tbuckley/cabot-search huggingface dataset:
SAT0705 Association between fracture sites in patients with a history of parental fracture
Authors: M. Dey, M. Bukhari
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Fragility fractures (FF) are fractures due to low energy force. Factors predisposing to FF in the general population include reduced bone mineral density (BMD), and family history of osteoporosis. FF most commonly occur in the vertebrae, proximal femur, and distal radius. Studies have demonstrated increased risk of FF in patients with decreased BMD and parental history of FF, particularly hip fracture.<sup>1,2</sup> Few data exist on the association between sites of fracture in patients with a history of parental fracture, especially whether they co-exist at several sites and if particular factors are associated with discrete sites. <h3>Objectives</h3> We aimed to find the correlation between sites of FF in patients with a history of parental fracture, and identify and examine the clinical association with any clusters of fractures. <h3>Methods</h3> 2094 patients with a history of parental FF and personal history of at least one FF, presenting for BMD estimation from their primary or secondary care practitioner, from 2006–2016, were included. Parameters recorded: height, weight, age at scan, average fat mass, site of fracture(s), smoking, alcohol, corticosteroid use, aromatase inhibitor use, Depo-Provera use, hormone replacement therapy (HRT), rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), breast or prostate cancer, and coeliac disease. Factor analyses with polychoric correlation matrices were applied to determine association between fracture sites. Any associations with Eigenvalues of more than one were then examined using a logistic model to analyse the effect of the above risk factors. <h3>Results</h3> Fracture sites with Eigenvalue of more than one (tibia/fibula, spine, ribs, pelvis) were compared to sites with least co-variability (humerus, forearm, femur). The two cohorts were significantly different in age; therefore, an age-adjusted model is reported below (table 1). Smoking, HRT, and increased age significantly impacted clustering of fractures in the tibia/fibula, spine, ribs, and pelvis, compared with clustering at the humerus, forearm, and femur. <h3>Conclusions</h3> In this cohort of patients, there was overlap between all fracture sites, with significant clustering seen in fractures of the tibia/fibula, spine, ribs, and pelvis. After adjusting for age, predictors of fracture in this cluster were smoking, HRT and increased age. This indicates that risk factors for FF are different at different sites, and affects the association of fracture between sites. Further work validating this finding is currently underway. <h3>References</h3> [1] A family history of fracture and fracture risk: a meta-analysis. Bone [Internet]. Elsevier 2004Nov 1 [cited 2017 Oct 27];35(5):1029–37. [2] Strong familial association of bone mineral density between parents and offspring: KNHANES 2008–2011. Osteoporos Int2017. <h3>Disclosure of Interest</h3> None declared
Association of maintenance of pre-existing memory T-cell responses following anti-CTLA-4 antibody treatment with improved overall survival.
Authors: Lawrence Fong, Edward Cha, Mark Klinger, Yafei Hou, Craig Cummings, Antoni Ribas, Malek Faham
Journal: Journal of Clinical Oncology (2014)

3016 Background: While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, the immunobiology and biomarkers associated with improved clinical outcomes is unknown. Methods: We used a next-generation sequencing to track changes in the T cell repertoire in 46 patients with metastatic castration resistant prostate cancer (CRPC) or metastatic melanoma (MM). Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified with locus-specific primer sets for T cell receptor (TCR) beta, and the amplified products were sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, the kinetics of specific T cell clonotypes were tracked with anti-CTLA-4 treatment. Naïveand memory T cells were also sorted and sequenced to define changes in these subsets. Results: CTLA-4 blockade resulted in both expansion and loss of T cell clonotypes, consistent with a global turnover of the T cell repertoire. While this treatment increased TCR diversity as reflected in the number of unique TCR clonotypes, the vast majority of change occurred in the memory T cell pool. Whereas the number of clonotypes that increased with treatment was not associated with clinical outcome, declines of the highest frequency clonotypes following treatment were associated with short overall survival. These declines were not evident in patients with longer overall survival. This association was seen in both CRPC (p<0.05) and MM patients (P<0.01, two-sided Mann Whitney). Conclusions: Together, these results indicate that CTLA-4 blockade induces T-cell repertoire evolution and diversification. However, improved clinical outcomes are associated with maintenance of pre-existing high frequency memory T cells during treatment. These clones may represent the presence of pre-existing T cells that may be relevant in the anti-tumor response. Detection of these high frequency T cell clones could help to identify patients that benefit from treatment.
Abstract 18679: Sympathetic Nerve Blocks Promote an Anti-Inflammatory Response by Activating the Jak2-stat3-Mediated Signaling Cascade: A Novel Mechanism With Clinical Implications
Authors: Hyelim Park, Hyewon Park, Hyo-Eun Kim, Michael Kim, Nam Kyun Kim, Hui-Nam Pak, Moon-Kyoung Lee, Boyoung Joung
Journal: Circulation (2016)

