tbuckley/cabot-search huggingface dataset:
Abstract 1839: Nanobodies against EGF enhance the antitumoral effect of osimertinib and overcome resistance in non-small cell lung cancer cell models
Authors: Salvador Guardiola, Macarena Sánchez-Navarro, Ernest Giralt, Rafael Rosell, Jordi Codony-Servat
Journal: Cancer Research (2021)

Abstract Background: The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) osimertinib improves therapy for non-small cell lung cancer (NSCLC) patients who possess EGFR mutations. However, acquired resistance appears invariably due to several mechanisms. The strategy of using EGF-targeted nanobodies (Nbs) to block the initial step of the EGFR pathway constitutes a new research area. Nbs also offer several advantages compared to traditional mAbs, such as their reduced size, higher stability and tissue penetration, low production costs and lack of Fc effector function, which provide key advantages for targeting soluble tumoral growth factors. In this study we investigated the efficacy of anti-EGF Nbs to reduce osimertinib-resistance. Experimental procedures: Cell viability and colony formation assays were performed in PC9 and PC9-osimertinib-resistant NSCLC cell lines tested with anti-EGF Nbs alone or in combination with osimertinib. To analyze the mechanism of action of these compounds and its combination, western blot analysis was carried out to study protein expression and activation. Summary of data: Two anti-EGF Nbs, generated in our laboratory, inhibited cell viability and colony formation in PC9 and PC9-derived osimertinib-resistant cell lines. The combination of these Nbs with osimertinib improved the antitumoral efficacy of this EGFR-TKI in cell viability and colony formation experiments. The combination of anti-EGF Nbs with osimertinib clearly decreases the activation of proteins involved in the EGFR pathway, such as, EGFR, Akt and Erk 1/2. In addition, it increases cellular apoptosis, and decreases the expression of Hes1, a marker of cancer stem cells involved in metastasis and osimertinib resistance mechanisms. Conclusions: We conclude that the combination of anti-EGF nanobodies and osimertinib exhibits a good efficacy in inhibiting cell viability and colony formation, while, inhibiting expression and activation of proteins involved in osimertinib resistance. Citation Format: Salvador Guardiola, Macarena Sánchez-Navarro, Ernest Giralt, Rafael Rosell, Jordi Codony-Servat. Nanobodies against EGF enhance the antitumoral effect of osimertinib and overcome resistance in non-small cell lung cancer cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1839.
Abstract 355: Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression
Authors: Xiancheng Zeng, Xinyi Liu, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: Gastric or GEJ cancer with positive PD-L1 expression have been proved a subgroup who can benefit from first-line and second-line therapy of PD-1 inhibitors. Positive PD-L1 expression promises to be the most effective biomarker in gastric/GEJ cancer patients. The results of CheckMate-649 further revealed that patients with PD-L1 CPS≥5 were more favorable to PD-1 inhibitors. On the other hand, high level of tumor mutational burden, MSI-H and mutations in DDR genes had also been identified as biomarkers in setting of immune checkpoint inhibitors in cancers. The difference of genomic features in subgroups with PD-L1 expression level in gastric/GEJ cancers is a question of interest. Method: 613 cases of Chinese gastric/GEJ cancer patients were included in our analysis. Immunohistochemistry and 381-gene panel next-generation sequencing (NGS) testing had been performed in their tumor tissue specimen. PD-L1 expression level was evaluated by the combined positive score (CPS). Tumor mutational burden and MSI status were evaluated via NGS testing. Somatic and germline mutations in 30 DDR genes had also been analyzed. Result: 493 out of 613 patients were CPS&amp;lt;1, 54 cases were CPS&amp;lt;5, 64 cases were CPS &amp;lt;49, 16 cases were CPS≥50. The median TMB score of four subgroups were 5.59, 7.26, 7.26 and 8.06 respectively. The proportion of MSI-H patients in four subgroups were 3.25%, 9.26%, 12.5%, and 12.5% respectively. ARID1A and ARTX genes only were detected somatic mutated. There was a negative correlation trend in germline mutational proportion and PD-L1 expression level in some genes, such as MSH2, POLE, POLD1, PALB2 and PTEN. However, the somatic mutational proportion of MSH6, PMS2, POLE genes had a positive correlation trend with PD-L1 expression level. Conclusion: In Chinese gastric/GEJ cancer population, the TMB level of CPS≥1 subgroup was significantly higher than CPS&amp;lt;1 subgroup. MSI-H patients were enriched in CPS&amp;gt;5 subgroup. In addition, DDR genes had distinct mutational frequency in subgroups with different levels of PD-L1 expression, indicating they impact the immunogenicity of gastric/GEJ cancer through different mechanisms. Citation Format: Xiancheng Zeng, Xinyi Liu, Mengli Huang. Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 355.
