tbuckley/cabot-search huggingface dataset:
Abstract 4578: Macrophages are important source of PD-L1 and PD-L1 expressing on central M2 macrophages leads to the poor prognosis of NSCLC patients: Via macrophage landscape analysis for NSCLC patients with tumor PD-L1 negative
Authors: Lili Cao, Xiaofang Che, Xiujuan Qu, Xueshan Qiu, Zhi Li, Bowen Yang, Shuo Wang, Yunpeng Liu
Journal: Cancer Research (2019)

Abstract PD-1 antibody has achieved significant clinical efficacy for advanced non-small cell lung cancer (NSCLC), but the ORR is not optimistic for the non-selected patients. PD-L1,as the therapeutic target, is still controversial to be a predictor of efficacy.It was noticed that some patients with tumor cell PD-L1 negative could still benefit from anti-PD-1/PDL1 antibody therapy.Besides the tumor cells, PD-L1 was also known to express in immune cells in TME. Therefore, in this study, we aimed to clarify the factors that affect the PD-L1 expression in TME, and their functions on the NSCLC prognosis and the effect on anti-PD-1/PD-L1 therapy.With the multiple quantitative immunofluorescence staining on 94 tissue specimens of NSCLC patients with PD-L1 expressing negative on tumor cells, we surprisingly found that macrophages,especially M2 macrophages,were the main source of PD-L1 for patients with tumor cells PD-L1 negative.Futhermore, the expression of PD-L1 in central M2 macrophages(M2 macrophages that infiltrate into tumor islets),was important for the poor prognosis of NSCLC patients,suggesting that the expression of PD-L1 in macrophages may also be associated with the benefit of anti-PD-1 therapy, which is an important factor to be considered in evaluating the efficacy of immunotherapy in the future. Note: This abstract was not presented at the meeting. Citation Format: Lili Cao, Xiaofang Che, Xiujuan Qu, Xueshan Qiu, Zhi Li, Bowen Yang, Shuo Wang, Yunpeng Liu. Macrophages are important source of PD-L1 and PD-L1 expressing on central M2 macrophages leads to the poor prognosis of NSCLC patients: Via macrophage landscape analysis for NSCLC patients with tumor PD-L1 negative [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 4578.
A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients
Authors: Marit M. Melssen, Gina R. Petroni, Kimberly A. Chianese-Bullock, Nolan A. Wages, William W. Grosh, Nikole Varhegyi, Mark E. Smolkin, Kelly T. Smith, Nadejda V. Galeassi, Donna H. Deacon, Elizabeth M. Gaughan, Craig L. Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8<sup>+</sup> T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses. <h3>Patients and methods</h3> Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS). <h3>Results</h3> Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6. <h3>Conclusions</h3> LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA. <h3>Trial registration</h3> The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.
Real-world use of carfilzomib among multiple myeloma patients with at least one prior therapy.
Authors: Evangelos Terpos, Barbara Gamberi, Jo Caers, Maaike Söhne, Sonja Heibl, Florence Suzan, Zsolt Szabo, Abeera Mohammad, Sally Wetten, Xavier Leleu
Journal: Journal of Clinical Oncology (2019)

e19515 Background: To understand how novel therapies approved in relapsed multiple myeloma, e.g. carfilzomib (CFZ), are used in real-life, we describe the results of a planned interim analysis from a large observational study (NCT03091127). Methods: The study enrolled adult patients (pts) who received ≥1 prior line of therapy and ≥1 CFZ dose in routine care. Pts were followed until 30 days after last CFZ dose or up to 18 months (mos) from initiation. Results: As of 22 Oct 2018, 293 pts from 10 included EU countries were observed for a median time of 7 mos. At CFZ initiation, pts who received CFZ, lenalidomide and dexamethasone (KRd) were younger than pts treated with CFZ and dexamethasone alone (Kd): 64 vs 70 years (median), respectively. Over half of KRd pts had received 1 prior line of therapy while nearly half of Kd pts had ≥4 prior lines. Hypertension (30%), cardiac disorder (14%), diabetes (12%) and renal disorder (9%) were reported at CFZ initiation. A best response (see Table) was achieved in 3-4 mos. The total dose received relative to EU label on average was 95% and 74% by KRd (20/27 mg/m 2 for K) and Kd pts (20/56 mg/m 2 for K), respectively. The Kaplan-Meier median estimate of treatment duration was 16.6 mos for KRd and 7.7 mos for Kd pts. Among the 138 pts who discontinued, disease progression/refractoriness was the most frequent reason (40%). Gr3+ AEs were reported in 37% pts, including hypertension (2%) and cardiac failure (1%). Conclusions: In this real-life setting, KRd pts are younger and receive CFZ in earlier lines than Kd pts and the benefit-risk profile is consistent with published trials. The estimated treatment duration was longer than observed in other real-life data. [Table: see text]
Endoscopic closure of gastrocolocutaneous fistula following percutaneous endoscopic gastrostomy, by OverStitch Endoscopic Suturing System
Authors: Dario Ligresti, Ilenia Barbuscio, Antonino Granata, Alberto Martino, Michele Amata, Riccardo Volpes, Mario Traina
Journal: Endoscopy (2019)

