tbuckley/cabot-search huggingface dataset:
Abstract 3081: DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations
Authors: Yan Xu, Lin Zhang, Lifang Zhu, Yingchun Wang, Mei Wang, Zhenfan Yang
Journal: Cancer Research (2019)

Abstract Background: Several EGFR TKIs have been approved for the treatment of non-small cell lung cancer (NSCLC) with L858R mutation, Exon 19 deletion, and T790M mutations. However, for patients with uncommon mutations, such as EGFR or HER2 Exon20ins, there lacks safe and effective therapy. All Exon20ins inhibitors under clinical development have a negative selectivity profile, inhibiting wild type EGFR more potently than mutant ones. Consequently, severe wild type EGFR-driven toxicities have been observed in patients. DZD9008 is an oral, potent, irreversible, wild type-selective EGFR TKI against EGFR or HER2 Exon20ins and other mutations. The present study shows anti-tumor activity of DZD9008 in tumor cell lines and xenograft models. Materials and Methods: The enzyme assay was performed by incubating DZD9008 with recombinant enzymes at 2 mM ATP concentrations. The cellular activity of DZD9008, including phosphorylation of EGFR or HER2 and cell proliferation, was evaluated in a panel of cell lines expressing wild type EGFR, mutant EGFR or HER2, using MSD assay and CellTiter-Glo assays. DZD9008 in vivo anti-tumor activity was evaluated in both cell line-derived (CDX) and patient-derived xenograft (PDX) models, carrying EGFR single or double mutations, Exon20ins mutations, and wild type EGFR. Results: The enzymatic IC50 of DZD9008 in mutant EGFR ranges from 0.4 to 2.1 nM. DZD9008 downregulated pEGFR with IC50 ranging from 1 to 22 nM in a panel of tumor cell lines expressing EGFR L858R, Exon19del, L858R/T790M, various Exon20ins or uncommon mutations. Similar activity against pHER2 was observed in tumor cells with HER2 Exon20ins mutation, with IC50 at 7 nM. In contrast, DZD9008 was less potent in modulating pEGFR in tumor cells expressing wild type EGFR, with IC50 greater than 80 nM. In cell proliferation assays, DZD9008 suppressed cell proliferation with GI50 of 1 to 60 nM in tumor cells carrying EGFR L858R, Exon19del, L858R/T790M, various Exon20ins or uncommon mutations. In CDX and PDX models carrying EGFR Exon19del single mutation, L858R/T790M double mutations, and PDX models harboring G719S/L861Q or Exon20ins, DZD9008 induced dose dependent tumor growth inhibition and regression. Good PK/PD relationship was established across these tumor models. Conclusion: DZD9008 is a potential EGFR TKI for NSCLC patients with EGFR or HER2 Exon20ins and other activating mutations. Citation Format: Yan Xu, Lin Zhang, Lifang Zhu, Yingchun Wang, Mei Wang, Zhenfan Yang. DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations [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 3081.
Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS
Authors: Rong Guo, Yang Long, Zhengze Lu, Miao Deng, Penghui He, Man Li, Qin He
Journal: Acta Pharmaceutica Sinica B (2019)

