tbuckley/cabot-search huggingface dataset:
Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma
Authors: Iris C. Salaroglio, Joanna Kopecka, Francesca Napoli, Monica Pradotto, Francesca Maletta, Lorena Costardi, Matteo Gagliasso, Vladan Milosevic, Preeta Ananthanarayanan, Paolo Bironzo, Fabrizio Tabbò, Carlotta F. Cartia, Erika Passone, Valentina Comunanza, Francesco Ardissone, Enrico Ruffini, Federico Bussolino, Luisella Righi, Silvia Novello, Massimo Di Maio, Mauro Papotti, Giorgio V. Scagliotti, Chiara Riganti
Journal: Journal of Thoracic Oncology (2019)

IntroductionA comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified.MethodsWe enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome.ResultsThe cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule–positive (CD4+) programmed death 1–positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3–positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3–positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival.ConclusionsA clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.
Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma
Authors: Liang Yang, Xueqiang Peng, Yan Li, Xiaodong Zhang, Yingbo Ma, Chunli Wu, Qing Fan, Shibo Wei, Hangyu Li, Jingang Liu
Journal: Molecular Cancer (2019)

Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear. We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments. We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling. Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.
Abstract 5275: Association of TERT polymorphism with acute myeloid leukemia risk and prognosis
Authors: Kourosh Lotfi, Mohamed Ali Mosrati, Kerstin Willander, Ingrid Jakobsen Falk, Monica Hermanson, Martin Höglund, Dick Stockelberg, Yuan Wei, Peter Söderkvist
Journal: Cancer Research (2015)

Abstract Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNPs in 256 acute myeloid leukemia (AML) patients. A significant association for increased risk of AML was found for TERT SNPs, rs2853669 (OR = 2.45, p = 0.00006) and rs2736100 (OR = 1.52, p = 0.02). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 (respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, age and treatment. No hot spot TERT promoter mutations at -228C&amp;gt;T or -250C&amp;gt;T or POT1 mutations could be identified in this AML cohort. We show for the first time that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify relative high risk NK-AML patients, for treatment guidance. Note: This abstract was not presented at the meeting. Citation Format: Kourosh Lotfi, Mohamed Ali Mosrati, Kerstin Willander, Ingrid Jakobsen Falk, Monica Hermanson, Martin Höglund, Dick Stockelberg, Yuan Wei, Peter Söderkvist. Association of TERT polymorphism with acute myeloid leukemia risk and prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5275. doi:10.1158/1538-7445.AM2015-5275
Abstract P6-17-01: Withdrawn
Authors: SM Tolaney, AM Wardley, S Zambelli, JF Hilton, TA Troso-Sandoval, F Ricci, S-A Im, S-B Kim, SR Johnston, A Chan, S Goel, K Catron, Z Yang, C Gainford, F André
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, Im S-A, Kim S-B, Johnston SR, Chan A, Goel S, Catron K, Yang Z, Gainford C, André F. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-01.
Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy
Authors: Daniel Gordin, Hetal Shah, Takanori Shinjo, Ronald St-Louis, Weier Qi, Kyoungmin Park, Samantha M. Paniagua, David M. Pober, I-Hsien Wu, Vanessa Bahnam, Megan J. Brissett, Liane J. Tinsley, Jonathan M. Dreyfuss, Hui Pan, Yutong Dong, Monika A. Niewczas, Peter Amenta, Thorsten Sadowski, Aimo Kannt, Hillary A. Keenan, George L. King
Journal: Diabetes Care (2019)

OBJECTIVE Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists’ plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD− versus CKD+ individuals with type 2 diabetes. Medalists’ plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.
Abstract P6-02-14: Not presented
Authors: W Xing, Q Li, G Sun, R Cao, B Chen, C Jiang, L Ma, K Wang
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Xing W, Li Q, Sun G, Cao R, Chen B, Jiang C, Ma L, Wang K. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-14.
Abstract P2-06-24: Cannabinoid receptors agonist induces lysosome-mediated cell death in TNBC
Authors: N Chatterjee, S Das, D Ahiwar, S Mishra, K Kaul, R Ganju
Journal: Cancer Research (2019)

