tbuckley/cabot-search huggingface dataset:
Abstract 1012: Determinants of immune evasion in <i>MET</i> driven lung cancer
Authors: Maria Saigi, Ryohei Yoshida, Erik H Knelson, Navin R Mahadevan, Amir Vajdi, Israel Cañadas, Tran C Thai, Mark M. Awad, Montse Sánchez-Céspedes, David A Barbie
Journal: Cancer Research (2020)

Abstract PURPOSE: The 5' ectonucleotidase (NT5E) encodes for the CD73 membrane protein that converts the extracellular AMP into adenosine (Ado), an immunosuppressive nucleoside that generates anti-inflammatory responses by stimulating T cell anergy. We aimed to analyze CD73 expression across non-small cell lung cancer (NSCLC) and explore its role in immunomodulation and its predictive value to immunotherapy (ICI). METHODS: We analyzed CD73 (NT5E) expression across lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) and determined top co-expressed genes or correlations with alterations in lung cancer (LC) driver genes. Correlations were validated in specific cancer cell lines using appropriate treatments to activate or inhibit selected pathways. A CRISPR-Cas9 CD73-knockout cell line model was generated to explore direct regulation of extracellular Ado production, as well as impact on secreted cytokines. Finally, we performed staining of CD73 and other immune-related molecules (CD8+ TILs, PD-L1, STING) in a pilot cohort of NSCLC patients (n=35) treated with first line ICI +/- chemotherapy at the DFCI. RESULTS: TCGA analysis revealed strong correlation between MET and CD73 expression and identified MET altered tumors, either by MET exon 14 skipping mutations (METex14) or MET amplification, as being enriched for high CD73 expression (p=0.03). Functional assays using LC cell lines showed that MET activation increases CD73 expression at a transcriptional and protein level by using qPCR, western-blot and flow-cytometry. Additional adenosinergic-related molecules, including the adenosine receptor A2BR (ADORA2B), were co-regulated in parallel with CD73, defining a specific phenotype. In our pilot cohort of patients, CD73 high expression (2+) was found in 20% of lung tumors, mostly adenocarcinomas, whereas 50% were negative (0+) for CD73 expression. CD73 was positively associated with high CD8+ (p= 0.02). Clinical outcomes are being evaluated to elucidate the potential role of CD73 as a predictive marker to ICI. CONCLUSIONS: MET altered tumors and LC cell lines express high levels of CD73 and other adenosinergic-related molecules, representing a potential mechanism of immune evasion and target for immunotherapy. The potential predictive role of CD73 expression in a larger cohort of patients treated with immune checkpoint inhibition (ICI) will be performed. Citation Format: Maria Saigi, Ryohei Yoshida, Erik H Knelson, Navin R Mahadevan, Amir Vajdi, Israel Cañadas, Tran C Thai, Mark M. Awad, Montse Sánchez-Céspedes, David A Barbie. Determinants of immune evasion in MET driven lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1012.
Abstract 1455: NANOG binds polycomb repressive complex 2 to reprogram metabolism to promote slow cycling phenotype in experimental mouse and clinical carcinoma
Authors: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida
Journal: Cancer Research (2020)

Abstract Pluripotency transcription factor NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, but activates fatty acid oxidation (FAO) to support self-renewal and drug resistance of tumor-initiating stem-like cells (TICs). Hepatoceullular carcinomas (HCCs: 39%) associated with HCV and alcohol have mutations in ARID1A, a component of the chromatin remodeling complex SWI/SNF. We hypothesized that NANOG binds polycomb repressive complex 2 (PRC2) to reprogram metabolism to promote slow cycling phenotype. Here, the Genome-scale CRISPR Knock-Out (GeCKO) screening with ARID1A mutation identified PRC2 complex genes (EZH2, SUZ12 and EED) in patient-derived TICs. NANOG together with the PRC2 complex inhibits OXPHOS to generate TICs with label-retaining ability and therapy resistance. NANOG binds PRC2 complex. ARID1A gene loss promotes sorafenib-resistance phenotype and self-renewal through PRC2 complex genes. ARID1A mutation promoted HCC development in humanized FRG mice with HCCs. The studies established a novel therapy to overcome the chemoresistance of TICs for HCC treatment. Citation Format: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida. NANOG binds polycomb repressive complex 2 to reprogram metabolism to promote slow cycling phenotype in experimental mouse and clinical carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1455.
Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma
Authors: Pei-Chang Lee, Yee Chao, Ming-Huang Chen, Keng-Hsin Lan, I-Cheng Lee, Ming-Chih Hou, Yi-Hsiang Huang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunotherapy with immune checkpoint inhibitor (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC). However, whether ICIs would have the risk of hepatitis B virus (HBV) reactivation and the necessary of nucleos(t)ide analogs (NUCs) prophylaxis are still unclear. We aimed to investigate the role of NUCs prophylaxis in HBV-infected patients who underwent ICIs treatment.The study was a retrospective prospective design to review and follow-up consecutive 62 patients with chronic hepatitis B or resolved HBV infection who had received ICIs treatment for the unresectable HCC. Of them, 60 patients with documented baseline serum HBV DNA value were classified into three categories according to the baseline HBV viral load and the status of antiviral therapy before ICI treatment. The clinical status, including tumor response, viral kinetics and liver function, was recorded and investigated.No HBV reactivation occurred in the 35 patients with HBV DNA ≤100 IU/mL on NUCs therapy. Of the 19 patients with HBV DNA >100 IU/mL who started NUCs simultaneously with ICI treatment, none encountered HBV reactivation during the immunotherapy. Of the six HBV patients without NUCs treatment, three had a greater than 1 log decrease in HBV viral load, and one maintained his serum HBV DNA in undetectable status during ICI treatment. Eventually, one out of six experienced HBV reactivation after 9 weeks of ICI treatment.No patients on antiviral therapy developed HBV reactivation, and one out of six not receiving antiviral therapy had HBV reactivation. HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated.
Abstract 4524: Non-genetic generation of IgG-like immune cell-redirecting antibodies lacking effector function
Authors: Floris L. van Delft, Remon van Geel
Journal: Cancer Research (2020)

Abstract Since the early approval of catumaxomab and blinatumomab, T cell-redirecting antibodies have emerged as a promising biologics in cancer treatment. New technologies are overcoming the limitations of the 1st generation T-cell redirecting bispecifics, especially extending half-life to allow intermittent dosing, reducing immunogenicity and improving the safety profile. Today, T cell-engagers are generated as a wide variety of molecular architectures, typically IgG-type. However, nearly without exception, these bispecifics are generated by genetic fusion of a cancer-binding and an anti-CD3 antibody, which inevitably requires genetic reengineering of an existing targeting antibody and/or extensive optimization of antibody format. We have shown earlier that the native glycan of a monoclonal antibody provides a privileged site for controlled attachment of small-molecule cytotoxic drugs.1 The resulting antibody-drug conjugates (ADCs) were found to display significantly improved therapeutic index versus conventional technologies, while improving manufacturability. This proprietary technology, known as GlycoConnect™, has been adapted by various ADC developers, and entered clinical phase early 2019. Here we present the adaption of GlycoConnect™ technology for the generation of immune cell-redirecting antibodies, without requiring prior protein reengineering. Instead, a two-stage chemoenzymatic process is applied that allows the conversion of any IgG isotype into a T cell-engager by selective attachment of anti-CD3 scFv to the antibody glycan. Studies are presented to precisely control conjugation stoichiometry, providing molecular architectures with defined 2:1 or 2:2 ratio (target-binding:CD3-binding), as well as functional studies to corroborate the biological activity of these GlycoConnect™ bispecifics. Finally, early results will be presented regarding extension of the concept to bispecifics designed to redirect natural killer (NK) cells, or to engage T-cells by activation of costimulatory molecules, such as CD137 (4-1BB). 1 van Geel et al. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved NGlycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody−Drug Conjugates. Bioconj. Chem. 2015, 26, 2233-2242. Citation Format: Floris L. van Delft, Remon van Geel. Non-genetic generation of IgG-like immune cell-redirecting antibodies lacking effector function [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4524.
Uncontrolled Innate and Impaired Adaptive Immune Responses in Patients with COVID-19 Acute Respiratory Distress Syndrome
Authors: Sophie Hue, Asma Beldi-Ferchiou, Inés Bendib, Mathieu Surenaud, Slim Fourati, Thomas Frapard, Simon Rivoal, Keyvan Razazi, Guillaume Carteaux, Marie-Héléne Delfau-Larue, Armand Mekontso-Dessap, Etienne Audureau, Nicolas de Prost
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19).Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non-COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS.Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non-COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1-2 and 4-6 of ICU admission.Measurements and Main Results: As compared with patients with non-COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4+ (P = 0.002), CD8+ (P < 0.0001), and B (P < 0.0001) lymphopenia, higher HLA-DR expression on monocytes (P < 0.001) and higher serum concentrations of EGF (epithelial growth factor), GM-CSF, IL-10, CCL2/MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/MIP-3a. After adjusting on age and Sequential Organ Failure Assessment, serum CXCL10/IP-10 (P = 0.047) and GM-CSF (P = 0.050) were higher and nasopharyngeal RT-PCR cycle threshold values lower (P = 0.010) in patients with COVID-19 who were dead at Day 28.Conclusions: Profound global lymphopenia and a "chemokine signature" were observed in COVID-19 ARDS. Increased serum concentrations of CXCL10/IP-10 and GM-CSF, together with higher nasopharyngeal SARS-CoV-2 viral load, were associated with Day-28 mortality.
Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth <i>In Vivo</i> More Effectively than Tamoxifen
Authors: Annelie Abrahamsson, Gabriela Vazquez Rodriguez, Charlotta Dabrosin
Journal: Cancer Research (2020)

Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. SIGNIFICANCE: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ER+ breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.
Cytokine Release Syndrome and Tumor Responses in a First-in-Man Trial of a Novel Affinity-Enhanced TCR-Gene Transduced T Cell Transfer Targeting NY-ESO-1 Antigen
Authors: Shinichi Kageyama, Mikiya Ishihara, Shigehisa Kitano, Yoshihiro Miyahara, Hidefumi Kato, Hideyuki Mishima, Noboru Yamamoto, Hiroyoshi Hattori, Hiroaki Iwase, Takeru Funakoshi, Takashi Kojima, Naoki Inoue, Tomohide Kidokoro, Daisuke Tomura, Sachiko Okamoto, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Hiroaki Ikeda, Takashi Watanabe, Hiroshi Shiku
Journal: Blood (2017)
Work related sexual harassment and risk of suicide and suicide attempts: prospective cohort study
Authors: Linda L Magnusson Hanson, Anna Nyberg, Ellenor Mittendorfer-Rutz, Fredrik Bondestam, Ida E H Madsen
Journal: BMJ (2020)

Abstract Objective To analyse the relation between exposure to workplace sexual harassment and suicide, as well as suicide attempts. Design Prospective cohort study. Setting Sweden. Participants 86 451 men and women of working age in paid work across different occupations responded to a self-report questionnaire including exposure to work related sexual harassment between 1995 and 2013. The analytical sample included 85 205 people with valid data on sexual harassment, follow-up time, and age. Main outcome measures Suicide and suicide attempts ascertained from administrative registers (mean follow-up time 13 years). Results Among the people included in the respective analyses of suicide and suicide attempts, 125 (0.1%) died from suicide and 816 (1%) had a suicide attempt during follow-up (rate 0.1 and 0.8 cases per 1000 person years). Overall, 11 of 4095 participants exposed to workplace sexual harassment and 114 of 81 110 unexposed participants committed suicide, and 61/4043 exposed and 755/80 513 unexposed participants had a record of suicide attempt. In Cox regression analyses adjusted for a range of sociodemographic characteristics, workplace sexual harassment was associated with an excess risk of both suicide (hazard ratio 2.82, 95% confidence interval 1.49 to 5.34) and suicide attempts (1.59, 1.21 to 2.08), and risk estimates remained significantly increased after adjustment for baseline health and certain work characteristics. No obvious differences between men and women were found. Conclusions The results support the hypothesis that workplace sexual harassment is prospectively associated with suicidal behaviour. This suggests that suicide prevention considering the social work environment may be useful. More research is, however, needed to determine causality, risk factors for workplace sexual harassment, and explanations for an association between work related sexual harassment and suicidal behaviour.
Abstract 4762: Metabolome in 5-FU resistant gastric cancer organoids
Authors: Naoya Sakamoto, Kazuhito Naka, Shoichi Ukai, Ririno Honma, Daiki Taniyama, Tsuyoshi Takashima, Ryota Maruyama, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui
Journal: Cancer Research (2020)

Abstract Recent advances in metabolomics have deepened our understandings of the roles that specific modes of metabolism play in the maintenance of stem cells. Several pieces of evidence have demonstrated that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. Organoid is a novel 3D cell culture system through using the specific niche factors in a dish and is believed to harbor abundant stem cells; cancer organoid could possibly be useful for scrutinizing CSC biology. In this study, we successfully established 5-FU resistant gastric cancer organoids (GCOs) from patient-derived specimens, which were further confirmed by significant changes in the expression of molecules related to 5-FU metabolism. We then performed metabolome analysis using 3 pairs of 5-FU resistant/ parental GCOs and 10 pairs of non-neoplastic gastric organoid/ GCOs generated from the same patients. PCA plotting revealed that 5-FU resistant GCOs showed a distinct signature compared to those of their parental GCOs and 10 pairs of non-neoplastic gastric organoid/ GCOs. Among various significant changes in the metabolic pathways, we focused on the excessive reliance on the energy from TAC cycle in 5-FU resistant GCO because the difference was specifically seen in the comparison between 5-FU resistant and parental GCOs: not found in the comparison between 10 pairs of non-neoplastic gastric organoid and GCOs. We examined IC50 value for Tigecyclin and VLX600, both of which have an inhibitory effect on TCA cycle, by MTT assay using 5-FU resistant GCO and 2 gastric cancer cell lines (MKN-45 and MKN-74). Although there was almost no difference in IC50 values for Tigecyclin and VLX600 between 2 gastric cell lines and their 5-FU resistant cells, IC50 for both of TCA cycle inhibitors in 5-FU resistant GCO was significantly lower compared to that in parental GCO. Further studies are ongoing in order to verify the significance of dependency on TCA cycle, which could potentially lead to the development of new therapy for 5-FU resistant gastric cancer. Citation Format: Naoya Sakamoto, Kazuhito Naka, Shoichi Ukai, Ririno Honma, Daiki Taniyama, Tsuyoshi Takashima, Ryota Maruyama, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui. Metabolome in 5-FU resistant gastric cancer organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4762.