Chemotherapy agents have been widely used for cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus, prodrug strategy was devised. Since some prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy. Gemcitabine (GEM) is a prescribed anticancer drug, however, the rapid clearance, growing resistance and serious side effects limit its clinical efficacy. Conjugating GEM with d-α-tocopherol succinate (TOS) is an effective solution, while the GEM-TOS (GT) is unstable in aqueous solution. d-α-Tocopherol polyethylene glycol succinate (TPGS) has been used to enhance the stability, but GT stabilized by TPGS (GTT) has limited effect on tumor metastases. Tumor metastases lead to high mortality in patients suffering from cancers. In order to further achieve antimetastatic effect, an amphiphilic polymer (LT) was synthesized by connecting low-molecular-weight heparin (LMWH) with TOS, and eventually obtained desired self-delivery micellar NPs (GLT) by co-assembly GT with LT. The GLT not only possessed excellent stability, but also inhibited the metastases by acting on different phases of the metastatic cascade. The hydrophobic TOS inhibited the secretion of matrix metalloproteinase-9 (MMP-9), the hydrophilic LMWH inhibited the interaction between tumor cells and platelets. As a result, GLT reduced tumor cells entering the blood and implanting at the distant organs, leading to a much more excellent inhibitory effect on the lung metastasis than GEM and GTT.
Development and validation of risk stratification trees for incident slow gait speed in persons at high risk for knee osteoarthritis
Authors: Leena Sharma, Kent Kwoh, Jungwha (Julia) Lee, Jane Cauley, Rebecca Jackson, Marc Hochberg, Alison H Chang, Charles Eaton, Michael Nevitt, Jing Song, Orit Almagor, Joan S Chmiel
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives</h3> Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. <h3>Methods</h3> Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. <h3>Results</h3> 1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%–29 % (derivation) and 2%–23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). <h3>Conclusions</h3> In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials.
Overall survival and progression-free survival in metastatic colorectal cancer patients with concomitant RAS and BRAF mutations: a single center experience
Authors: A. Pretta, E. Lai, N. Liscia, V. Impera, S. Camera, F. Musio, S. Mariani, P. Soro, M. Persano, C. Donisi, S. Tolu, F. Balconi, F. Atzori, M. Dessì, E. Massa, C. Madeddu, V. Pusceddu, G. Astara, L. Demurtas, M. Puzzoni, P. Ziranu, M. Scartozzi
Journal: Annals of Oncology (2019)
Abstract 2034: Activation of cancer-associated fibroblasts via the transfer of miR-125b containing extracellular vesicles from tumor cells
Authors: Luyen Tien Vu, Boya Peng, Daniel Xin Zhang, Victor Ma, Andrew Grimson, William C. Cho, Judy Lieberman, Minh TN Le
Journal: Cancer Research (2019)

Abstract Tumor cells secrete elevated amounts of extracellular vesicles (EVs) as a mean of communication between them and other cells in the tumor microenvironment. Here, we established a series of breast cancer cell lines releasing fluorescent EVs to identify the common cell types that receive tumor EVs within the tumor microenvironment. Among the different cell types, cancer-associated fibroblasts consistently take up the most EVs from cancer cells. Using next generation sequencing, we find that miR-125b is among the top enriched miRNAs in EVs released by mouse isogenic triple-negative breast cancer 4T1 and 4TO7 cell lines. Co-injection of 4TO7 cells with 4T1 EVs results in an upregulation of fibroblast activation in vivo while blockage of miR-125b in 4T1 EVs rescues the effect indicating that EV-delivery of miR-125b is crucial for the fibroblast activation in mouse breast cancer models. Moreover, EVs from human breast cancer cells also contain abundant miR-125b and fibroblasts within the xenografted tumor that take up these EVs gain higher levels of miR-125b and upregulation of cancer-associated fibroblast markers. Both mouse and human fibroblasts that are transfected with miR-125b mimics show an activated phenotype similar to the knockdown of established miR-125b targets. In summary, normal fibroblasts within the tumor microenvironment actively take up the miR-125b-containing EVs from breast cancer cells and develop into cancer-associated fibroblasts. Citation Format: Luyen Tien Vu, Boya Peng, Daniel Xin Zhang, Victor Ma, Andrew Grimson, William C. Cho, Judy Lieberman, Minh TN Le. Activation of cancer-associated fibroblasts via the transfer of miR-125b containing extracellular vesicles from tumor cells [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 2034.
Abstract CT149: A Phase II study of Genexol-PM and cisplatin as induction chemotherapy in locally advanced head and neck squamous cell carcinoma
Authors: Keun-Wook Lee, Bhumsuk Keam, Jin-Soo Kim, Se-Hoon Lee
Journal: Cancer Research (2019)