Abstract Breast cancer is one of the leading causes of death among women in the United States. Among all the breast cancer subtypes, triple-negative breast cancer (TNBC) is denoted as having the highest rate of mortality due to inefficacious therapy, drug resistance, and high recurrences rate. Despite many therapeutic advances over the past decades, novel therapeutic approaches are required to treat TNBC. Although lysosomes have recently been identified as novel targets in a variety of cancers, not much known about their role in breast cancer especially in TNBC. Due to the altered features of lysosomes in cancerous cells, its functional ability affects cell proliferation, metabolism, adaptation, and autophagy in tumor cells. Thus, the induction of lysosomal membrane permeabilization (LMP) may be used as a novel approach in controlling the aberrant cellular functions in TNBC. Cannabinoid receptor 2 (CB2) is expressed in breast cancer and its agonist JWH-015 has been shown to inhibit TNBC growth and metastasis. However, not much is known about the mechanisms by which JWH015 inhibit growth and metastasis. To investigate JWH015-mediated therapeutic mechanisms, we examined the lysosome-mediated cell death in TNBC cells. We found that JWH015 induces cell death in TNBC cells through lysosomal disruption mechanism. We also showed that JWH-015 treatment increases releases of lysosomal proteins, cathepsin D/B, and autophagy marker LC3B and that leads to activation of apoptotic cell death signaling in TNBC. These alterations result in the formation of autolysosomes to promote LMP. Our findings elucidate the mechanism by which JWH-015 promotes LMP induced autophagy and regulates TNBC cell proliferation. These studies elucidate novel lysosomal-mediated cell death mechanisms through activation of CB2 receptors in TNBC. Citation Format: Chatterjee N, Das S, Ahiwar D, Mishra S, Kaul K, Ganju R. Cannabinoid receptors agonist induces lysosome-mediated cell death in TNBC [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-24.
Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells
Authors: Cristina D'Aniello, Federica Cermola, Andrea Palamidessi, Luca G. Wanderlingh, Miriam Gagliardi, Agnese Migliaccio, Francesca Varrone, Laura Casalino, Maria R. Matarazzo, Dario De Cesare, Giorgio Scita, Eduardo J. Patriarca, Gabriella Minchiotti
Journal: Cancer Research (2019)

Abstract Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells in vivo by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. Significance: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.
Abstract 13628: Circulating microRNA-1914 is Associated With Both Oxidative Stress and Platelet Activation, and Plays a Crucial Roles in Atherothrombosis
Authors: Tomonori Sugiura, Yasuaki Dohi, Soichiro Iwaki, Satoshi Fujii, Nobuyuki Ohte
Journal: Circulation (2017)

Introduction: Serotonin incorporated into platelets, and released into plasma on activation of platelets, modulates vascular tonus and thrombus formation in circulating blood. Oxidative stress is i...
You’ve been bleeped: symptom control in the unwell patient
Authors: Richard Kitchen, Nicholas Budhram
Journal: BMJ (2016)

As a junior doctor you need to know how to recognise a deteriorating patient and to initially manage symptoms that the patient may be experiencing, such as pain, breathlessness, and nausea. This article shows you how to work out the causes of pain in a patient who has gastric cancer and who is deteriorating, so that you can formulate an appropriate management plan.

#### Scenario

You are a foundation year one doctor (FY1) working a weekend on-call rota that covers the oncology and haematology wards at a teaching hospital. It is 14:30 on Saturday and you have just reviewed a patient on oncology ward A who has hyperglycaemia. You are about to chase up some blood test results that were handed to you before the weekend when you receive a bleep.

