tbuckley/cabot-search huggingface dataset:
Identifying mechanisms of macrophage-induced metastasis in pancreatic ductal adenocarcinoma.
Authors: Tony James Wu
Journal: Journal of Clinical Oncology (2019)

e15705 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease. Macrophages are one of the most abundant, multifunctional immune cell populations in the tumor microenvironment and a major component of the immune infiltrate in many solid tumors. Methods: Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Results: Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT (epithelial-to-mesenchymal transition) status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype. Conclusions: Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the tumor microenvironment and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.
Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels.
Authors: Alexios Matikas, Ioannis Zerdes, John Lovrot, François Richard, Christos Sotiriou, Jonas C. S. Bergh, Antonios Valachis, Theodoros Foukakis
Journal: Journal of Clinical Oncology (2019)

e14284 Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE). Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I 2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed. Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p &lt; 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p &lt; 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p &lt; 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p &lt; 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p &lt; 0.001 for OS), p interaction 0.124 for DFS and 0.005 for OS. Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.
Evaluation of clonal hematopoiesis in late stage NSCLC using a next-generation sequencing panel targeting cancer genes.
Authors: Stephanie J. Yaung, Frederike Fuhlbrück, Johnny Wu, Fergal Casey, Maureen Peterson, Wei Zou, John F. Palma, Namrata S. Patil, Yuqiu Jiang
Journal: Journal of Clinical Oncology (2019)

9050 Background: Somatic mutations derived from the expansion of clonal populations of blood cells (clonal hematopoiesis of indeterminate potential, or CHIP) may be detected in sequencing of cell-free DNA (cfDNA) samples. We evaluated the potential implications of CHIP in targeted sequencing of lung cancer plasma samples using matched peripheral blood mononuclear cells (PBMC) to identify CHIP. Methods: Samples were evaluated from OAK, a phase 3 trial of atezolizumab in locally advanced or metastatic NSCLC following failure with platinum-based therapy. 94 samples from Cycle 1 Day 1 (C1D1) plasma and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a 198-kb next-generation sequencing panel targeting cancer genes. Plasma samples from subsequent cycles of therapy (C2D1, C3D1, and C4D1) were also sequenced with the same panel. Using median input amounts of 22.8 ng cfDNA and 50 ng PBMC DNA, we obtained median deduplicated depths of 5413 and 5070, respectively. Results: In C1D1 cfDNA, a median of 120 single nucleotide variants were detected per sample, with 5.13% of variants not identified in matched PBMC (i.e., putative tumor-derived somatic variants) versus 94.87% of variants identified in matched PBMC (i.e., germline or CHIP variants). While the majority of PBMC-matched variants were SNPs with allele frequency (AF) around 50% or 100% as expected, there was a median of 1 (range 0-8) PBMC-matched cfDNA variants per sample with AF below 10%. Consistent with CHIP, the number of PBMC-matched cfDNA variants per subject below AF 10% were positively associated with age (p-value = 0.0145), and TP53 was the most frequently mutated gene. We found similar results in plasma samples from subsequent cycles. Conclusions: Plasma and PBMC sequencing analysis identified potential mutations derived from CHIP. However, 39% of cfDNA samples had zero potential CHIP mutations identified in the study, possibly due to the specific regions targeted by the AVENIO assay. While this study suggests that only a small percentage of variants detected by the AVENIO Surveillance panel in lung cancer are derived from CHIP, further studies are warranted to assess the impact and removal of these variants.
Abstract 14724: Mitophagy in Ischemia/Reperfusion: Effects of High Fat Diet and Melatonin
Authors: Amanda Lochner, Karthik Dhanalaban, Sibo R Mzezewa, Barbara Huisamen
Journal: Circulation (2016)