A 48-year-old liver transplant patient with acute graft rejection, sepsis, and malnutrition was referred to our unit for a percutaneous endoscopic gastrostomy (PEG).
Potential antibiotic resistant pathogens in community-acquired pneumonia: playing it safe is anything but
Authors: Grant W. Waterer
Journal: European Respiratory Journal (2019)

Since the introduction of the concept of healthcare-associated pneumonia (HCAP) in the 2005 update on the treatment of nosocomial pneumonias by the American Thoracic Society and the Infectious Diseases Society of America [1], there has been considerable controversy over whether this new category has been helpful or harmful. The core of the problem is the tension between clinicians perceiving that missing a methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa may have dire consequences for their patient and the goals of antibiotic stewardship in reducing the use of too broad spectrum antibiotics driving patient-specific side effects like renal toxicity, Clostridium difficile or vancomycin-resistant enterocoli [2] infection, and the more generalised harm through the promotion of antibiotic-resistant bacteria within the hospital environment. Do not think that using broad-spectrum antibiotics is safer! <http://bit.ly/2Qu0PBf>
Abstract 3742: Exosome-mediated EGR1 transportation controls the radiation-induced abscopal effect in head and neck cancer
Authors: Mohammady Akbor, Liang-Ting Lin
Journal: Cancer Research (2019)

Abstract Head and neck cancer (HNC) are one of the vital types of metastatic cancer, and radiotherapy (RT) is the convincing treatment regarding its location. RT can regulate cancer growth in not only directly irradiated cells but also non-irradiated remote cells by abscopal or bystander effects. It is evident that radiation-induced Early Growth Response 1 (EGR1) is involved in the control of such type cancer progression. Also, exosomes are established carriers for biological factors basically in cell communication. In this study, we would like to identify the EGR1 as a functional molecule that carried by the radiation-induced exosome to control the HNC growth to disclose the molecular mechanism of the abscopal effect. In this case, we used FaDu cell, a hypopharyngeal cancer, for in vitro experiments. Irradiation was given to the cells in a dose-dependent manner from 0 to 12 Gy followed by exosome isolation using miRCURY Exosome Cell Kit. Characterization of the isolated exosomes was performed by Nanoparticle Tracking Analysis (NTA) for vesicle sizes and concentration, and by transmembrane markers CD63 and CD9 through western blot. We treated unirradiated FaDu cells with isolated exosomes to address the phenotypic changes. MTT assay and colony-forming assay observed the cell viability and survival. Moreover, the expression of EGR1 in both radiation-induced exosome and the exosome-treated cells were determined by western blot. To validate the causal effect of exosomal transportation of EGR1, we assessed the viability changes in EGR1-silenced FaDu cells with exosome treatment. Our results indicated that the number of exosomes was increased while the amounts of protein in each isolated exosome were also increased in a radiation dose-dependent manner. CD63 and CD9 had been identified through western blotting. Moreover, the enhanced expression of EGR1 was observed in both radiation-induced exosomes and the cells treated with isolated exosomes. The possible abscopal effect was evident by the significant decrease of the viability of unirradiated FaDu cells treated with radiation-induced exosomes. Besides, elevated expression of EGR1 was noticed in the radiation-induced exosomes comparing to non-irradiated cohorts. Notably, EGR1-containing exosomes can suppress the proliferation of the unirradiated FaDu cells. Alternatively, radiation-induced EGR1-containing exosome failed to inhibit the proliferation of EGR1 knockdown FaDu cells. In conclusion, radiation-induced EGR1 via exosome transportation contributes to the mechanism of the abscopal effect for metastatic head and neck cancer. Citation Format: Mohammady Akbor, Liang-Ting Lin. Exosome-mediated EGR1 transportation controls the radiation-induced abscopal effect in head and neck cancer [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 3742.
Abstract 17192: Angioscopic Comparison of Arterial Repair 4 Months After the Implantation Between Bioresorbable Polymer Drug-Eluting Stent and Durable Polymer Drug-Eluting Stent
Authors: Shota Okuno, Takayuki Ishihara, Masashi Fujita, Osamu Iida, Masaharu Masuda, Shin Okamoto, Kiyonori Nanto, Takashi Kanda, Takuya Tsujimura, Yasuhiro Matsuda, Takuya Ohashi, Aki Tsuji, Hiroyuki Kawai, Yosuke Hata, Toshiaki Mano
Journal: Circulation (2017)