#### Bleep

“Hi doctor, it’s Rob, charge nurse on oncology ward C. I’m ringing you about Mr Lewis, a 65 year old man with metastatic gastric cancer. He came into hospital with haematemesis, although this settled after he received palliative radiotherapy to the stomach. More recently, he has been treated for a chest infection, but over the past few days he has been deteriorating, and now he has worsening abdominal pain. He has vomited once, although I don’t think there was any blood. He is very uncomfortable and looks distressed. Could you come to review him please?”

### How would you react to this bleep on the phone?

In this case you need to consider two main points. The first is the symptoms that Mr Lewis is experiencing: abdominal pain and vomiting. You need to work out the cause of both of these symptoms and develop a management plan. The second point you need to deal with is what is causing the patient to deteriorate.

Abdominal pain can have many causes, so you should carry out a thorough history and physical examination. In patients …
Abstract P6-02-17: Hand-held impulse-radar detector for breast cancer: development and a pilot study
Authors: S Sasada, N Masumoto, H Song, N Goda, K Kajitani, A Emi, T Kadoya, K Arihiro, T Kikkawa, M Okada
Journal: Cancer Research (2019)

Abstract Background: Microwave breast imaging, which using the difference in the dielectric properties between breast cancer and normal breast tissue, is a painless and non-radiation method. We have created a novel hand-held prototype of breast cancer detector using impulse-radar based imaging system, and conducted a pilot clinical study. Methods: The detector consists of complementary metal-oxide-semiconductor (CMOS) integrated circuits covering the ultrawideband width from 3.1 to 10.6 GHz, which enable the generation and transmission of Gaussian monocycle pulse (GMP) trains and single port eight throw switching matrices (SP8T-SW) for controlling a 4×4 cross-shaped dome antenna array. The size of the detector was 19.1 × 17.7 × 18.8 cm. After evaluation using a breast tumor phantom and the resected breast specimens obtained through mastectomy, we recruited 5 patients with histologically confirmed breast cancers in the clinical study. The detector was placed on the breast with the patient in a supine position. The primary endpoint was a detection rate of breast cancers, and the secondary endpoints were positional accuracy and adverse event. This study was registered with the UMIN Clinical Trials Registry (UMIN000026181). Results: The three-dimensional positions of the tumors in the imaging results using a phantom and resected specimens are consistent with the results of histopathology analysis. In the clinical study, all 5 targeted breast cancers were detected and were visualized at the sites confirmed by other diagnostic modalities. Among 5 tumors, one was not detected via mammography because of heterogeneously dense breast and another was a microinvasive carcinoma of invasive tumor size 0.5 mm. No study-related adverse events occurred. Conclusions: We succeeded in creating a new device of hand-held impulse-radar detector for breast cancer. The detector has sufficient detective capability, is safe for clinical use, and might detect an early stage breast cancer. In the future, we will proceed with the development to clinical application. Citation Format: Sasada S, Masumoto N, Song H, Goda N, Kajitani K, Emi A, Kadoya T, Arihiro K, Kikkawa T, Okada M. Hand-held impulse-radar detector for breast cancer: development and a pilot study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-17.
Abstract P2-07-12: A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis
Authors: L Tan, K Chen, WG Jiang, N You, Y Wang, A Sanders, G Liang, Z Liu, Y Ling, W Zhong, Z Tian, C Gong
Journal: Cancer Research (2019)

