tbuckley/cabot-search huggingface dataset:
Abstract A048: Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
Authors: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström
Journal: Cancer Research (2018)

Abstract Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histologic evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2), and osteocytes (SOST), we found high osteoblast activity to be coupled to high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2-positive osteoblasts and TRAP (ACP5)-positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment-naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity in metastasis tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and to patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histologic evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserves further exploration. Citation Format: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström. Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A048.
Abstract A14: Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma
Authors: Kathleen I. Pishas, Sunil Sharma, Stephen L. Lessnick
Journal: Cancer Research (2018)

Abstract Objective: Multiagent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/LSD1 (Lysine Specific Demethylase 1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P=0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). Methods: The antiproliferative effects of SP-2509 was determined through Cell Titre Glo assays following 72 hours of treatment in a comprehensive panel of 17 Ewing sarcoma cell lines with varying STAG2/TP53 mutational status and basal KDM1A expression levels. RNA-seq analysis of six Ewing sarcoma cell lines -/+ SP-2509 treatment (2μM) was also conducted. Results: We report that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (72hr IC50 range 81nM-1593nM); in contrast, resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (144hr IC50&amp;gt;300μM). Although TP53/STAG2 mutational status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B (mammalian homologue of KDM1A) following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity (R2=0.562). Indeed, shRNA-mediated knockdown of KDM1B significantly reduced the cytotoxic effects of SP-2509 (4.3-fold IC50 increase) only in hypersensitive cell lines. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum (ER) stress pathway, and that hypersensitive cell lines (IC50&amp;lt;300nM) share similar transcriptomic profiles. In addition, ETS1/ HIST1H2BM were specifically induced/repressed, respectively, following SP-2509 treatment only in our hypersensitive cell lines. Finally, we demonstrate that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Conclusion: Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Citation Format: Kathleen I. Pishas, Sunil Sharma, Stephen L. Lessnick. Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A14.
Care Practices for Patients With Advanced Kidney Disease Who Forgo Maintenance Dialysis
Authors: Susan P. Y. Wong, Lynne V. McFarland, Chuan-Fen Liu, Ryan J. Laundry, Paul L. Hebert, Ann M. O’Hare
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Although maintenance dialysis is a treatment choice with potential benefits and harms, little is known about care practices for patients with advanced chronic kidney disease who forgo this treatment. <h3>Objective</h3> To describe how decisions not to start dialysis unfold in the clinical setting. <h3>Design, Setting, and Participants</h3> A qualitative study was performed of documentation in the electronic medical records of 851 adults receiving care from the US Veterans Health Administration between January 1, 2000, and October 1, 2011, who had chosen not to start dialysis. Qualitative analysis was performed between March 1, 2017, and April 1, 2018. <h3>Main Outcomes and Measures</h3> Dominant themes that emerged from clinician documentation of clinical events and health care interactions between patients, family members, and clinicians relevant to the decision to forgo dialysis. <h3>Results</h3> In the cohort of 851 patients (842 men and 9 women; mean [SD] age, 75.0 [10.3] years), 567 (66.6%) were white. Three major dynamics relevant to understanding how decisions to forgo dialysis unfolded were identified. The first dynamic was that of dialysis as the norm: when patients expressed a desire to forgo dialysis, it was unusual for clinicians to readily accept patients' decisions. Clinicians tended to repeatedly question this preference over time, deliberated about patients' competency to make this decision, used a variety of strategies to encourage patients to initiate dialysis, and prepared for patients to change their minds and start dialysis. The second dynamic arose when patients were not candidates for dialysis: clinicians viewed particular patients as not candidates or appropriate for dialysis, usually on the basis of specific characteristics and/or expected prognosis, rather than after consideration of patients' goals and values. When clinicians decided patients were not candidates for dialysis, there seemed to be little room for uncertainty in these decisions. The third dynamic occurred when clinicians believed they had little to offer patients beyond dialysis: when it was clear that patients would not be starting dialysis, nephrologists often signed off from their care and had few recommendations other than referral to hospice care. <h3>Conclusions and Relevance</h3> These findings describe an all-or-nothing approach to caring for patients with advanced chronic kidney disease in which initiation of dialysis served as a powerful default option with few perceived alternatives. Stronger efforts are needed to develop a more patient-centered approach to caring for patients with advanced chronic kidney disease that is capable of proactively supporting those who do not wish to start dialysis.
Circulating tumor derived cell-free DNA (ctDNA) to predict recurrence of metastatic colorectal cancer (mCRC) following curative intent surgery or radiation.
Authors: Bryant Chee, Faaiz Ibrahim, Mikaela Esquivel, Emily E. Van Seventer, Joy X. Jarnagin, Li Zhang, Jin Hyun Ju, Kristin Sedgwick Price, Victoria M. Raymond, Carlos U. Corvera, Kenzo Hirose, Eric K. Nakakura, Katherine Van Loon, Ryan Bruce Corcoran, Aparna Raj Parikh, Chloe Evelyn Atreya
Journal: Journal of Clinical Oncology (2021)