Chronic pain and localized hypoesthesia following minimally invasive adrenalectomy: Prevalence and impact on quality of life
Authors: A. Van Uitert, E.V. Van Helden, K.I. Albers, M. Steegers, H.J. Timmers, F.C.H. D’Ancona, S. Van Der Wal, G.J. Scheffer, C. Keijzer, M.C. Warlé, J.F. Langenhuijsen
Journal: European Urology (2021)
Excess Mortality in COVID-19-Positive Versus COVID-19-Negative Inpatients With Diabetes: A Nationwide Study
Authors: Elias K. Spanakis, Ashley Yoo, Oluwagbemiga N. Ajayi, Tariq Siddiqui, Mohd M. Khan, Stephen L. Seliger, David C. Klonoff, Zhaoyong Feng, John D. Sorkin
Journal: Diabetes Care (2021)

Diabetes is a major risk factor for death in those with coronavirus disease 2019 (COVID-19) infection (1).However, even those with diabetes who do not have a COVID-19 infection have an increased risk for mortality compared with those without diabetes (2).In the current study, we focused on hospitalized patients with diabetes and compared those who tested positive for COVID-19 infection to those who tested negative.Our aim was to identify the excess risk of mortality that COVID-19 infection adds among inpatients with diabetes and to assess if this increased mortality can be explained by underlying comorbidities/complications or if it is more closely related to the COVID-19 disease.For this cohort study, we used data from the Veterans Affairs (VA) Central Data Warehouse.We focused only on inpatients with diabetes who were evaluated for COVID-19 infection from 3 March 2020 to 21 May 2020 and for whom we were able to extract the available covariates.To avoid inaccurate diagnoses of diabetes, such as stressinduced hyperglycemia, we included only those who had diabetes prior to 1 January 2019.
Genomics-informed responses in the elimination of COVID-19 in Victoria, Australia: an observational, genomic epidemiological study
Authors: Courtney R Lane, Norelle L Sherry, Ashleigh F Porter, Sebastian Duchene, Kristy Horan, Patiyan Andersson, Mathilda Wilmot, Annabelle Turner, Sally Dougall, Sandra A Johnson, Michelle Sait, Anders Gonçalves da Silva, Susan A Ballard, Tuyet Hoang, Timothy P Stinear, Leon Caly, Vitali Sintchenko, Rikki Graham, Jamie McMahon, David Smith, Lex EX Leong, Ella M Meumann, Louise Cooley, Benjamin Schwessinger, William Rawlinson, Sebastiaan J van Hal, Nicola Stephens, Mike Catton, Clare Looker, Simon Crouch, Brett Sutton, Charles Alpren, Deborah A Williamson, Torsten Seemann, Benjamin P Howden
Journal: The Lancet Public Health (2021)
Preclinical modeling in glioblastoma patient-derived xenograft (GBM PDX) xenografts to guide clinical development of lisavanbulin—a novel tumor checkpoint controller targeting microtubules
Authors: Danielle M Burgenske, Surabhi Talele, Jenny L Pokorny, Ann C Mladek, Katrina K Bakken, Brett L Carlson, Mark A Schroeder, Lihong He, Zeng Hu, Gautham Gampa, Matthew L Kosel, Paul A Decker, Gaspar J Kitange, Anne Schmitt-Hoffmann, Felix Bachmann, Rachael A Vaubel, Jeanette E Eckel-Passow, Caterina Giannini, Paul McSheehy, Heidi A Lane, William F Elmquist, Jann N Sarkaria
Journal: Neuro-Oncology (2021)

Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.Mice bearing intracranial tumors received lisavanbulin +/-RT +/-TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.Lisavanbulin monotherapy showed significant benefit (P < .01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01).Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
Abstract 2654: Differential effect of MGMT methylation between moderate or high vascular profile in <i>IDH</i> wild-type glioblastoma
Authors: Maria del Mar Álvarez-Torres, Elies Fuster-García, Javier Juan-Albarracín, Josep Puig, Carmen Balaña, Jaume Capellades, Kyrre Eeg Emblem, Juan Miguel García-Gómez
Journal: Cancer Research (2021)

