tbuckley/cabot-search huggingface dataset:
Abstract A33: An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma
Authors: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Jessica Roberts, Clinton F. Stewart, András Sablauer
Journal: Cancer Research (2017)

Abstract Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we present an individualized predictive three-dimensional (3D) model of tumor response to topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma. This model is integrated with an individualized physiologically-based pharmacokinetic (PBPK) model of TPT and accounts for the effects of inter- and intra-tumor heterogeneities in blood perfusion on tumor response. This model uses a set of 3D reaction-diffusion equations to simulate transport of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. The transport model takes inputs from three spatial scales (systemic, tissue and cells) to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT, b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. The transport model also gives feedback to the PBPK model. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (γ-H2AX response). Based on these rules and exposure maps predicted by the transport model, we then compute probabilities of effects for the entire tumor volume. We validate the predicted drug effect maps by comparing them to observed effect data (from three dosage levels) measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched serial sections) using spatial correlation techniques. Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Jessica Roberts, Clinton F. Stewart, András Sablauer. An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A33.
IFP Research Awards: Call for Nominations - Mid-Career Research Award
Authors: Julie M. Zito, Evelien Snippe, K. Annika Tovote, Robbert Sanderman, Maya J. Schroevers, Joke Fleer, Paul M.G. Emmelkamp, Peter Meulenbeek, Lieke Christenhusz, Ernst Bohlmeijer, Guy Chouinard, Jean-Marc Cloos, Valéry Bocquet, Isabelle Rolland-Portal, Paul Koch, Fei-Wan Ngai, Paul Wai-Ching Wong, Kwok-Yin Leung, Pui-Hing Chau, Ka-Fai Chung, Steinar Lorentzen, Anette Fjeldstad, Torleif Ruud, Per A. Høglend, Piero Porcelli, Jenny Guidi, Fiammetta Cosci, Jenny Guidi, Richard Balon, Fiammetta Cosci, Giovanni A. Fava, Harold van Megen, Merijn Eikelenboom, Maarten Kaarsemaker, Anton J. van Balkom, Stefan Priebe, Lauren Kelley, Serif Omer, Eoin Golden, Sophie Walsh, Patricia van Oppen, Henny A. Visser, Adriaan W. Hoogendorn, Husnara Khanom, David Kingdon, Clare Rutterford, Paul McCrone, Rosemarie McCabe, Satz Mengensatzproduktion, Druckerei Stückle, Druckerei Stückle
Journal: Psychotherapy and Psychosomatics (2015)
Abstract #5373: Glycoproteomic characterization of human gamma-glutamyl transpeptidase
Authors: Matthew West, Pilsoo Kang, Iveta Klouckova, Yehia Mechref, Milos Novotny, Marie Hanigan
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The timely and accurate diagnosis of liver and pancreatic cancer is critical for maximizing the efficacy of therapeutic intervention. Currently, there are no reliable clinical screening tests for these two high-mortality forms of cancer. A primary obstacle to the development of early detection assays is the considerable overlap in symptoms and serum composition between malignant and non-malignant forms of liver and pancreatic diseases. Both hepatocellular carcinoma and pancreatic adenocarcinoma are associated with elevated levels of the glycoprotein gamma-glutamyl transpeptidase (GGT). While elevated serum GGT levels are not specific to malignant forms of liver and pancreatic disease, an accumulating body of data has provided evidence for the existence of distinct tissue- and tumor-specific glycosylation patterns on GGT, which may serve as reporters for enhancing the sensitivity and specificity of diagnosis. To better understand how these tumor-specific glycosylation changes are manifested, we have investigated the structural composition and site occupancy of the glycan moieties on GGT from normal human liver and pancreatic tissue. Using mass spectrometry, we have characterized all six N -linked glycosylation sites on the large subunit of GGT expressed in the normal human tissues. Moreover, high-resolution glycomic analyses on these samples have demonstrated that GGT serves as a faithful reporter protein for recapitulating the tissue-specific glycosylation patterns observed within the organ. These results are being utilized for analytical comparisons against GGT isolated from tumor tissue samples with the objective of identifying novel keystone glycan epitopes present on the high levels of circulating GGT in the serum of patients with pancreatic and liver cancer. This work will generate new insights into tumor-specific post-translational modification regimes and broaden our understanding of the efficacy of altered glycosylation patterns on serum glycoproteins as reliable biomarkers for cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5373.
Eight Colors Flow Cytometry Phenotyping for Blood Minimal Residual Disease Monitoring in Hairy Cell Leukaemia Patients.
Authors: Marie-Olivia Chandesris, Francine Garnache, Ludovic Lhermitte, Kheira Beldjord, Anne-Sophie Bedin, Felipe Suarez, Olivier Hermine, Vahid Asnafi, Bruno Varet, Elizabeth Macintyre
Journal: Blood (2009)
Association of Patent Ductus Arteriosus Ligation With Death or Neurodevelopmental Impairment Among Extremely Preterm Infants
Authors: Dany E. Weisz, Lucia Mirea, Erin Rosenberg, Maximus Jang, Linh Ly, Paige T. Church, Edmond Kelly, S. Joseph Kim, Amish Jain, Patrick J. McNamara, Prakesh S. Shah
Journal: JAMA Pediatrics (2017)