Introduction: Myocarditis is a major risk factor for heart failure and sudden death. The cholinergic anti-inflammatory pathway (CAIP) is a complex immune mechanism that regulates peripheral inflammatory responses and can be triggered by the central nervous system. Hypothesis: Sympathectomy’s ability to attenuate inflammation and its potential mechanism of action are unknown. Methods: Experimental autoimmune myocarditis (EAM) was produced by injecting 2 mg of porcine cardiac myosin into footpads. Fifty-two rats were assigned to the normal control group (control, n=10), the EAM group (Myo, n=15), the sympathectomy plus EAM group (MyoNB, n=15), the β-blocker pus EAM group (MyoBB, n=9), and the only sympathectomy group (NB, n=8). Relevant signaling pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, electrophysiological changes, and cytokine levels. Results: In the Myo group, 4 (27%) rats died suddenly at 14 ± 4 days after acute myocarditis and 7 (47%) surv...
Epithelial membrane protein 2 and inhibition of epithelial mesenchymal transition by interaction with integrin α5β1 and induction its ubiquitination in colon cancer.
Authors: Peng Zhang, Jin Yi Lang, Ruyan Liu
Journal: Journal of Clinical Oncology (2014)

e14650 Background: Epithelial membrane protein 2 (EMP2), a 4-transmembrane protein, has a discrete tissue distribution, with high expression in secretory endometrium, lung alveolar epithelium, and in retinal pigmented epithelium within the eye. Dysregulation of EMP2 has been implicated in endometrial cancer, in which EMP2 expression correlates with poor prognosis and survival. Methods: Colorectal cancer (CRC) is the third form of cancer in both men and women. EMT is a critical early event involved in invasion and metastasis of colorectal cancer. But its mechanism is unclear. Here, we investigated the molecular mechanism underlying Epithelial membrane protein 2 (EMP2) in the process of EMT in colon carcinoma and the clinical relevance of EMP2 in human colon cancer. Results: Our study firstly identifies the EMP2 inhibits the process of EMT in human colon cancer cells and in zebrafish animal models. In this process, it is very important that EMP2 can interact with integrin α5β1 and degrade it by increasing ubiquitination. Furthermore, p38/MAPK signaling is verified as an essential pathway in regulating EMP2 induced EMT in a TGF-β-dependent manner. Interestingly, it is found that EMP2 expression is negative correlation with tumor stages (p=0.005) and patients survival rates (p=0.01) in colon carcinoma patients (n=158). Conclusions: This indicates that EMP2 may be a novel cancer therapy target and a predictive marker for tumor migration in colon carcinoma.
Exclusion of patients with prior cancers from clinical trials: Is this justified?
Authors: Noelia Tarazona, Elizabeth Catherine Smyth, Edward Armstrong, Clare Peckitt, Sonia Mansukhani, Ian Chau
Journal: Journal of Clinical Oncology (2014)

