signalosome, linking angiotensin (Ang) II, and antigen-dependent immune-cell activation to nuclear factor kappa-B signalling. We showed earlier that Bcl10 plays a role in Ang II-induced cardiac fibrosis and remodelling, independent of blood pressure. We now investigated the role of Bcl10 in Ang II-induced renal damage.Bcl10 knockout mice (Bcl10 KO) and wild-type (WT) controls were given 1% NaCl in the drinking water and Ang II (1.44 mg/kg/day) for 14 days. Additionally, Bcl10 KO or WT kidneys were transplanted onto WT mice that were challenged by the same protocol for 7 days. Kidneys of Ang II-treated Bcl10 KO mice developed less fibrosis and showed fewer infiltrating cells. Nevertheless, neutrophil gelatinase-associated lipocalin (Ngal) and kidney injury molecule (Kim)1 expression was higher in the kidneys of Ang II-treated Bcl10 KO mice, indicating exacerbated tubular damage. Furthermore, albuminuria was significantly higher in Ang II-treated Bcl10 KO mice accompanied by reduced glomerular nephrin expression and podocyte number. Ang II-treated WT mice transplanted with Bcl10 KO kidney showed more albuminuria and renal Ngal, compared to WT- > WT kidney-transplanted mice, as well as lower podocyte number but similar fibrosis and cell infiltration. Interestingly, mice lacking Bcl10 in the kidney exhibited less Ang II-induced cardiac hypertrophy than controls.Bcl10 has multi-faceted actions in Ang II-induced renal damage. On the one hand, global Bcl10 deficiency ameliorates renal fibrosis and cell infiltration; on the other hand, lack of renal Bcl10 aggravates albuminuria and podocyte damage. These data suggest that Bcl10 maintains podocyte integrity and renal function.
Clinical and prognostic features of adult patients with gangliogliomas.
Authors: Shlomit Yust-Katz, Mark Daniel Anderson, Diane Liu, Ying Yuan, Greg Fuller, John Frederick De Groot
Journal: Journal of Clinical Oncology (2013)

2063 Background: Gangliogliomas (GG) represent less than 1% of primary brain tumors in adults. Little is known regarding prognostic features, clinical characteristics or the impact of treatment on patient (pt) outcomes. Methods: In this IRB approved retrospective study, our neuro-oncology longitudinal database was screened for pts with GG from 1992-2012. 67 adult pts (age&gt;18) were identified. Results: 60 pts presented with low grade GG and 7 with anaplastic GG. The median age at diagnosis was 27 years (18-59). 22 pts developed recurrent disease (18 low grade and 4 high grade) with a median time to recurrence of 87 weeks from surgery. 7 of the pts with low grade GG had malignant transformation to a malignant tumor (anaplastic GG or GBM). 22 pts received radiation therapy, 16 at diagnosis. 14 pts received chemotherapy at recurrence. Pts with incomplete resections or higher grade tumors were more likely to receive chemotherapy or radiation. The median overall survival (OS) time for these pts was not reached with a median follow-up time of 4.6 years. The 2-, 5- and 10-year OS were 98%, 87%, and 76%. Factors on univariate analysis that were significantly associated with OS were KPS at presentation (HR 10.1; 95% CI 2.6, 39.1; p = 0.0008), extent of resection (EOR) (biopsy vs gross total; HR 12.1; 95% CI 2.3, 63.6; p = 0.003), histologic grade (Grade 1-2 vs Grade 3-4; HR 0.06; 95% CI 0.01, 0.3; p = 0.0002), and seizure control following surgery (Engel I vs Engel 2-3; HR 0.1; 95% CI 0.01, 0.9; p = 0.02). Factors on univariate analysis that were significantly associated with progression free survival (PFS) were EOR (biopsy vs gross total; HR 4.0; 95% CI 1.4, 11.9; p = 0.01) and histologic grade (Grade 1-2 vs .Grade 3-4; HR 0.3; 95% CI 0.08, 0.8; p = 0.02). On multivariate analysis, EOR is most significant for PFS (p = 0.01), while tumor grade is most significant for OS (p = 0.004). Conclusions: While GG have an excellent prognosis, malignant histological grade, diagnosis with a biopsy only, poor initial KPS, and presence of seizures following surgery could indicate a worse prognosis. The role of chemotherapy and radiation therapy for incompletely resected or inaccessible low grade GG is unclear.
Is patient and public involvement being privatised?
Authors: Sarah Carr, Jonathan Boote
Journal: BMJ (2019)

The National Institute for Health Research (NIHR) recently announced a new NIHR Centre that will merge NIHR INVOLVE and the NIHR Dissemination Centre and will be operational in April 2020.12 Established in 1996, NIHR INVOLVE promotes and supports patient and public involvement in research funded by the NIHR. The Department of Health and Social Care decided to invite tenders for this new centre before the end of the current …