3565 Background: Over half of patients (pts) with oligometastatic CRC treated with curative intent surgery or radiotherapy experience cancer recurrence with or without adjuvant chemotherapy. ctDNA detection post-definitive treatment could identify high risk pts for additional intervention to eliminate molecular residual disease. Here we report results of a prospective observational study aiming to determine ctDNA detection rates using a sensitive liquid biopsy and to correlate post-procedure ctDNA detection (post-ctDNA (+)) with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at two US sites. ctDNA was collected pre-procedure, 3 weeks post-procedure, and at multiple structured follow-up timepoints. The presence of ctDNA was evaluated using a plasma-only integrated genomic and epigenomic assay (Guardant Reveal, Guardant Health). A bioinformatic classifier was applied to differentiate tumor derived versus non-tumor derived cell-free DNA. Results: Among 52 enrolled pts, post-ctDNA data is available for 45 pts (87%), with a median of 4 (range 1-10) timepoints per pt. The sample analysis failure rate was 1% (2/217). As of 1/1/2021, the radiographic recurrence rate was 60% with a median follow-up time of 50 (range 4-192) weeks. 23 of 25 pts with post-ctDNA(+) have had recurrence (Positive Predictive Value [PPV], 92%). On average, ctDNA was detected 28 weeks before radiographic recurrence (mean 12 vs. 40 weeks, respectively). The two pts with post-ctDNA(+) but no recurrence have &gt; 3 years follow-up; one pt received adjuvant chemotherapy and cleared ctDNA. With a median event-free follow-up time of 97 (range 4-192) weeks, 4 of 20 pts with no post-ctDNA detection (-) have recurred (Negative Predictive Value, 80%). 3 of 4 pts with recurrence despite post-ctDNA(-) also were pre-ctDNA(-). We observed a sensitivity of 85% and a specificity of 89% for the ctDNA assay. The median time to radiographic recurrence was 36 wks for ctDNA(+) vs. not reached for ctDNA(-) (Hazard Ratio, 7.7; 95% CI, 2.6-22.5; P &lt;.001). Conclusions: In mCRC pts undergoing curative intent surgery or radiotherapy, detection of ctDNA post-procedure had a high PPV for cancer recurrence, with a median lead time of 6 months compared to surveillance imaging. Thus, ctDNA holds promise as a biomarker for pt enrollment on clinical trials and as an endpoint for monitoring of response to experimental therapies in this oligometastatic CRC population.
Optimizing Prehospital Trauma Triage—A Step Closer?
Authors: Jason S. Haukoos, Eric M. Campion, Peter T. Pons
Journal: JAMA Surgery (2019)

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
Ixazomib in Combination with Thalidomide and Dexamethasone for Induction and Ixazomib Maintenance Therapy Overcomes High-Risk Cytogenetics (but not of 1q21 Gain) in Relapsed/Refractory Multiple Myeloma — AGMT_MM1
Authors: Heinz Ludwig, Wolfram Pönisch, Stefan Knop, Martin Schreder, Daniel Lechner, Roman Hajek, Eberhard Gunsilius, Karl Jochen Krenosz, Andreas Petzer, Katja Weisel, Hermann Einsele, Richard Greil, Niklas Zojer
Journal: Blood (2018)
Human parthenogenetic neural stem cell grafts promote multiple regenerative processes in a traumatic brain injury model
Authors: Jea-Young Lee, Sandra Acosta, Julian P Tuazon, Kaya Xu, Hung Nguyen, Trenton Lippert, Michael G Liska, Andrey Semechkin, Ibon Garitaonandia, Rodolfo Gonzalez, Russell Kern, Cesario V Borlongan
Journal: Theranostics (2019)

International Stem Cell Corporation human parthenogenetic neural stem cells (ISC-hpNSC) have potential therapeutic value for patients suffering from traumatic brain injury (TBI). Here, we demonstrate the behavioral and histological effects of transplanting ISC-hpNSC intracerebrally in an animal model of TBI. Methods: Sprague-Dawley rats underwent a moderate controlled cortical impact TBI surgery. Transplantation occurred at 72 h post-TBI with functional readouts of behavioral and histological deficits conducted during the subsequent 3-month period after TBI. We characterized locomotor, neurological, and cognitive performance at baseline (before TBI), then on days 0, 1, 7, 14, 30, 60, and 90 (locomotor and neurological), and on days 28-30, 58-60, and 88-90 (cognitive) after TBI. Following completion of behavioral testing at 3 months post-TBI, animals were euthanized by transcardial perfusion and brains harvested to histologically characterize the extent of brain damage. Neuronal survival was revealed by Nissl staining, and stem cell engraftment and host tissue repair mechanisms such as the anti-inflammatory response in peri-TBI lesion areas were examined by immunohistochemical analyses. Results: We observed that TBI groups given high and moderate doses of ISC-hpNSC had an improved swing bias on an elevated body swing test for motor function, increased scores on forelimb akinesia and paw grasp neurological tests, and committed significantly fewer errors on a radial arm water maze test for cognition. Furthermore, histological analyses indicated that high and moderate doses of stem cells increased the expression of phenotypic markers related to the neural lineage and myelination and decreased reactive gliosis and inflammation in the brain, increased neuronal survival in the peri-impact area of the cortex, and decreased inflammation in the spleen at 90 days post-TBI. Conclusion: These results provide evidence that high and moderate doses of ISC-hpNSC ameliorate TBI-associated histological alterations and motor, neurological, and cognitive deficits.
Abstract 17464: RhoA Signaling Stabilizes PINK1 and Induces Mitophagy in Cardiomyocytes
Authors: Valerie P Tan, Raghav Tripathi, Zahna Bigham, Joan Heller Brown, Shigeki Miyamoto
Journal: Circulation (2017)