6544 Background: Strict eligibility criteria are necessary for clinical trials to maintain patient (pt) safety and scientific validity. However exclusion of pt populations leads to impaired generalizability of results. As survival in gastrointestinal (GI) cancer relates mainly to the GI malignancy, we hypothesised that previous unrelated cancers do not impact on pt survival and are not a rational reason to exclude pts from trials. Methods: Pts were identified for this retrospective observational study from the electronic patient record at the Royal Marsden Hospital, UK. Eligibility criteria included age ≥ 18 years, diagnosis of colorectal (CRC), gastric, pancreatic or hepatocellular cancer, and treated with chemotherapy from 1/1/2006 – 31/12/2006. Chart review was performed and pt age, gender, GI cancer stage, prior cancer stage, clinical trial availability/eligibility, and dates of cancer recurrence, death and last follow up were identified. Overall (OS) and GI cancer specific survival (SS) were estimated using the Kaplan Meier method and compared by the log-rank test for pts with/without prior cancer. Results: 701 pts were identified. Most GI cancers were CRC (74%) and stage III (41%) or IV (38%) at diagnosis. 58 pts (8%) had a prior cancer; commonly breast (26%), prostate (19%), colon (9%), or melanoma (7%) and most were stage I (52%) or II (27%). 299 (65%) pts had GI cancer recurrence, 8 (14%) pts had relapse of a prior cancer. Median follow up was 84 months (m): 505 (72%) pts have died, 172 (25%) are alive with no cancer and 24 (3%) pts are alive with cancer. 477 (95%) died of GI cancer, 2 (0.3%) of their prior cancer and 16 (3%) from other causes. 492 (70%) of all pts had an available trial but of pts with a prior cancer who had an available trial 30% were ineligible due to the previous cancer. OS and GI cancer SS were comparable for pts with/without a prior cancer at 45.9 versus 40.6 m, p=0.93 and 49.2 versus 41.2 m, p=0.74, respectively. Conclusions: Survival for pts with a GI cancer requiring chemotherapy relates to the GI cancer and rarely a prior cancer. As there is no statistically significant difference in OS and GI cancer specific survival between pts with and without prior cancer, these pts should not be excluded from clinical trial participation.
Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas
Authors: Estela Area-Gomez, Cristina Guardia-Laguarta, Eric A. Schon, Serge Przedborski
Journal: Journal of Clinical Investigation (2019)

Mitochondrial respiratory deficiencies have been observed in numerous neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. For decades, these reductions in oxidative phosphorylation (OxPhos) have been presumed to trigger an overall bioenergetic crisis in the neuron, resulting in cell death. While the connection between respiratory defects and neuronal death has never been proven, this hypothesis has been supported by the detection of nonspecific mitochondrial DNA mutations in these disorders. These findings led to the notion that mitochondrial respiratory defects could be initiators of these common neurodegenerative disorders, instead of being consequences of a prior insult, a theory we believe to be misconstrued. Herein, we review the roots of this mitochondrial hypothesis and offer a new perspective wherein mitochondria are analyzed not only from the OxPhos point of view, but also as a complex organelle residing at the epicenter of many metabolic pathways.
A multicohort trial of the safety and efficacy of the PD-1 inhibitor MK-3475 in patients with hematologic malignancies.
Authors: Guillermo Garcia-Manero, Giovanni Martinelli, Joshua F. Zeidner, David Avigan, Kenneth Carl Anderson, Vincent Ribrag, Craig Moskowitz, Pier Luigi Zinzani, Dianna Wu, Kenneth Emancipator, Marisa Dolled-Filhart, Christine Gause, Holly Brown, Ryan D. Geschwindt, Robert Iannone, Shelonitda Rose, Phillippe Armand
Journal: Journal of Clinical Oncology (2014)