Abstract Purpose The aim of the study was to develop a specific nomogram for prediction of prognosis for breast Paget's disease with infiltrating ductal carcinoma (PD-IDC) patients. Patients and Methods Patients data were obtained by the Surveillance, Epidemiology, and End Results (SEER) program (N=2502). Study outcome was Breast Cancer Specific Survival (BCSS). Cox proportional hazards model was applied to identify risk factors and develop predictive model. For internal validation, discrimination was calculated with the concordance index (C-index) using the bootstrap method and calibration assessed. Results NPI classification, skin symptom, tumor site and age showed significant association with BCSS(table.1)and were used to build the PDIDC nomogram and to calculate risk score. PDIDC nomogram's C-index (0.791, 95%CI 0.783-0.818) showed better discrimination power than NPI classification (0.691, 95%CI, 0.650-0.735, P= 0.000) and AJCC staging (0.718, 95%CI, 0.695-0.741, P=0.000). Patients were divided into high-risk (1882/2502, 75.21%) and low-risk (620/2502, 24.78%) subgroups with the optimal cut-off of risk scores (4.28). The total BCSS of low-risk subgroup was 77.8% (95%CI 74.4%-81.4%) vs. 31.1% (95%CI 19.4-49.8) of high-risk group (P=0.000). Bootstrap internal validation demonstrated an average C-index of 0.739 (95% CI, 0.692-0.746). The nomogram calibration was validated to be accurate in predicting 5-year and 10-year survival. Variable finally selected for risk predicted model.PredictorHazard RatioP Value95% CINPI classification Good1 Moderate2.170.0001.51-3.14Poor7.260.0004.96-10.63Skin symptom Without1 With1.760.0001.34-2.32Tumor site Centrally located1 Non-centrally located1.250.0421.07-1.56Age*1.010.0001.01-1.03* Continuous variable. Conclusion Utilizing NPI classification, skin symptom, tumor site and age, we developed the PDIDC nomogram to predict the 5-year and 10-year BCSS of breast PD-IDC patients. Citation Format: Tan L, Chen K, Jiang WG, You N, Wang Y, Sanders A, Liang G, Liu Z, Ling Y, Zhong W, Tian Z, Gong C. A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-12.
Abstract 5064: Venous Thrombosis after Air Travel: Prevention with Aspirin vs Low-Molecular-Weight Heparin (lmwh) in High-Risk Subjects. A Prospective Study
Authors: Gianni Belcaro, Maria Rosaria Cesarone, Umberto Cornelli
Journal: Circulation (2008)

LONFLIT studies have observed that in subjects at high-risk (HRS) for deep venous thrombosis (DVT) during/after long (&gt;10 hours) flights, the incidence DVT (by ultrasound scans) may be between 4% and 6% (including subclinical thrombi), This study evaluated DVT prevention in HRS: 886 subjects were approached and 600 were included. They were divided into 3 groups and advised to use during the flights: a:exercise only (no pharmacological prophylaxis) b: aspirin (400 mg tablets, soluble aspirin; one dose daily for 3 days, starting 24 hours before flights) c: low-molecular-weight heparin (LMWH; enoxaparine - Lovenox - injected 2– 4 hours before flights. The single dose was weight-adjusted (1000 IU - equivalent to 0.1 ml per 10kg of weight). Subjects with possible problems due to aspirin or LMWH, using anticoagulants and other drugs (at risk of interactions) were excluded. High-resolotion ultrasound scans included femoral,popliteal and soleal veins and were performed within 24 hours after the second flight. The time separation between the two flights was &lt;8 days (average 6.5;SD1.1). 458 subjects completed the two-flights study. Dropouts were due to low compliance or traveling/connections problems. Age/sex and risk distribution were comparable in the three groups. Mean age was 44.7 (range, 24 – 66; SD 7.1; 54% males). In the control group (160), there were 6.87% of subjects with DVT plus 2 superficial thromboses (SVT)(total events 8.1%). Of 142 subjects in the aspirin treatment group, there were 4.9% of subjects with DVT plus 3 SVTs (total 7% of subjects with a thrombotic event). In the LMWH group (156) there were no cases of DVT and 2 superficial thrombosis (1.28%); (P&lt;0.002 in comparison with the other two groups). DVT was asymptomatic in 64% of subjects; D-dimer was elevated in 78% o subjects with events and in 28% of subjects without events. Mild gastrointestinal symptoms were reported in 15% of patients using aspirin. No side-effects were observed in the LMWH group. In conclusion, one dose of LMWH is an important option to consider for HRS during long-haul flights.