Introduction: RhoA is a small GTPase that regulates myriad cellular events, including cellular protection. Our previous research demonstrated that activation of RhoA in the heart protects cardiomyo...
Circulating heparan sulfate fragments mediate septic cognitive dysfunction
Authors: Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Schmidt
Journal: Journal of Clinical Investigation (2019)

Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor-mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O- and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O- and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.
Extracellular matrix (ECM) remodeling and lung mechanics in early and late ards: differences between pulmonary and extra-pulmonary disease
Authors: E. M. Negri, C. Hoelz, C. S. V. Barbas, Gregório Santiago Montes, Paulo Hilário Nascimento Saldiva, Vera Luiza Capelozzi
Journal: American Journal of Respiratory and Critical Care Medicine (1999)
A 5-year summary of real-life dietary egg consumption after completion of a 4-year egg powder oral immunotherapy (eOIT) protocol
Authors: Edwin H. Kim, Stacie M. Jones, A. Wesley Burks, Robert A. Wood, Scott H. Sicherer, Donald Y.M. Leung, Alice K. Henning, Robert W. Lindblad, Peter Dawson, Corinne Keet, Amy M. Scurlock, Marshall Plaut, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 10111: Transcatheter Aortic Valve Implantation Without Intensive Care Unit Admission is Possible in Selected "Low Risk" Patients
Authors: Florence Leclercq, Anais Iemmi, Jean Christophe Macia, Benoit Lattuca, Audrey Agullo, Richard Gervasoni, Laurent Schmutz, Thomas Gandet, Erika Nogues, Nicolas Nagot, Bernard Albat, Guillaume Cayla
Journal: Circulation (2015)

Introduction: Admission to the intensive care unit (ICU) after transcatheter aortic valve implantation (TAVI) is a standard of care. Hypothesis: We assessed the hypothesis that TAVI can be performed safely without ICU admission in patients considered at low risk using simple clinical, ECG and echographic criteria. Methods: In this prospective monocentric cohort study we included all consecutive patients who underwent a TAVI procedure between December 2014 and May 2015. Low risk group included patients with LVEF &gt; 40 %, transfemoral (TF) access, absence of severe pulmonary disease, stable hemodynamic state and absence of complications occurring until 2 hours after the procedure. High risk group included all other patients. Patients were admitted to the ICU or conventional cardiology unit depending on their risk evaluation. In-hospital major adverse events (VARC-2 criteria) were recorded in the two groups Results: On the 144 patients included, 67 were men (46.5 %), median age was 85 years (80-88) and median Euroscore II was 4.2 (3-6.9). The balloon expandable Edwards Sapien 3 valve was mainly used (n=118; 82%), with TF approach (n=136; 94.4% ) and general anesthesia (n=138; 95.8%). Of the 46 low risk patients (31.9%), only 1 was secondarily transferred to ICU due to non compressive pericardial effusion (minor complication) giving a negative predictive value of our triage strategy of 97.8% (CI:88.5-99.9). Conversely, of the 98 high risk patients, 40 developed major complications, mainly conductive disturbances. Positive predictive value was 40.8% (CI: 31.0-51.2). (Table 1) By univariate analysis, the main pre procedural predictive factors of complications were use of self expandable prosthesis (p&lt;0.00005) and right bundle branch block (p&lt;0.004). In conclusion, our results suggested that TAVI can be performed safely without ICU admission in selected patients. This new “minimalist” strategy may optimize efficiency and cost effectiveness of the procedure.
Abstract 13345: Relationship Between Parasympathetic Nervous System and QT Dynamics in Patients with Brugada Syndrome
Authors: Hiromi Kamiya, Yasuya Inden, Shinjirou Miyata, Naoki Yoshida, Masayoshi Koyasu, Tomohiro Uchikawa, Kazuhisa Kitamura, Masayuki Shimano, Toyoaki Murohara, Yukiomi Tsuji, Makoto Hirai
Journal: Circulation (2010)

Background: Brugada syndrome is an arrythmogenic disease characterized by a particular electrocardiogram pattern and an increased risk for sudden cardiac death due to ventricular tachyarrythmias. T...