Abstract A significant association between MGMT methylation and prolonged overall survival (OS) was observed for patients with glioblastoma (GB) that present moderately relative cerebral blood volume (rCBV) 1. However, that study should be updated to the current glioma WHO classification. In the current study we assess the combined effect of rCBV and MGMT methylation combined on OS in patients with IDH wild-type GB. An independent cohort of 95 IDH wild-type GB patients with OS&amp;gt;30 days and with tumor resection was included for this study. The rCBV values of the highest angiogenic tumor regions were automatically calculated using ONCOhabitats analysis services2. Finally, the whole cohort was divided into moderately and highly vascularized GB by the median of the previously calculated rCBVs (rCBVmedian=9.56). We observed a significant association between MGMT methylation and prolonged OS for the whole cohort (p = 0.003, HR = 0.49), as well as for patients with moderate rCBV (p = 0.002, AUC = 0.30). The difference in OS between patients with MGMT methylated and patients with MGMT unmethylated was 4 times higher in the group with moderate rCBV than for the group with high rCBV (205 vs. 42 days). Finally, no association was found between MGMT methylation and OS in patients with high rCBV (p &amp;gt; 0.05) (Table below). Our results highlight the combined prognostic effect of MGMT methylation and moderate vascularity in IDH wild-type GB patients. As demonstrated, non-invasive MRI perfusion markers may identify those patients who will mostly benefit in terms of prolonged OS owing to their MGMT methylation status. 1: doi.org/10.1007/s00330-020-07297-4 2: doi.org/10.1016/j.ijmedinf.2019.05.002 Number of patientsMedian OS (days)ResultsStatistical resultsTotalMeth MGMTUnmethMGMTMeth MGMTUnmethMGMTΔOSHR [95% CI]pAUCAll9551445894501390.49 [0.30-0.78]0.0028*0.61Moderate rCBV4221216534482050.30 [0.14-0.64]0.0020*0.72High rCBV533023493451420.68 [0.37-1.26]0.21800.52 Citation Format: Maria del Mar Álvarez-Torres, Elies Fuster-García, Javier Juan-Albarracín, Josep Puig, Carmen Balaña, Jaume Capellades, Kyrre Eeg Emblem, Juan Miguel García-Gómez. Differential effect of MGMT methylation between moderate or high vascular profile in IDH wild-type glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2654.
Abstract 2847: Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway
Authors: Yeo-Jung Kwon, Sangyun Shin, Young-Jin Chun
Journal: Cancer Research (2021)

Abstract Human CYP1B1 is known as a major metabolizer for estrogen and shows tumor-specific hyper-expression. To explore the role of CYP1B1 on metastasis of human cancer cells, we studied the effects of CYP1B1 inhibition and activation in MCF-10A, MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 significantly induced expression of urokinase-type plasminogen activator receptor (uPAR) as well as uPA. Treatment with DMBA, a well-known CYP1B1 inducer, enhanced uPAR expression while CYP1B1 siRNA and TMS (tetramethoxystilbene), a specific CYP1B1 inhibitor, suppressed uPAR. We also found that CYP1B1 activated uPAR signaling through regulation of related factors including integrin β1 and α5. Interestingly, uPAR overexpression only caused a significant increase of integrin β1 and α5 in protein levels, indicating protein degradation may play an important role in regulating integrin protein level. Surprisingly, CYP1B1 down-regulated p53 expression through MDM2 activation and nutlin-3a, an inhibitor for MDM2, blocked the promoting effects of DMBA on uPAR, which explains that CYP1B1 induced uPAR expression through regulation of MDM2-p53 system. In addition, we revealed that CYP1B1 regulates uPAR through activation of Sp1 transcription factor. CYP1B1 and its enzymatic product, 4-OHE2, promote Sp1 expression levels in both mRNA and protein levels and subsequently Sp1 elevates the transcriptional activity of uPAR through binding to promoter region of uPAR. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPAR pathway which is one of the targets of p53 and Sp1 signaling. Citation Format: Yeo-Jung Kwon, Sangyun Shin, Young-Jin Chun. Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2847.