Introduction: Mitophagy removes damaged mitochondria and prevents ROS overproduction and may be important in the outcome of myocardial ischemia/reperfusion (I/R). However little is known about mito...
A prospective study of anti-mullerian hormone (AMH) as a predictor of chemotherapy-induced menopause.
Authors: Bogda Koczwara, Shahid Ullah, M Nazim Abbas, Alex Scott-Hoy, Fiona Young, Ganessan Kichenadasse, Christos Stelios Karapetis, Amitesh Chandra Roy, Shawgi Sukumaran, David M. Ross, Muhammad Adnan Khattak, Elinor Atkinson, Hilary Martin
Journal: Journal of Clinical Oncology (2019)

e23076 Background: Chemotherapy-induced premature menopause is a distressing side effect of cancer treatment. Currently there are no validated tools to predict the loss of ovarian function. Anti-Mullerian hormone (AMH) in healthy women correlates with ovarian reserve and predicts menopause but its utility in chemotherapy-treated patients is underexplored. We examined the utility of AMH levels as a predictor of chemotherapy-induced amenorrhea at 1-year post chemotherapy - a reliable surrogate for chemotherapy-induced menopause. Methods: Premenopausal women, 45 years or younger, about to receive curative chemotherapy for breast cancer or lymphoma, without ovarian suppression, were assessed for menopausal symptoms using Menopausal Symptom Score (MSS), quality of life (QOL) using EORTC – QLQ-C30 questionnaire, and had serum AMH, oestradiol, FSH, LH collected prior to first chemo, and at 3 and 6 weeks, at completion and 12 months after chemotherapy. Results: Twenty-two premenopausal women, median age 40.5 (37-43) were enrolled. Twenty became amenorrhoeic during chemotherapy and four had return of menses at 1 year after treatment completion. Median AMH level at baseline was 12.9 pmol/L (IQR 5.2 – 26.5), fell sharply following first chemotherapy and remained low at &lt; 3pmol/L (IQR &lt; .3 ) at 1 year with only 2 subjects with AMH levels above 3 pmol/L. Women who regained menses at 12 months had higher baseline AMH than those who remained amenorrheic (p &lt; 0.001). Older age was associated with lower AMH at baseline and at 1 year. Median MSSs increased significantly at 1 year: 0.8 (IQR 0.5-1.8) versus 0.3 (IQR 0-0.4) (p = 0.5). While there was no significant change in QOL scores between baseline and 1 year, there was a significant negative correlation between menopausal symptom score and QOL at 1 year (p = 0.03). Conclusions: In this small study, pre-treatment AMH correlated with amenorrhea at 1-year post chemotherapy suggesting potential role of AMH levels in counselling women regarding their reproductive potential post chemotherapy. Further research in a larger sample of women is needed.
PDL1 landscape in checkpoint inhibitor ineligible patients by IHC and cfRNA.
Authors: Shumei Kato, Noor Khalid, Rebecca Jimenez, Suzanna Lee, Leylah Drusbosky, Christopher Szeto, Chad Garner, Sandeep K. Reddy, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2019)

e14570 Background: Immune checkpoint inhibitors (ICT) are indicated in patients with PDL1+ IHC and restricted to certain histologies . Other tumor histologies express PDL1 at various frequencies with no established threshold for therapeutic efficacy. We evaluated traditionally ICT non-indicated histologies by IHC and cfRNA to determine potential therapeutic thresholds. Methods: A total of 97 pts (cancer of unknown primary [N = 10], appendix [N = 6], bile duct [N = 4], colorectal cancer [N = 25], esophageal [N = 6], ovary [N = 7], pancreas [N = 15], other [N = 24]) with IHC (Dako 76 22C3, 21 SP142) and cfRNA for PDL1 were available for analysis. cfRNA was a random draw not matched with the time of tissue collection and performed by qPCR. A cutoff of &gt; 1.5x for PDL1 normalized to beta actin was defined as PDL1+ in cfRNA. IHC &gt; 10% was used as the threshold for IHC+. Results: Most patients were PDL1- by IHC: 90/97 (93%), PDL1 TPS: 0% (N = 72), 1% (N = 7), 5% (N = 8), 10% (N = 3), &gt; 10% (N = 3), &gt; 50% (N = 4). No difference was seen between 22C3 and SP142 antibodies. PDL1+ cfRNA (N = 59), PDL1- cfRNA (N = 38). Positive concordance for cfRNA PDL1+ and IHC PDL1+ was 10.2% (6/59). Negative concordance for cfRNA PDL1 - and IHC PDL1- was 97.4% (37/38) (p = 0.079). Conclusions: In ICIs ineligible patients a &gt; 50% IHC threshold is rarely met (4%). Random draw qPCR PDL1 is poorly correlated with IHC, with higher rates of PDL1+ in cfRNA in setting of IHC PDL1-. In the other hand, cfRNA PDL1- is strongly associated with an IHC negative result. Further investigation incorporating both cfRNA and IHC result to predict the response from ICIs are warranted.
Influence of agomelatine and trastuzumab on the HER2/neu(+), MT1 (+) and MT2 (+) chemo and immunoresistant breast cancer cells lines from the previously treated patients by targeted therapy with trastuzumab.
Authors: Alexandre Tavartkiladze, Pati Revazishvili, Ani Gvajaia
Journal: Journal of Clinical Oncology (2019)