Introduction: The arterial repair after bioresorbable polymer drug-eluting stent (BP-DES) implantation is expected to be different from that after durable polymer drug-eluting stent (DP-DES) becaus...
Abstract 13049: Serum FABP5 Concentration, a Novel Determinant of Cholesterol Efflux From Macrophages, is a Potential Biomarker for Residual Risk of Atherosclerosis
Authors: Masato Furuhashi, Masatsune Ogura, Megumi Matsumoto, Satoshi Yuda, Atsuko Muranaka, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Mariko Harada-Shiba, Tetsuji Miura
Journal: Circulation (2016)

Introduction: Cholesterol efflux capacity (CEC) from macrophages, represents the reverse cholesterol transport pathway, is inversely associated with risk for atherosclerotic cardiovascular disease. Fatty acid-binding protein 4 (FABP4) and 5 (FABP5) are expressed in both adipocytes and macrophages and play significant roles in the development of insulin resistance and atherosclerosis. FABP4 and FABP5 have been shown to be secreted from cells, and the circulating levels are associated with insulin resistance and atherosclerosis. Hypothesis: Serum levels of FABP4 and FABP5 are independently associated with CEC. Methods: A total of 250 subjects who were not on medication were recruited from subjects of the Tanno-Sobetsu Study, a study with a population-based cohort design. Concentrations of FABP4 and FABP5 were measured using commercially available enzyme-linked immunosorbent assay kits. CEC was measured using apolipoprotein B-depleted serum and J774.1 cells, a murine macrophage cell line. Results: CEC was positively correlated with HDL cholesterol and was negatively correlated with concentrations of high-sensitivity C-reactive protein (hsCRP) and FABP5 (r = -0.180, P = 0.041) but not with FABP4 level. Multiple regression analysis demonstrated that FABP5 level was an independent predictor of CEC after adjustment of age, gender and levels of HDL cholesterol and hsCRP. In 129 out of 250 subjects who underwent carotid ultrasonography, mean intima-media thickness was negatively correlated with CEC (r = -0.248, P = 0.005) and was positively correlated with concentrations of FABP4 (r = 0.178, P = 0.043) and FABP5 (r = 0.194, P = 0.028). Conclusions: In contrast to FABP4, FABP5 is independently associated with both carotid atherosclerosis and decreased CEC, suggesting that FABP5 level is a novel regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages.
Abstract 2921: A dual role of genomic instability on radiosensitivity in cancer cells
Authors: Yuji Seo, Keisuke Tamari, Yutaka Takahashi, Kazumasa Minami, Keisuke Otani, Fumiaki Isohashi, Kazuhiko Ogawa
Journal: Cancer Research (2019)

Abstract Background: Genomic instability is a hallmark of cancer, which may lead to heterogeneity and provide an advantage on tumor survival and proliferation. However, we previously found that a greater number of genomic mutations were associated with reduced tolerance to radiation. The aim of this study is to elucidate a role of genomic instability on cellular radiosensitivity. Materials and Methods: We used 59 cancer cell lines derived from various types of solid tumors. Radiation-induced cell death was measured by the standard colony-forming assay at the dose range of 0 to 10 Gy. Based on the resulting survival curves, the mean inactivation dose (MID) was calculated as a single value representing cellular radiosensitivity. Somatic gene aberration data for the 59 cell lines were obtained from the Catalogue Of Somatic Mutations In Cancer cell line project v.80. The genomic analysis focused on cancer-related pathways defined by Kyoto Encyclopedia Genes and Genomes. The genomic mutations included nucleotide variations (substitutions, insertions, or deletions) and copy number variations (CNV). Only pathogenic mutations were selected and neutral mutations were disregarded according to the functional analysis through hidden Markov model. Both gain and loss in CNVs were included. Results: There were either nucleotide variations or copy number variations in 598 genes in the 59 cancer cell lines. The mutations were found in 16 caretakers, 51 gatekeepers, 105 oncogenes, and 449 passengers. There were significant positive correlations between the MIDs and the proportions of mutations in the gatekeepers or the oncogenes to the whole mutations. Namely, radioresistant cell lines harbored gatekeeper mutations or oncogene mutations at higher proportions. Conversely, radiosensitive cell lines showed significantly higher proportions of passenger mutations. No correlation was found in between the MIDs and the proportions of caretaker mutations. Conclusions: Genomic instability caused by caretaker mutations may result in not only increased tolerance to radiation through mutations in gatekeeper genes and oncogenes but also reduced tolerance to radiation through accumulating passenger mutations. A balance between the two opposing phenomena is a significant determinant of cancer cell radiosensitivity. Citation Format: Yuji Seo, Keisuke Tamari, Yutaka Takahashi, Kazumasa Minami, Keisuke Otani, Fumiaki Isohashi, Kazuhiko Ogawa. A dual role of genomic instability on radiosensitivity in cancer 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 2921.
Abstract 17105: Is There a Difference in Lean and Fat Mass in HF Patients Based on NYHA Classifications (I-II versus III-IV)?
Authors: Christine Haedtke, Debra K Moser, Susan J Pressler, Terry Lennie
Journal: Circulation (2018)

