tbuckley/cabot-search huggingface dataset:
TGF-β2 suppression by the antisense oligonucleotide AP 12009 as treatment for pancreatic cancer: preclinical efficacy data
Authors: G. Stauder, A. Bischof, T. Egger, M. Hafner, H. Herrmuth, P. Jachimczak, M. Kielmanowicz, R. Schlingensiepen, K.-H. Schlingensiepen
Journal: Journal of Clinical Oncology (2004)

4106 Background: With a 5-year-survival rate of less than 1% pancreatic cancer is one of the most aggressive human cancers. Overexpression of TGF-beta2 in malignancies correlates with decreased survival and is associated with advanced tumor stage due to its pivotal role in malignant progression by inducing key mechanisms including immunosuppression, metastasis, angiogenesis and tumor cell proliferation. In pancreatic cancer patients TGF-beta2 levels were significanty elevated (median: 1,198 pg/ml; range: 319–1,713 pg/ml) as compared to healthy controls (median: 378 pg/ml; range: 241–575 pg/ml). Methods: Aiming at a highly specific anti-tumor therapy, AP 12009, a phosphorothioate antisense oligonucleotide specific for the human TGF-beta2 mRNA, has been developed and tested for its anti-tumor activity in a variety of preclinical studies with pancreatic cancer cells. Results: AP 12009 significantly reduced the TGF-beta2 secretion in several human pancreatic cancer cell lines (Hup-T3, Hup-T4, PA-TU 8902). In functional assays AP 12009 inhibited pancreatic tumor cell proliferation in a dose-dependent manner by up to 76%. Migration of PA-TU 8902 cells was completely blocked as compared to untreated controls in a spheroid migration model while TGF-beta2 antibody had no effect. Additionally, AP 12009 reversed TGF-beta2 mediated immunosuppression in an allogenic PA-TU 8902 system targeted by IL-2 activated PBMC (LAK cells) derived from healthy donors. After AP 12009 treatment LAK cell cytotoxicity was increased in a donor-dependent manner up to 708% of the untreated control (effector/target ratio 20:1). Conclusions: AP 12009 has already shown efficacy in phase I/II clinical studies as therapy for high-grade glioma. Based on this successful application of AP 12009 in clinical studies and the presented preclinical efficacy in tumor proliferation, migration and inhibition of escape from immunosurveillance in pancreatic cancer a multi-site dose-escalation trial with AP 12009 in pancreatic carcinoma is currently being initiated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma
P2X <sub>7</sub> Deficiency Blocks Lesional Inflammasome Activity and Ameliorates Atherosclerosis in Mice
Authors: Peter Stachon, Adrian Heidenreich, Julian Merz, Ingo Hilgendorf, Dennis Wolf, Florian Willecke, Sunaina von Garlen, Philipp Albrecht, Carmen Härdtner, Nicolas Ehrat, Natalie Hoppe, Jochen Reinöhl, Constantin von zur Mühlen, Christoph Bode, Marco Idzko, Andreas Zirlik
Journal: Circulation (2017)

Extracellular adenosine triphosphate (ATP) binds as a danger signal to purinergic receptor P2X7 and promotes inflammasome assembly and interleukin-1β expression. We hypothesized a functional role of the signal axis ATP-P2X7 in inflammasome activation and the chronic inflammation driving atherosclerosis.P2X7-competent and P2X7-deficient macrophages were isolated and stimulated with lipopolysaccharide, ATP, or both. To assess whether P2X7 may have a role in atherosclerosis, P2X7 expression was analyzed in aortic arches from low density lipoprotein receptor-/- mice consuming a high-cholesterol or chow diet. P2X7+/+ and P2X7-/- low density lipoprotein receptor-/- mice were fed a high-cholesterol diet to investigate the functional role of P2X7 knockout in atherosclerosis. Human plaques were derived from carotid endarterectomy and stained against P2X7.Lipopolysaccharide or ATP stimulation alone did not activate caspase 1 in isolated macrophages. However, priming with lipopolysaccharide, followed by stimulation with ATP, led to an activation of caspase 1 and interleukin-1β in P2X7-competent macrophages. In contrast, P2X7-deficient macrophages showed no activation of caspase 1 after sequential stimulation while still expressing a basal amount of interleukin-1β. P2X7 receptor was higher expressed in murine atherosclerotic lesions, particularly by lesional macrophages. After 16 weeks of a high-cholesterol diet, P2X7-deficient mice showed smaller atherosclerotic lesions than P2X7-competent mice (0.162 cm2±0.023 [n=9], P2X7-/- low density lipoprotein receptor-/- : 0.084 cm2±0.01 [n=11], P=0.004) with a reduced amount of lesional macrophages. In accord with our in vitro findings, lesional caspase 1 activity was abolished in P2X7-/- mice. In addition, intravital microscopy revealed reduced leukocyte rolling and adhesion in P2X7-deficient mice. Last, we observe increased P2X7 expression in human atherosclerotic lesions, suggesting that our findings in mice are relevant for human disease.P2X7 deficiency resolved plaque inflammation by inhibition of lesional inflammasome activation and reduced experimental atherosclerosis. Therefore, P2X7 represents an interesting potential new target to combat atherosclerosis.
Post hoc rationalism in science
Authors: Eric Luis Uhlmann
Journal: Behavioral and Brain Sciences (2011)