TPS3116 Background: Hematologic malignancies (HMs) are responsive to immunotherapy, but in some cases appear to usurp the PD-1 pathway for tumor immune escape. MK-3475 is a potent, highly selective, humanized IgG4/kappa isotype, anti-PD-1 monoclonal antibody designed to block PD-1 interaction with PD-L1 and PD-L2. In some patients with solid tumors, MK-3475 enhances anti-tumor immune activity and has demonstrated therapeutic activity. We are testing the safety and preliminary activity of MK-3475 in patients with HMs. Methods: This is a multicenter, nonrandomized, open-label phase 1b trial in patients with HMs, enrolling patients in 3 separate cohorts : hypomethylating agent failure myelodysplastic syndrome (MDS); relapsed/refractory (R/R) Hodgkin lymphoma (HL); and primary mediastinal large B cell lymphoma (MLBCL)/PD-L1 positive non-Hodgkin lymphoma (NHL). Approximately 78 pts will be enrolled. The primary objectives are to determine safety, tolerability, and objective response rate or complete remission rate of 10 mg/kg MK-3475 dosed every 2 weeks until disease progression or excessive toxicity. Secondary objectives include analysis of efficacy parameters (DOR/PFS/OS) for each indication, and association between PD-L1 expression and response. Exploratory objectives include PK and the relationship of candidate efficacy/resistance biomarkers and anti-tumor activity. Response will be evaluated using standard criteria. Patients receiving at least 1 dose will be included in the safety analysis. For the primary endpoint, the study provides ~80% power to detect a difference under the null hypothesis in a given cohort (20% difference in ORR for MDS; 20% difference in CRR for HL, 25% difference in ORR for MLBCL/NHL) with one-sided type I error rate of 5%. Clinical trial information: NCT01953692.
Results of the Myeloproliferative Neoplasms - Research Consortium (MPN-RC) 112 Randomized Trial of Pegylated Interferon Alfa-2a (PEG) Versus Hydroxyurea (HU) Therapy for the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)
Authors: John Mascarenhas, Heidi E. Kosiorek, Josef T. Prchal, Alessandro Rambaldi, Dmitriy Berenzon, Abdulraheem Yacoub, Claire N. Harrison, Mary Frances McMullin, Alessandro M. Vannucchi, Joanne Ewing, Casey L. O'Connell, Jean-Jacques Kiladjian, Adam J. Mead, Elliott F. Winton, David S. Leibowitz, Valerio De Stefano, Murat O. Arcasoy, Craig M. Kessler, Rosalind Catchatourian, Damiano Rondelli, Richard T. Silver, Andrea Bacigalupo, Arnon Nagler, Marina Kremyanskaya, Lonette Sandy, Mohamed E. Salama, Vesna Najfeld, Joseph Tripodi, Rona Singer Weinberg, Leah Price, Judith D Goldberg, Raajit K. Rampal, Ruben A. Mesa, Amylou C. Dueck, Ronald Hoffman
Journal: Blood (2018)
Effect of liposome-encapsulation of doxorubicin on expression level of metabolic and oxidative genes and reduction of cardiotoxicity under experimental conditions.
Authors: Mariann Gyongyosi, Christian Geier, Gerald Maurer, Jutta Bergler-Klein
Journal: Journal of Clinical Oncology (2014)

e13518 Background: The objective of the present experimental study was to explore the changes in gene expression profiles of porcine hearts after treatment with cardiotoxic drugs doxorubicine (DOX) and liposome–encapsulated doxorubicin–citrate complex (Myocet MYO). Methods: Fifteen domestic pigs received either DOX (n=6) or MYO (n=9) in 3 cycles of treatment of human dose. Cardiac magnetic resonance imaging (cMRI) with late enhancement (LE) were performed at baseline and after the last dose application. Routine blood cell counts and liver, kidney parameter and electrolytes were controlled during the treatment. The left (LV) and right (RV) ventricular systolic (ejection fraction, EF), and diastolic (peak filling rate, PFR) function and myocardial fibrosis was assessed by hyperintensity by LE-cMRI images. The diastolic parameter E/E` ratios was measured by transthoracic echocardiography. Gene expression profile of the LV, RV and left atrium was analyzed by next generation sequencing (NGS). Results: Five of 6 of DOX and 6 of 9 MYO animals completed the study. Mortality was caused by pancytopenia and infections. Animals receiving MYO showed significantly better LV EF (56.4±5.6% vs 41.9±13.5%, p=0.039) and RV EF (42.1±2.8% vs 28.9±8.9%, p=0.009) compared with DOX, with better LV diastolic function (PFR: 10.7±4.8 vs 7.9±2.5 ml/s, p<0.1; average E/E`: 6.1±1.3 vs 8.6±1.6, p=0.02). Trend towards less myocardial fibrosis was observed in MYO-treated animals vs DOX, confirmed by cMRI and picrosirius red staining (LV: 5.8±4.1% vs 6.6±2.9%; RV: 6.2±1.9% vs 8.6±3.9%). NGS revealed several up-regulated metabolic and cell cycle and energy gene clusters (eg. respiratory chain, mitochondrial genes, oxidative phosphorylation, NADH activity) in MYO LV and RV myocytes, as compared to DOX, while no difference in gene expression profile of the left atrium was observed between the groups. Conclusions: MYO proved to be less cardiotoxic as compared with DOX, resulting in better LV and RV systolic and LV diastolic function in association with higher level of oxidative, cell cycle and energy gene expressions of LV and RV in an experimental model of cardiotoxicity.
Recruitment and Collection of Dermal Interstitial Fluid Using a Microneedle Patch
Authors: Chandana Kolluru, Mikayla Williams, Jeremy Chae, Mark R. Prausnitz
Journal: Advanced Healthcare Materials (2019)