Abstract 2520: Detection of transcriptional active HPV 16/18 in patients with oropharyngeal squamous cell carcinoma by dual immunohistochemistry p16INK4 and in situ hybridization E6/E7 mRNA in archival material older than 25 years
Authors: Stian Tornaas, Siren Fromreid, Hans Jørgen Aarstad, Olav Karsten Vintermyr, Daniela Elena Costea, Harsh Nitin Dongre
Journal: Cancer Research (2021)

Abstract Introduction: Determination of Human Papillomavirus (HPV) status in oropharyngeal squamous cell carcinomas (OPSCC) is important because it influences the therapeutic decision. A dual protocol combining immunohistochemistry (IHC) for detection of p16INK4 overexpression with in situ hybridization (ISH) for mRNA E6/E7 detection may improve the accuracy of determining the HPV status in OPSCC patients. The aim of this study was to optimize a multiplex method for simultaneous detection of p16 and mRNA E6/E7 on the same formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: IHC for the detection of p16INK4 and chromogenic ISH for mRNA E6/E7 were combined in different sequences and with different intermediate steps for fixation on OPSCC tissue samples from primary tumors and lymph node metastases. Archival tissue samples stored at Department of Pathology at Haukeland University Hospital since 1990 has been used for tests. Results: A combined method for simultaneous detection of p16INK4 and mRNA E6/E7 transcripts on the same tissue slides were successfully developed. Active HPV status was detected in OPSCC tissue samples from both primary and metastatic lymph nodes for all cases tested, including tissue samples stored for 30 years. The result was correlated to DNA HPV status. Conclusion: This study confirms that a more precise detection of active HPV infection is possible on FFPE tissue slides. This method could be easily implemented in clinical settings for more specific stratification of OPSCC patients. At the same time, the method is also robust and sensitive on retrospective archival material, and this could be used for answering important research questions on HPV-related OPSCC. Citation Format: Stian Tornaas, Siren Fromreid, Hans Jørgen Aarstad, Olav Karsten Vintermyr, Daniela Elena Costea, Harsh Nitin Dongre. Detection of transcriptional active HPV 16/18 in patients with oropharyngeal squamous cell carcinoma by dual immunohistochemistry p16INK4 and in situ hybridization E6/E7 mRNA in archival material older than 25 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2520.
Abstract 3036: ALK protein expression and its prognostic significance in MYCN non amplified neuroblastoma
Authors: Natarajan Aravindan, Dinesh Babu Somasundaram, Santny Shanmugarama, Sheeja Aravindan
Journal: Cancer Research (2021)

Abstract Anaplastic lymphoma kinase (ALK) point mutations (within the kinase domain), gene amplification and protein overexpression are identified (8-14%) both in familial and sporadic high-risk neuroblastoma (HR-NB). ALK mutations are much more frequent at time of relapse and were associated with poor clinical outcomes for children with HR-NB. Evidently, ALK is near exclusively co-amplified with MYCN, and the cooperative activity of ALK and MYCN are known to drive HR-NB pathogenesis. However, the ALK protein expression and its role in the prognosis of MYCN non-amplified NB remained unexplored. In this study, NB tumors representing varied stages, ages, sites, diagnosis/progressive disease, primary/metastatic site from a cohort MYCN non-amplified NB patients (n=92) were custom archived in TMAs and stained with ALK (immunohistochemistry) antibody. The correlations between ALK protein expression, and clinico-pathological and biological variables of MYCN non-amplified NB tumors were analyzed. Assessing the strong positivity, high expression of ALK protein could be detected in 47 (51%) of the 92 NB tumors. The majority of NBs with evident of ALK protein high expression exhibited undifferentiated or poorly differentiated histology (39/47, 82.9%). ALK protein high expression significantly predicted worse survival outcomes for NB (and HR-NB subset) patients with MYCN non-amplified status. Transcriptional data mining (R2: Genomics Analysis and Visualization Platform) across multiple cohorts of MYCN non-amplified NB patients revealed unique and defined associations of ALK to the adverse clinical prognostic factors (e.g. advanced disease stage, risk) and poor survival outcomes. Our study recognized the prognostic role of ALK protein expression in MYCN non-amplified NB. Since, ALK is indicated to transactivate MYCN, increase MYCN protein expression, and coordinate disease progression; further studies are warranted to define the mechanism(s) of ALK high-expression associated disease evolution in MYCN non-amplified HR-NB.Funding: This work was partially or in full, funded by Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-04; National Institutes of Health, NIH-P20GM103639 and; NIH-NCI- Cancer Center Support Grant P30CA225520 Citation Format: Natarajan Aravindan, Dinesh Babu Somasundaram, Santny Shanmugarama, Sheeja Aravindan. ALK protein expression and its prognostic significance in MYCN non amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3036.