Observational studies have associated patent ductus arteriosus (PDA) ligation among preterm infants with adverse neonatal outcomes and neurodevelopmental impairment in early childhood, with a resultant secular trend away from surgical treatment. However, to our knowledge, studies have inadequately addressed sources of residual bias, including survival bias and major neonatal morbidities arising before exposure to ligation.Evaluate the association between PDA ligation vs medical management and neonatal and neurodevelopmental outcomes.This retrospective cohort study of preterm infants younger than 28 weeks gestational age born between January 1, 2006, and December 31, 2012, with clinical and echocardiography diagnoses of hemodynamically significant PDA was conducted at 3 tertiary neonatal intensive care units and affiliated follow-up programs.Surgical ligation vs medical management.The primary outcome was a composite of death or neurodevelopmental impairment (NDI) at 18 to 24 months corrected age. Secondary outcomes included death before discharge, NDI, moderate-severe chronic lung disease, and severe retinopathy of prematurity. Multivariable logistic regression analysis was used to adjust for perinatal and postnatal confounders.Of 754 infants with hemodynamically significant PDA (mean [standard deviation] gestational age 25.7 [1.2] weeks and birth weight 813 [183] grams), 184 (24%) underwent ligation. Infants who underwent ligation had a higher frequency of morbidities before PDA closure, including sepsis, necrotizing enterocolitis, and a dependence on mechanical ventilation. After adjusting for perinatal characteristics and preligation morbidities, there was no difference in the odds of death or NDI (adjusted odds ratio (aOR), 0.83; 95% CI, 0.52-1.32), NDI (aOR, 1.27; 95% CI, 0.78-2.06), chronic lung disease (aOR, 1.36; 95% CI, 0.78-2.39) or severe retinopathy of prematurity (aOR, 1.61; 95% CI, 0.85-3.06). Ligation was associated with lower odds of mortality (aOR, 0.09; 95% CI, 0.04-0.21).Patent ductus arteriosus ligation among preterm neonates younger than 28 weeks gestational age was not associated with the composite outcome of death or NDI, and there were no differences in chronic lung disease, retinopathy of prematurity, or NDI among survivors. Mortality was lower among infants who underwent ligation, though residual survival bias could not be excluded. Previously reported associations of ligation with increased morbidity may be because of bias from confounding by indication.
Expanding Burn Care Knowledge in a Rural Region Through Project Extension for Community Healthcare Outcomes
Authors: Gregory J. Keough, Annette F. Matherly, Amalia Cochran
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Abstract P6-06-01: Comprehensive analysis of the DNA damage repair and maintenance pathways that regulate TNBC sensitivity to replication stress
Authors: AB Redwood, S Seth, S Cai, H Piwnica-Worms
Journal: Cancer Research (2018)