e14056 Background: Agomelatine is a melatonin receptor agonist (MT 1 and MT 2 ) and a 5-HT 2C receptor antagonist. Melatonin is a lipophilic compound that is capable of binding to cell surface receptors, cytosolic sites (calmodulin), and directly to nuclear DNA binding sites (nuclear receptors RZR/RORα). Its direct antioxidant, antimitotic, antiestrogenic, prodifferentiating and antimetastatic effects have been well characterized. Nitric oxide (NO) is an inorganic free radical gas synthesized from L-arginine by a family of isoenzymes called NO synthases. Two of these are constitutively expressed and a third is inducible by immunological stimules. The NO released by the constitutive enzymes acts as an important signaling molecule in the cardiovascular and nervous systems and NO released by the inducible NO synthase (iNOS) is generated for long periods, by cells of the immune system among others, and has been shown to be cytostatic/cytotoxic for tumor cells and a variety of microorganisms. Methods: We have studied oncostatic/citostatic influence by ATP-TCA method of agomelatine and agomelatine + trastuzumab solution on the cellular cultures Her2/neu (+), MT1 and MT2 receptor (+) mammary ductal adenocarcinoma (17 cases). Data of ATP-TCA test in healthy patients breast’s cellular cultures with only trastuzumab were used as control. In parallel, we have studied expression of enzyme universal nitric oxide synthase (u-NOS) in cellular cultures of mammary ductal adenocarcinoma all three cells lines using Western blot method. The findings were compared to the data of u-NOS expression in healthy patients breast’s breast cellular cultures. Results: The study demonstrated that influence of citostatic effect of only agomelatine by ATP-TCA method are increased by 32.5% and citostatic effect of agomelatine + trastuzumab by ATP-TCA method also are increased by 45% in compared to control. Expression of universal nitric oxide synthase (u-NOS) is increased in case of mammary ductal adenocarcinoma by 14.2% in case only agomelatine and by 26.7% in case agomelatin + trastuzumab compared to control. Conclusions: Results of this research describe the positive role of agonists melatonin receptors (agomelatin) in the treatment previously treated and after progressed breast cancer (while this mechanism in details is unknown for us) and increased expression of NOS indicate the possibly augmentation sensitivity the cells lines for the citostatics medicines.
Electron microscopic characteristic of local immune processes during regression of developed experimental tumors under the influence of magnetite nanoparticles.
Authors: Galina V. Zhukova, Oleg I. Kit, Marina I. Bragina, Tatiana N. Gudtskova, Alla I. Shikhlyarova, Elena A. Shirnina, Anastasia I. Zhadobina, Vladimir Alekseevich Zernov, Mikhail Yu. Rudenko
Journal: Journal of Clinical Oncology (2019)