Abstract 305: ELU001, a targeted C'Dot drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers
Authors: Gregory Paul Adams, Kai Ma, Aranapakam Venkatesan, Feng Chen, Fei Wu, Melik Turker, Thomas Gardinier, Peiming Chen, Vaibhav Patel, Eliel Bayever, Paul Rudick, Geno Germano
Journal: Cancer Research (2021)

Abstract CDCs are novel ultra-small (6-7 nm) nanoparticle drug conjugates that have been demonstrated to be capable of faster tumor targeting and deeper tumor penetration than antibody drug conjugates in animal models. CDCs are capable of targeting tumors in the brain and pancreas that are difficult to access, while exhibiting limited exposure to normal tissues due their efficient renal elimination. CDCs are composed of a silica core, in which Cy5, a far red dye is covalently encapsulated. The silica core is covalently coated with a layer of polyethylene glycol which is then functionalized with targeting moieties and payloads. ELU001 is a CDC functionalized with ~20 molecules of the topoisomerase-1 inhibitor exatecan linked via a proteolytic cleavable linker as a payload and ~15 folic acids to provide targeting to FRα overexpressing cancers. ELU001 is rapidly internalized into FRα expressing cells and is trafficked to the lysosome where the payload is released from the CDC. ELU001 exhibits potency in the low single digit nanomolar to sub-nanomolar range against cancer cells that express 3+ (KB, IGROV-1) and 2+ (SK-OV-3, HCC827 and OVCAR-3) levels of FRα after a 6-hr exposure in a 7-day viability study. In contrast, an anti-FRα ADC based ADC mirvetuximab soravtansine exhibits lower potency (&amp;gt;100 nM IC50) against SK-OV-3 and HCC827 cells and 40 nM IC50 against OVCAR-3 cells. ELU001 exhibits potent efficacy against established s.c. KB human cervical tumor xenografts in immunodeficient mice with significantly better efficacy and safety than free exatecan payload. It is also effective in treating established SK-OV-3 tumors with lower (2+) FRα expression, a setting where the ADC is again less effective. IND-enabling nonclinical studies are currently underway to prepare for initiation of a first-in-human phase 1 clinical trial in subjects with FRα overexpressing cancers in the second half of 2021. Citation Format: Gregory Paul Adams, Kai Ma, Aranapakam Venkatesan, Feng Chen, Fei Wu, Melik Turker, Thomas Gardinier, Peiming Chen, Vaibhav Patel, Eliel Bayever, Paul Rudick, Geno Germano. ELU001, a targeted C'Dot drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 305.
Optimizing the Management of Iron Overload in Patients with Hemoglobin Disorders in Centers with Limited Access to Magnetic Resonance Imaging
Authors: Alvaro Henrique Junqueira Tavares, Otavio Rizzi Coelho-Filho, Sara Teresinha Olalla Saad, Fernando Ferreira Costa, Kleber Yotsumoto Fertrin
Journal: Blood (2017)