Abstract B14: Atovaquone targets STAT3 in ovarian cancer spheroids
Authors: Kayli E. Neil, Sarah J. Lacroix, David F. Walker, Suhu Liu, David A. Frank, Sarah R. Walker
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer remains a deadly disease for countless women. Recent evidence demonstrates that ovarian cancer cell clusters, spheroids, are important in promoting ovarian recurrence and metastasis. Often these spheroids are resistant to therapy. Therefore, we were interested in identifying drugs that could target ovarian cancer spheroids. To do this, we wanted to identify pathways that were activated in cells growing in three-dimensional (3D) clusters. Analysis of gene expression from 2D and 3D growing cells identified STAT3 as a pathway enriched in 3D growing cells. STAT3 is a transcription factor that is activated by tyrosine phosphorylation. In ovarian cancer cells, activation usually occurs from interleukin 6 (IL-6) binding to the IL-6 receptor and recruiting the signal transducer molecule (GP130, IL6ST). This activates Jak kinases that then tyrosine phosphorylates STAT3. Once activated, STAT3 dimerizes, translocates into the nucleus, and regulates the expression of target genes. Using shRNA targeting STAT3 and the upstream signaling molecule, GP130, we found that reduction of both STAT3 and its upstream signaling molecule GP130 reduced the growth of spheroids. This suggested that targeting STAT3 or an upstream signaling molecule might be a viable treatment option. Atovaquone, used normally for the treatment of malaria or the prevention of pneumocystis pneumonia, inhibits STAT3 activation by inhibiting the expression of GP130 on the cell surface. Therefore, we hypothesized that atovaquone would have efficacy in ovarian cancer spheroids. Treatment of ovarian spheroids with atovaquone reduced their growth and viability. Importantly, atovaquone inhibited STAT3 tyrosine phosphorylation and target gene expression, demonstrating that atovaquone is inhibiting STAT3 in ovarian spheroids. Preliminary data suggest that overexpression of STAT3 partially rescues the effects of atovaquone on spheroid growth. As spheroids are also involved in ovarian cancer metastasis, we are currently assessing the effects of atovaquone on spheroid-mediated ovarian cancer metastasis. Taken together, our data suggest that atovaquone may be a beneficial treatment for ovarian cancer patients. Citation Format: Kayli E. Neil, Sarah J. Lacroix, David F. Walker, Suhu Liu, David A. Frank, Sarah R. Walker. Atovaquone targets STAT3 in ovarian cancer spheroids [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B14.
FRI0251 Musculoskeletal disorders of the upper limb and workrelated factors
Authors: M De la Hera, M Gandarillas
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To study the association between upper extremity physical requirements (UEPR) at workplace and soft tissue lessions. <h3>Methods</h3> A retrospective analysis (from 1–01–95 to 31–12–99) was carried out comparing temporal disability due to lateral, medial epicondylitis (LE), (ME) and shoulder tendinitis (ST) in two factories with different UEPR: a shipyard of 305 workers (AS) with high UEPR and a nuclear components manufacturing plant of 405 workers (EN) with low/medium UEPR. The UEPR were estimated by the investigators, as low, medium and high according to the repetitive and force work in the upper extremity. <h3>Results</h3> All patients were male. Median age was 49 years (range: 33 to 52) in AS and 51 (25 to 60) in EN. Nineteen (6,2%) cases were diagnosed in AS (10 ST, 8 LE and 1 ME), and only 9 (2,2%) in EN (7 ST and 2 LE) (p = 0.009). The cases were classified according to the factory and to the level of UEPR as follow: AS/EN Low (2/5) Medium (6/3) High (11/1). Annual and cummulative (95–99) risk proportion (%) were (see Table 1): An association between the type of factory (EN or AS) and the level of UEPR was observed, being the latter higher in AS (p = 0.04). Relative risk of suffering LE, ME and ST was 2.8 (IC95: 1,3–6,1) in AS. Dominant side was affected in most cases 22 (79%), (p = 0.002). <h3>Conclusion</h3> Our data suggest that tasks with high UEPR have a relevant role in soft tissue lessions of the upper extremity and they are more frequent in the dominant side.