Abstract Background Genexol-PM is a polymeric micellar formulation of paclitaxel without Cremophor EL. We investigated the efficacy and safety of Genexol-PM plus cisplatin as induction chemotherapy (IC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Methods Patients received Genexol-PM (230 mg/m2) and cisplatin (60 mg/m2) every 3 weeks as IC. After 3 cycles of IC, definitive treatment of either concurrent chemoradiotherapy (CCRT) with weekly cisplatin (30 mg/m2) or surgery was performed. The primary endpoint was objective response rate (ORR) after IC. Results Of 52 patients enrolled, 47 completed three cycles of IC and the ORR was 55.8% (95% confidence interval, 42.3-69.3). Although there was one treatment-related death, toxicity profiles to IC were generally favorable and the most common grade 3 or 4 toxicities were neutropenia (15.4%), anorexia (7.7%) and general weakness (7.7%). Fifty one patients received the definitive treatment [CCRT (n=44) or radical surgery (n=7)]. The rate of complete response following CCRT was 81.8% (36/44). After a median follow-up of 39 months, estimates of progression-free survival and overall survival at 3 years were 54.3% and 71.3%, respectively. Conclusions IC with Genexol-PM and cisplatin demonstrated modest tumor response with well-tolerated toxicity profiles for patients with LA-HNSCC. Citation Format: Keun-Wook Lee, Bhumsuk Keam, Jin-Soo Kim, Se-Hoon Lee. A Phase II study of Genexol-PM and cisplatin as induction chemotherapy in locally advanced head and neck squamous cell 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 CT149.
Abstract 1515: Removal of innate suppressors facilitates tumor-immune surveillance
Authors: Yao Zhang, Christina Lee, Na Diao, Liwu Li
Journal: Cancer Research (2019)

Abstract Although tumor immune environment is increasingly recognized to be highly important during the modulation of tumorigenesis and tumor regression, the role and regulation of innate leukocytes such as neutrophils during the modulation of tumor immune environment remain controversial and less defined. In this study, we tested the hypothesis that removal of innate signaling suppressors may boost the anti-tumor immune function of innate neutrophils in vitro and in vivo. To this regard, we examined two key innate signaling suppressors Tollip and IRAK-M and their roles in modulating neutrophil anti-tumor immune functions. We observed that selective deletion of Tollip enhanced tumor immune surveillance in the AOM-DSS chemically induced colon cancer model. Tollip deficiency released the neutrophil suppression on T cell proliferation and activation. The adoptive transfer of Tollip deficient neutrophils were sufficient to transfer enhanced tumor immune surveillance and reduce tumor burden. Likewise, the study of another innate suppressor IRAK-M revealed that IRAK-M expression was up-regulated in the human patients with colorectal cancer. We also demonstrated that IRAK-M deficient mice exhibited reduced tumor burden following AOM-DSS challenge. Together, our data reveal a novel anti-tumor immune-enhancement strategy through utilizing reprogrammed neutrophils with targeted removal of innate signaling suppressors. Citation Format: Yao Zhang, Christina Lee, Na Diao, Liwu Li. Removal of innate suppressors facilitates tumor-immune surveillance [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 1515.
Cardiotoxicity and related risk factors in long-term trastuzumab (T) administration for metastatic breast cancer (MBC): A retrospective analysis.
Authors: Barbara Pistilli, Andrea Marcellusi, Michele Valeri, Umberto Torresi, Dania Nacciarriti, Tiziana Saladino, Cinzia Mariani, Alfredo Santinelli, Benedetta Ferretti, Luciano Latini, Giovanni Benedetti
Journal: Journal of Clinical Oncology (2013)