Abstract Interstitial fluid (ISF) that surrounds cells in tissues of the body is a novel source of biomarker that complements conventional sources like blood, urine, and saliva. To overcome difficulties in harvesting ISF, a minimally invasive, rapid, simple‐to‐use, cost‐effective method is developed to collect ISF from the skin involving a microneedle (MN) patch. By pressing 650 µm long MNs at an angle just below the skin surface, blood‐free ISF flows through micropores to the skin surface and is absorbed into a thin strip of paper on the MN patch backing for subsequent analysis. An optimized method in rat skin in vivo is well tolerated and able to collect &gt;2 µL of ISF within 1 min. Brief skin pretreatment with MNs followed by a 5 min delay dramatically increases subsequent ISF collection by a mechanism believed to involve increased skin hydration. ISF collection using an MN patch has the potential to simplify access to biomarkers in ISF for research and future medical diagnostic and monitoring applications.
Factors associated with overall survival in patients with squamous carcinoma of esophagus compared to adenocarcinoma of esophagus.
Authors: Feng Ming Kong, Julie George, Ling Li, Paul Stanton, Ahmad Albasheer, Cathryn Bock, Fawn Vigneau
Journal: Journal of Clinical Oncology (2014)

e15061 Background: It is believed that squamous cell carcinoma and adenocarcinoma of esophagus have distinct biological behaviors. This study aimed to examine whether factors associated with overall survival (OS) in squamous carcinoma are also significant for adenocarcinoma. Methods: Patients in the Surveillance, Epidemiology and End Results Registry (SEER) registry with esophageal cancer from 1988-2010 were used for this study. Age, gender, race, tumor grade, SEER-reported cancer stage, and treatment were assessed for association with OS, with sub-analysis of treatment groups: neo-adjuvant radiation +surgery; surgery+ adjuvant radiation; definitive radiation only and definitive surgery only. Surgery data was only cancer-directed treatment and chemotherapy information is not in SEER. OS was analyzed using proportional hazard model. Data are presented as mean (95% confidence interval). Results: 17891 patients with squamous cell carcinoma, and 21871 patients with adenocarcinoma were analyzed. In patients with squamous cell carcinoma, age (younger than 66 years vs older), gender (female vs male), race (black vs white), nodal metastasis (yes vs no), tumor grade (grade 3 vs lower), SEER stage (advanced stage), surgery (vs none), radiation alone (radiation vs none), neoadjuvant radiation followed by surgery or surgery followed by radiation were all significantly associated with OS, with adjusted Hazard Ratios for death of 0.81 (0.79, 0.84), 0.90 (0.87, 0.93), 1.16 (1.12, 1.21),1.39 (1.28, 1.51), 0.40 (0.37, 0.43), 0.44 ( 0.42, 0.46), 0.27 (0.24, 0.29), respectively. These factors were significant for OS in adenocarcinoma patients as well, except female gender which was a favorable factor (HR 0.90, 95%CI 0.87, 0.93) for survival in squamous carcinoma patients but presents as a borderline significant risk factor (Adjusted HR1.02, 95%CI 0.98-1.07) adenocarcinoma patients. Conclusions: Factors significantly associated with overall OS squamous carcinoma patients are significant for adenocarcinoma of esophagus except for gender.Younger age, white race, earlier stage, lower grade and local treatment by any modality are independent factors for better OS.
Reduced Intensity Vs. Myeloablative Conditioning Followed By Allogeneic Stem Cell Transplantation for Patients with Myelodysplastic Syndrome: Long Term Follow-up of a Prospective Randomized EBMT Phase III Study (RICMAC-Trial)
Authors: Nicolaus Kroeger, Simona Iacobelli, Linda Koster, Dietger Niederwieser, Uwe Platzbecker, Kai Huebel, Christoph Scheid, Thomas Weber, Matthias Stelljes, Boris Afanasiev, Dominik Heim, Giorgio Lambertenghi Deliliers, Francesco Onida, Peter Dreger, Massimo Pini, Stefano Guidi, Liisa Volin, Andreas Guenther, Wolfgang Bethge, Xavier Poire, Guido Kobbe, Marleen van Os, Ibrahim Yakoub-Agha, Marie Robin
Journal: Blood (2018)