Abstract Agents that induce replication stress, such as inhibitors of Chk1 or ATR, are advancing in clinical development and are being tested for treatment of various solid tumors, including triple-negative breast cancer (TNBC). While the preclinical data are encouraging, additional studies are needed to predict with precision (i) which patients will most likely benefit from these inhibitors, (ii) the genetic and proteomic contexts in which these inhibitors will provide maximum therapeutic benefit as a single agent, or require additional sensitization via combination with a targeted- or chemotherapeutic agent, and (iii) exactly which targeted/chemotherapeutic agent will provide maximum therapeutic benefit for combination with replication stress inducers. To address these challenges in TNBC, we have attempted to gain a comprehensive understanding of how the DNA damage response pathways regulate TNBC cell survival in response to Chk1 inhibitors, by performing high throughput loss-of-function screens. We have identified genes whose loss induces death of TNBC cells in the presence of (1) CHK1i alone, (2) chemotherapy alone or (3) CHK1i plus chemotherapy. In addition, given the role of TP53 as the most frequently mutated gene in TNBC, we also determined whether distinct vulnerabilities could be identified in TNBC cells that are p53-proficient versus p53-deficient. Thus, we have also identified the top synthetic lethal interactions that are either common to both p53-proficient and p53-deficient TNBC, or unique to p53-deficient TNBC; we are currently performing in vitro studies to validate the identified mechanisms. We anticipate these studies to be applicable to other agents that induce replication stress and cell cycle checkpoint bypass. Ongoing in vivo preclinical studies, which utilize patient-derived xenografts (PDXs) of TNBC to validate these findings are expected to impact patient selection for clinical trials, and also allow us to predict which chemotherapeutic agents will be most effective for combination with different cell-cycle checkpoint inhibitors. Citation Format: Redwood AB, Seth S, Cai S, Piwnica-Worms H. Comprehensive analysis of the DNA damage repair and maintenance pathways that regulate TNBC sensitivity to replication stress [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-01.
Lymph Node Activation by PET/CT Following Vaccination With Licensed Vaccines for Human Papillomaviruses
Authors: Emily E. Coates, Pamela J. Costner, Martha C. Nason, Douglas M. Herrin, Shielah Conant, Peter Herscovitch, Uzma N. Sarwar, Lasonji Holman, Jillian Mitchell, Galina Yamshchikov, Richard A. Koup, Barney S. Graham, Corina M. Millo, Julie E. Ledgerwood
Journal: Clinical Nuclear Medicine (2017)

While PET using F-FDG is most commonly used for imaging malignant tumors, vaccination is known to cause transient inflammation of lymph nodes inducing positive findings on F-FDG PET scans. The pattern, magnitude, and duration of lymph node activation following vaccination have not been clearly defined. Furthermore, the addition of adjuvants to vaccines can further enhance the immune response. The presented study was designed to define lymph node activation following administration of the Food and Drug Administration-licensed human papillomavirus vaccines, Cervarix and Gardasil, which contain similar antigens with different adjuvants.Twenty-seven women aged 18 to 25 years were randomized to receive either Cervarix or Gardasil in the clinical trial VRC 900. Fifteen subjects participated in the PET/CT portion of the trial and received scans of lymph node activation at prevaccination and "1 week" (8-14 days) and "1 month" (23-36 days) after the first or third vaccination.PET/CT scans revealed that all vaccine recipients had ipsilateral axillary lymph node activity. Three of 4 Cervarix recipients also showed contralateral lymph node activity 1 month after the first vaccination. For both Cervarix and Gardasil, the SUV activity resolved over time, with activity extended up to day 37 after the first and third vaccinations.Following intramuscular vaccination, there were no major differences between duration of uptake and intensity of SUV between Cervarix and Gardasil recipients in ipsilateral axillary lymph nodes. Contralateral node activation was detected up to 1 month after the first vaccination in Cervarix recipients only, possibly reflecting differences in vaccine adjuvant formulation.
Thrombin-Thrombomodulin Interactions Are An Important Determinant of Metastatic Potential
Authors: Netanel A Horowitz, Elizabeth A. Blevins, Whitney M Miller, Ashely R Perry, Kathryn E Talmage, Eric S. Mullins, Brett P. Monia, Jay L. Degen, Joseph S. Palumbo
Journal: Blood (2010)
Margaret McCartney: Are we too captivated by precision medicine?
Authors: Margaret McCartney
Journal: BMJ (2017)

Barack Obama’s state of the union address in 2015 kicked precision medicine into the mainstream. He wanted the US to lead “a new era of medicine—one that delivers the right treatment at the right time,” with a precision medicine initiative to “bring us closer to curing diseases like cancer and diabetes—and to give all of us access to the personalised information we need to keep ourselves and our families healthier.”1 So far $215m (£175m; €200m) has been invested into the initiative, and one million American people will provide genetic data and biological samples with the aim of “better predicting disease risk, understanding how diseases occur, and finding …
Exploratory pharmacodynamics (PD) trial to investigate the mechanism of action of RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), compared with cetuximab (C) in neoadjuvant head and neck squamous cell carcinoma (HNSCC).
Authors: Stéphane Temam, James F. Spicer, Carlos Gomez-Roca, Yann Berge, Jean-Pierre Jeannon, Jean-Charles Soria, Sophia Soehrman Brossard, Paul Delmar, Sophie Golding, David Oppenheim, Alexandre Passioukov, Luigi Manenti, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2012)