e11616 Background: Continuing T beyond progression has become a common strategy in the treatment of human epidermal growth receptor 2- overexpressing (HER2) MBC. However, T administered for several years with concomitant chemotherapy elicits concern about cardiac safety especially in patients (pts) with risk factors. Methods: Cardiac events (CEs) and survival of HER2 MBC pts treated with T +/- chemotherapy at our institution from Dec 2003 to Jun 2012 were evaluated. CEs were graded by NCI-CTCAE v 3.0. Risk factors assessed for cardiotoxicity were: age, body mass index, antihypertensive therapy, history of cardiac disease, diabetes, hypothyroidism, smoking, prior radiotherapy on the chest wall, prior cumulative dose of anthracycline(A), interval between last A dose and first T dose, baseline LVEF, continued/interrupted T exposure, concomitant chemotherapy. Chi-square test was used to compare distribution of CEs over different times of T exposure (p≤ 0.05). Univariate and multivariate Cox regression analysis were used to assess the effect of risk predictors. Results: Sixty-two pts assessable. Median age 52 years (range, 29 to 76), median cumulative time receiving T 29.5 months (range, 3 to 99 months); 40 pts (64.5%) received T without interruption and 19 pts (30.6%) were treated for more than 36 months. CEs occurred in 11 out of all pts (17.7%): grade 1 in 3 pts (4.8%), grade 2 in 5 (8.1%) and grade 3 in 3 (4.8%). The rate of CEs showed no statistically significant difference in pts receiving T for up to 36 months and over: 7/43 (16.3%) and 4/19 (21%), respectively, (p =0.724). In univariate Cox regression analysis significant risk factors were: history of cardiac disease (HR 6,814, 95% CI: 1,384-33,542) and smoking (HR 5,228, 95% CI: 1,403-19,491). In multivariate analysis smoking was the only independent predictor (HR 5,886, 95% CI: 1,479-23,247). Median survival from MBC diagnosis was 50 months (range, 6 to 101 months). Conclusions: Despite the limited sample size, our analysis suggests that cardiotoxicity does not hamper a long-term use of T, since the rate of CEs did not increase in pts treated over 36 months. Moreover, smoking appears to be a predictive factor of T cardiotoxicity.
“Hostile and demeaning” universal credit system worsens physical and mental health, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Universal credit (UC)—the new benefits system which combines six separate welfare benefits into one monthly payment—has a negative impact on the wellbeing, physical, and mental health of those who use it, according to a study in BMJ Open .1

Researchers interviewed 33 claimants with complex needs, disabilities, and health conditions and 37 staff from local government, housing, voluntary, and community sector organisations, and found that both groups reported major …
基于表型方法的红斑痤疮干预:包括 GRADE 评估在内的 最新系统综述
Authors: E.J. Zuuren, Z. Fedorowicz, J. Tan, M.M.D. Linden, B.W.M. Arents, B. Carter, L. Charland
Journal: British Journal of Dermatology (2019)

红斑痤疮是一种常见的慢性皮肤疾病,可导致面部发红、红肿、红丘疹和脓疱。全球大约 1‐20% 的人口受此病困扰。红斑痤疮还可能引起眼睛/眼睑发炎(眼部红斑痤疮)和皮肤增厚,尤其是鼻子(鼻赘)。虽然红斑痤疮的病因尚不清楚,但这种令人苦恼的疾病已有治疗方法。来自荷兰、英国和加拿大的这篇综述旨在找出对红斑痤疮有效的治疗方法。作者收集了 152 项研究的数据。为了减少红肿,溴莫尼定和羟甲唑啉在使用后的 3 ‐ 12 小时内开始发挥作用。对于通过局部(应用于皮肤)治疗来减少丘疹和脓疱,壬二酸、伊维菌素和甲硝唑是有效和安全的。伊维菌素的疗效略高于甲硝唑。二甲胺四环素泡沫也显示出能够大量减少丘疹和脓疱。口服(用口服用)抗生素、四环素、强力霉素 40 毫克或米诺环素 45 毫克可减少丘疹和脓疱的数量。多西环素 40 毫克可能和 100 毫克一样有效,副作用(比如腹泻和恶心)更少。口服米诺环素 100 毫克与强力霉素 40 毫克效果相同。阿奇霉素可能与 100 毫克强力霉素一样有效。异维甲酸 0.25 毫克/千克可减少 90% 的丘疹和脓疱,提高患者的生活质量和满意度。异维甲酸 0.3 毫克/千克似乎比 50‐100 毫克强力霉素略有效。然而,异维甲酸已知会导致严重的先天性缺陷,因此在使用时必须避免怀孕。对于扩张血管的治疗,激光治疗和强脉冲光治疗都是有效的,但这些研究的数据有限。在眼红斑痤疮中,环孢霉素 0.05% 眼用乳剂提高了患者的生活质量,改善了泪液的量/质,并且其疗效略优于口服多西环素。Omega‐3 脂肪酸可能会改善干眼症和泪腺功能。
Mandatory vaccination: suited to enhance vaccination coverage in Europe?
Authors: Heidemarie Holzmann, Ursula Wiedermann
Journal: Eurosurveillance (2019)