e14179 Background: Previously, regression of the developed transplanted tumors under the influence of magnetite nanoparticles (NPs) as monofactor was shown. The purpose of the study was to reveal signs of intercellular interactions in the zone of tumors regressed under the influence of magnetite NPs. Methods: Experiments were carried out on 14 white outbred male rats (180-200 g) with transplanted sarcoma 45 of an initial volume of 0.7-1.3 cm 3 . After 6 peritumoral injections of magnetite NPs (10 ± 2 nm) in the form of magnetic fluid AM-01 ("AM-Kub", Ekaterinburg) twice a week in a single dose of 17.7 mg/kg, 5 out of 7 rats of the main group demonstrated a regression of the tumor from 1.5-3 cm 3 to 0.7 ± 0.2 cm 3 (in the control group – 9.7 ± 1.9 cm 3 , p &lt; 0.01). Ultrathin sections of the tumor tissue of 12 animals (including 7 rats of the main group) were examined in electron microscope JEOL JEM-1011 (Japan). Results: Under effective action of magnetite NPs in tumor tissue, in addition to necrosis, apoptosis and autophagy were marked. In the case of apoptosis, chromatin condensation in compact masses and separation of apoptotic bodies were observed. Significantly more common autophagic cell death was identified by violation of the integrity of the cell membrane and the presence of autophagosomes. Numerous signs of activation of cell-cell interactions with participation of immune cells were observed. Diverse groups of 2-4 contacting cells included macrophages, lymphocytes, plasmocytes, degranulated mast cells, neutrophils in various combinations with distinct signs of the metabolic activity. Invagination of macrophages cytoplasm into the cytoplasm of tumor cells, close adjacency of the cytoplasmic membranes of neutrophils and lymphocytes at considerable length, tight intertwining of mast cell cytoplasmic processes and engulfing of the mast cell granules by macrophages were noted. Conclusions: The results supplement the characteristics of immune processes during the self-dependent antitumor action of magnetite NPs.
Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
Authors: Samia Mora, C. Lan Chang, M. Vinayaga Moorthy, Peter S. Sever
Journal: JAMA Internal Medicine (2019)

Recent guidelines have recommended nonfasting for routine testing of lipid levels based on comparisons of nonfasting and fasting populations. However, no previous study has examined the association of cardiovascular outcomes with fasting vs nonfasting lipid levels measured in the same individuals.
Advances in intracellular delivery through supramolecular self-assembly of oligonucleotides and peptides
Authors: Jeonghwan Kim, Ashwanikumar Narayana, Siddharth Patel, Gaurav Sahay
Journal: Theranostics (2019)

Cells utilize natural supramolecular assemblies to maintain homeostasis and biological functions. Naturally inspired modular assembly of biomaterials are now being exploited for understanding or manipulating cell biology for treatment, diagnosis, and detection of diseases. Supramolecular biomaterials, in particular peptides and oligonucleotides, can be precisely tuned to have diverse structural, mechanical, physicochemical and biological properties. These merits of oligonucleotides and peptides as building blocks have given rise to the evolution of numerous nucleic acid- and peptide-based self-assembling nanomaterials for various medical applications, including drug delivery, tissue engineering, regenerative medicine, and immunotherapy. In this review, we provide an extensive overview of the intracellular delivery approaches using supramolecular self-assembly of DNA, RNA, and peptides. Furthermore, we discuss the current challenges related to subcellular delivery and provide future perspectives of the application of supramolecular biomaterials for intracellular delivery in theranostics.
Machine learning methods with salivary metabolomics for breast cancer detection.
Authors: Takeshi Murata, Takako Yanagisawa, Toshiaki Kurihara, Miku Kaneko, Sana Ota, Ayame Enomoto, Masaru Tomita, Masahiro Sugimoto, Makoto Sunamura, Tetsu Hayashida, Yuko Kitagawa, Hiromitsu Jinno
Journal: Journal of Clinical Oncology (2019)