5522 Background: GA201 efficacy was superior to C in orthotopic xenograft models in terms of activity and PD. In a phase I study, objective responses and long lasting stable disease were observed in heavily pre-treated patients (pts). Methods: HNSCC pts (T2-4, any N, M0) received i.v. neo-adjuvant 700/1400 mg GA201 or C (as per SPC), on D1 and 8. Tumor biopsies were taken at baseline (BL) and pre-surgery. The primary objective was determination of changes in tumor immune cell infiltration after treatment. Peripheral CD3+, CD16+, CD56+ cells, plasma cytokines, tumor EGFR and 18F-FDG-PET avidity were also studied. Results: To date, 39 pts (15/10 vs 14 pts for 700/1400 GA201 vs C, respectively) were evaluable for the primary objective and 4 pts are on-going. Patient characteristics at BL were as follows: median age, 57/62 vs 62 years; gender, 11/10 vs 12 male; tumor size ≤ 4 cm, 7/3 vs 3 pts. A greater proportion of pts receiving GA201 compared to C had metabolic tumor reduction (&gt; 25% of SUVmax) (10/15 at 700 mg [1 pathological CR], 7/10 at 1400 mg GA201 vs 7/14 C pts) and symptomatic relief (6/12 at 700 mg, 6/7 at 1,400 mg GA201 vs 2/10 C pts). Table shows changes in PD markers. Conclusions: GA201 treatment, compared to C, exhibited more extensive tumor immune cell infiltration and a greater metabolic response. Consistent with the proposed mechanism of action of GA201, peripheral NK cells dropped and a unique cytokine profile was observed. The data support the immunomodulatory superiority of GA201 - a mAb designed to enhance ADCC compared to C. [Table: see text]
Association of the phosphorylation of the estrogen receptor at serine 118 and 167 with prognosis in postmenopausal breast cancer patients.
Authors: Karin J. Beelen, Mark Opdam, Rutger H.T. Koornstra, Andrew D. Vincent, Jan Baptist Vermorken, Paul J. van Diest, Joyce Sanders, Jelle Wesseling, Sabine C. Linn
Journal: Journal of Clinical Oncology (2012)

562 Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.
Community dynamics drive punctuated engraftment of the fecal microbiome following transplantation using freeze-dried, encapsulated fecal microbiota
Authors: Christopher Staley, Byron P. Vaughn, Carolyn T. Graiziger, Stephanie Singroy, Matthew J. Hamilton, Dan Yao, Chi Chen, Alexander Khoruts, Michael J. Sadowsky
Journal: Gut Microbes (2017)

Fecal microbiota transplantation (FMT) is a highly effective treatment of recurrent and recalcitrant Clostridium difficile infection (rCDI). In a recent study oral-delivery of encapsulated, freeze-dried donor material, resulted in comparable rates of cure to colonoscopic approaches. Here we characterize shifts in the fecal bacterial community structure of patients treated for rCDI using encapsulated donor material. Prior to FMT, patient fecal samples showed declines in diversity and abundance of Firmicutes and Bacteroidetes, with concurrent increases in members of the Proteobacteria, specifically Enterobacteriaceae. Moreover, patients who experienced recurrence of CDI within the 2-month clinical follow-up had greater abundances of Enterobacteriaceae and did not show resolution of dysbioses. Despite resolution of rCDI following oral-administration of encapsulated fecal microbiota, community composition was slow to return to a normal donor-like assemblage. Post-FMT taxa within the Firmicutes showed rapid increases in relative abundance and did not vary significantly over time. Conversely, Bacteroidetes taxa only showed significant increases in abundance after one month post-FMT, corresponding to significant increases in the community attributable to the donors. Changes in the associations among dominant OTUs were observed at days, weeks, and months post-FMT, suggesting shifts in community dynamics may be related to the timing of increases in abundance of specific taxa. Administration of encapsulated, freeze-dried, fecal microbiota to rCDI patients resulted in restoration of bacterial diversity and resolution of dysbiosis. However, shifts in the fecal microbiome were incremental rather than immediate, and may be driven by changes in community dynamics reflecting changes in the host environment.
Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair–deficient Prostate Cancer
Authors: Matti Annala, Werner J. Struss, Evan W. Warner, Kevin Beja, Gillian Vandekerkhove, Amanda Wong, Daniel Khalaf, Irma-Liisa Seppälä, Alan So, Gregory Lo, Rahul Aggarwal, Eric J. Small, Matti Nykter, Martin E. Gleave, Kim N. Chi, Alexander W. Wyatt
Journal: European Urology (2017)