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Fibrocytes in Chronic Periaortitis: A Novel Mechanism Linking Inflammation and Fibrosis
Authors: Maria Nicastro, Rosanna Vescovini, Federica Maritati, Alessandra Palmisano, Maria L. Urban, Monia Incerti, Paride Fenaroli, Francesco Peyronel, Giuseppe D. Benigno, Domenica Mangieri, Riccardo Volpi, Gabriella Becchi, Paola Romagnani, Domenico Corradi, Augusto Vaglio
Journal: Arthritis & Rheumatology (2019)

Objective Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. Methods We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti–type I procollagen, anti‐CXCR4, and anti‐CD45 antibodies and analyzed by confocal microscopy to detect tissue‐infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme‐linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. Results The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls ( P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls ( P = 0.0056), and tissue‐infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin‐13 [IL‐13] and IL‐10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA‐3+ cells, also indicating Th2 polarization; Th2‐skewed responses are known to promote fibrocyte differentiation. Conclusion Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2‐skewed immune responses are likely to facilitate their differentiation.
Abstract 2249: Checkpoint inhibitor therapy after dendritic cell vaccination elicits tumor response in mesothelioma patients
Authors: Robin Cornelissen, Robert Belderbos, Joachim Aerts
Journal: Cancer Research (2019)

Abstract In mesothelioma most patients do not have functional T cells present in the tumor. Therefore, PD-1/PD-L1 checkpoint inhibitor (CI) therapy is likely to induce an anti-tumor response in only a small portion of patients. Activated autologous dendritic cells (DCs) that have been directed against mesothelioma tumor cells have been shown to reinvigorate T cell responses. This T cell response that is induced is prone to be blocked by the tumor using the PD-1/PD-L1 mechanism. Earlier, we published the results of three phase I/II trials in which patients were treated with DC immunotherapy as first line therapy of after completion of first line chemotherapy. 9 patients were subsequently treated with checkpoint inhibitor therapy in several trials and compassionate use programs. Six patients were treated with nivolumab, two with pembrolizumab and one patient was treated with combination treatment of nivolumab and ipilimumab. In all patients, the initial biopsy was stained for PD-L1 and TIM3, in five patients, repeat biopsy was done at time of progression. Radiological response was measured on CT scan using modified response evaluation criteria in solid tumors (RECIST). A radiological partial response was seen in three patients after PD-1 inhibition, stable disease was seen in five patients and one patients had progression of disease as best response on CI therapy, giving a disease control rate of 88%. No CTCAE grade 3-4 adverse events were seen. Updated adverse events, median PFS and OS will be presented at the meeting, as well as correlation of response with PD-L1 and TIM3 status. We conclude that CI treatment after DC immunotherapy is safe and feasible. In addition, after induction of a T cell response, disease control could be achieved in all but one treated patient on subsequent CI therapy. This report is a proof of concept that the induced T cell response from DC immune therapy may be blocked by PD-L1 upregulation from the tumor which in turn can be targeted by CI. Citation Format: Robin Cornelissen, Robert Belderbos, Joachim Aerts. Checkpoint inhibitor therapy after dendritic cell vaccination elicits tumor response in mesothelioma patients [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 2249.