3135 Background: Saliva is non-invasively accessible and informative biological fluid which has high potential for the early diagnosis of various diseases. The aim of this study is to develop machine learning methods and to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls. Methods: We conducted a comprehensive metabolite analysis of saliva samples obtained from 101 patients with invasive carcinoma (IC), 23 patients with ductal carcinoma in situ (DCIS) and 42 healthy controls, using capillary electrophoresis and liquid chromatography with mass spectrometry to quantify hundreds of hydrophilic metabolites. Saliva samples were collected under 9h fasting and were split into training and validation data. Conventional statistical analyses and artificial intelligence-based methods were used to access the discrimination abilities of the quantified metabolite. Multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning methods were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods. Results: Among quantified 260 metabolites, amino acids and polyamines showed significantly elevated in saliva from breast cancer patients, e.g. spermine showed the highest area under the receiver operating characteristic curves (AUC) to discriminate IC from C; 0.766 (95% confidence interval [CI]; 0.671 – 0.840, P &lt; 0.0001). These metabolites showed no significant difference between C and DICS, i.e., these metabolites were elevated only in the samples of IC. The MLR yielded higher AUC to discriminate IC from C; 0.790 (95% CI; 0.699 – 0.859, P &lt; 0.0001). The ADTree with ensemble approach showed the best AUC; 0.912 (95% CI; 0.838 – 0.961, P &lt; 0.0001). In the comparison of these metabolites in the analysis of each subtype, seven metabolites were significantly different between Luminal A-like and Luminal B-like while, but few metabolites were significantly different among the other subtypes. Conclusions: These data indicated the combination of salivary metabolomic profiles including polyamines showed potential ability to screening breast cancer in a non-invasive way.
Survival differences based on tumor size among stage 1B cervical cancer patients in Louisiana using revised FIGO staging system.
Authors: Navya Nair, Lu Zhang, Anna Kuan-Celarier, Xiao-cheng Wu, Amelia Jernigan
Journal: Journal of Clinical Oncology (2019)

e17017 Background: In the recently revised 2018 FIGO cervical cancer staging, stage IB is sub-classified into 3 classes based on tumor size. We aim to determine if larger tumor size confers worse survival outcomes in women with stage IB cervical cancer in Louisiana. Methods: Women with stage IB cervical cancer diagnosed between 2010 and 2016 were identified from the Louisiana Tumor Registry. Patients with positive pelvic or para-aortic lymph nodes and those with less than 30 days follow up were excluded. Subjects were classified into three groups based on tumor size: stage IB1 ( &lt; 2cm), stage IB2 (≥ 2cm and &lt; 4cm), and stage IB3 (≥ 4cm). Cox proportional hazards were used to estimate differences in overall (OS) and cause-specific survival (CSS). Covariates included age, race, insurance, census tract-poverty level, and marital status. Results: 198 patients were included with a median follow up time of 43.8 months. Mean age of patients in this cohort was 46.8 years. The subjects were well distributed between the groups: 79 (39.4%) stage IB1, 60 (30.3%) stage IB2, and 60 (30.3%) stage IB3. White women comprised a larger percentage of earlier stage tumors (79.5% 1B1 vs 68.3% 1B2 vs 53.3% 1B3, p &lt; 0.01); Black women were overrepresented in later stage disease (45.0% IB3, 28.3% IB2, 20.5% IB1, p &lt; 0.01). There were no significant differences between the three groups in age, insurance status, poverty level, or marital status. After adjusting for covariates, patients with stage 1B3 disease had worse survival than those with stage 1B1 disease in both OS [HR 6.01 (1.96,18.50)] and CSS [HR 24.31 (2.97,199.00)]. Patients with stage 1B2 disease had worse survival than those with 1B1 disease but this did not reach statistical significance: OS HR 1.88 (0.52,6.74); CSS HR 6.79 (0.77, 59.99). Kaplan-Meier curves of OS and CSS show significant survival differences between the three groups (p &lt; 0.0001) with best outcomes in stage 1B1 and worst in stage 1B3 patients. Conclusions: This analysis of contemporary stage IB cervical cancer patients in Louisiana confirms that tumor size &gt; 4cm confers worse clinical prognosis. Black women are overrepresented advanced stage IB disease. While patients with tumors 2-4cm did worse than those with tumors &lt; 2cm, this did not reach statistical significance. This could be due to the limited sample size of our cohort.