Introduction: As NYHA Class increases from I (ordinary physical activity does not cause undue fatigue), to Class IV (Symptoms are present while at rest) physical limitations become severe. It has previously been shown that HF patients have increased fat within the muscle thus decreasing exercise performance and tolerance. It is unclear if all NYHA classes are similarly affected. Hypothesis: HF patients with NYHA class III-IV will have more fat and less lean mass than those with NYHA class I-II. Methods: Secondary data analysis using cross sectional data from N=253. The parent study was a multicenter study about nutrition and body composition among patients with HF (preserved or reduced, and NYHA classification I-IV) who had been on a stable medication regimen, able to participate in dual-energy X-ray absorptiometry scan and/or BodPod body composition measures, able to read and speak English, and had no cognitive impairment. Women and men were analyzed separately due to known differences in fat and lean mass. Results: Table 1: Sample characteristic’s Testing the hypothesis using 2-way ANOVA and comparing the percentage of body weight that is lean and fat mass in NYHA class I-II vs III-IV found the interaction of gender and NYHA was not significant in either % lean or %fat (p=0.221, 0.190 respectively). NYHA class by itself was not significant (p=0.067) in %lean but was significant in %fat (p=0.046). Gender was significant in both %lean and %fat with men having 9.6% less fat (1.139 SE) and 9.8% more lean mass (1.066 SE) (p≤0.001). NYHA class III-IV had 2.3% (1.139 SE) more fat than those in NYHA class I-II. The R squared was 0.265 and adjusted R squared was 0.256. Conclusions: Part of our hypothesis was correct in that NYHA class III-IV had more fat mass than those in class I-II, but no difference was found in lean. This is an unexpected finding as healthy people gain fat mass while losing lean mass as they age. Additional studies are needed to further examine this result.
Abstract 5289: Gain-of-function mutant p53 predisposes head and neck keratinocytes and squamous cell carcinoma cells to replicative stress and genomic instability through minichromosome maintenance complex component 5
Authors: Mei Zhao, Tianxiao Wang, Chen Zhen, Jing Wang, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou
Journal: Cancer Research (2019)

Abstract As the guardian of genome, p53 plays important roles in maintaining the genome integrity, and TP53 mutations thereby often lead to genomic instability in cancers. In addition to the loss-of-function, many TP53 mutations can lead to the gain-of-functions (GOF) that often promote tumor development and tumor progression. As an effort to identify the mechanisms involved in mutant p53 GOF activities in head and neck squamous cell carcinoma (HNSCC), we performed an unbiased proteomic screen to identify the mutant p53 G245D interactome in HNSCC cells by immunoprecipitation, and quantitative proteomics using stable isotope labeling with amino acids in cell culture and liquid chromatography coupled with tandem mass spectrometry. Our results identified that MCM5, a member of replication licensing heterohexameric origin recognition complex minichromosome maintenance 2-7 (MCM2-7), interacts with mutant p53s, which suggests a possible role of mutant p53 in regulation of DNA replication. Consistent with this, we show that overexpression of mutant p53 in p53-depelted oral keratinocytes and HNSCC cells predisposes cells susceptibility to replication stress by inhibiting the dormant origin firing, leading to increased chromosomal instability (CIN) under replication stress. Moreover, by overexpressing and downregulating MCM5, we demonstrate that MCM5 modulates GOF mutant p53-mediated susceptibility to replication stress and CIN. Given the importance of MCM2-7 in replication licensing, initiation, and elongation, our discovery of the relationship between mutant p53 and MCM5 suggests that the MCM2-7 complex is one of the key downstream effectors, through which GOF mutant p53s regulate DNA replication and genomic instability in HNSCC. Citation Format: Mei Zhao, Tianxiao Wang, Chen Zhen, Jing Wang, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou. Gain-of-function mutant p53 predisposes head and neck keratinocytes and squamous cell carcinoma cells to replicative stress and genomic instability through minichromosome maintenance complex component 5 [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 5289.