Abstract In advocating Bayesian Enlightenment as a solution to Bayesian Fundamentalism, Jones &amp; Love (J&amp;L) rule out a broader critique of rationalist approaches to cognition. However, Bayesian Fundamentalism is merely one example of the more general phenomenon of Rationalist Fundamentalism: the tendency to characterize human judgments as rational and optimal in a post hoc manner, after the empirical data are already known.
Effects of the 26S proteasome inhibitor, bortezomib, on BCL-2 in small cell lung cancer: Implications for SWOG-0327
Authors: M. M. Mortenson, M. G. Schlieman, S. Virudachalam, P. N. Lara, D. G. Gandara, A. M. Davies, R. J. Bold
Journal: Journal of Clinical Oncology (2004)

9560 Background: Overexpression of the anti-apoptotic protein BCL-2 is seen in approximately 80% of small cell lung cancer (SCLC) and has been associated with chemoresistance and poor prognosis. We have previously shown that the the serine protein kinase AKT signals through the transcriptional factor NF-kB to increase BCL-2 levels and that inhibition of NF-kB activity with the 26S proteasome inhibitor bortezomib decreases BCL-2 levels and induces apoptosis in a pancreatic cancer model. We tested the hypothesis that the AKT/NF-kB signaling pathway is involved in the overexpression of BCL-2 in SCLC, and whether inhibition of NF-kB through 26S proteasome inhibition with bortezomib would decrease BCL-2 levels. Methods: The H526 human SCLC line was used for all studies. The activity of the BCL-2 promoter was determined by promoter/luciferase reporter constructs following transient transfection. Similarly, NF-kB function was determined following transient transfection of a luciferase reporter construct containing four tandem NF-kB sites as a minimal promoter. Western blot analysis was used to evaluate protein levels and modifications of BCL-2. Results: Constitutive activation of AKT through transfection of a myrstilated form had no effect on BCL-2 levels in H526 cells, nor did it alter NF-kB activity. However, mutation of a NF-kB site in the BCL-2 promoter reduced BCL-2 promoter activity to less than 25% of the wild-type promoter. Treatment of H526 cells with bortezomib decreased BCL-2 protein levels, as well as induced inactivation of BCL-2 by phosphorylation and increased degradation. Conclusions: BCL-2 overexpression in H526 SCLC cells is not mediated by activation of AKT, though NF-kB plays a major role in transcriptional activation. Treatment with the 26S proteasome inhibitor bortezomib has effects on BCL-2 transcription, likely through inhibition of NF-kB, as well as effects involving BCL-2 inactivation through protein modification.These data provide the preclinical basis for SWOG-0327, an ongoing phase II trial of bortezomib in relapsed refractory SCLC patients. (CA 32102, CA 62505) No significant financial relationships to disclose.
Emotions in Depression: What Do We Really Know?
Authors: Jonathan Rottenberg
Journal: Annual Review of Clinical Psychology (2017)

Major depressive disorder is among the most common and costly of all mental health conditions, and in the last 20 years, emotional dysfunction has been increasingly seen as central to depression. Accordingly, research on emotions in depression has proceeded with fury. The urgency of the work has tempted investigators to issue premature declarations and to sometimes overlook theoretical and methodological challenges entailed in studying emotion. I report on what we have learned thus far about how depression influences emotional reactivity and emotion regulation, and also carefully demarcate the vast terrain of what we do not yet know. Ironically, an attitude of humility may enable the field to achieve the ambitious but elusive goal of developing a rich, contextually specific account of depression-related changes in emotional reactivity and regulation. Such an account is a precondition for using knowledge about emotion to intervene more effectively to reduce depression's worldwide burden.
Stem Cell Differentiation: Electrical Differentiation of Mesenchymal Stem Cells into Schwann‐Cell‐Like Phenotypes Using Inkjet‐Printed Graphene Circuits (Adv. Healthcare Mater. 7/2017)
Authors: Suprem R. Das, Metin Uz, Shaowei Ding, Matthew T. Lentner, John A. Hondred, Allison A. Cargill, Donald S. Sakaguchi, Surya Mallapragada, Jonathan C. Claussen
Journal: Advanced Healthcare Materials (2017)

Jonathan C. Claussen, Surya Mallapragada, Donald S. Sakaguchi, and co-workers demonstrate how the application of electrical stimuli via an inkjet printed graphene electrode can induce the differentiation of mesenchymal stem cells (MSCs) into Schwann cell (SC)-like phenotypes in article number 1601087. This thin and flexible graphene-based electrode could potentially be used as an implantable neural interface material for peripheral nerve regeneration.
Real-world concordance of clinical practice with ASCO and NCCN guidelines for EGFR/ALK testing in aNSCLC.
Authors: John E. Ruggiero, Jay Rughani, Josh Neiman, Steven Swanson, Cindy Revol, Robert J. Green
Journal: Journal of Clinical Oncology (2017)

212 Background: Timely and appropriate biomarker testing guides evidence-based treatment decision-making in advanced non-small cell lung cancer (aNSCLC). American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines recommend that all treatment-eligible patients with non-squamous, or squamous histology in non-smokers undergo EGFR and ALK biomarker testing prior to initiating first line therapy. Genentech’s Learning and Clinical Integration team and Flatiron Health explored the frequency of EGFR/ALK testing and overall time between advanced disease diagnosis, results receipt and treatment initiation in clinical oncology practices. Methods: Structured and unstructured data were obtained from Flatiron’s electronic health record database. 6,991 patients from 166 clinics diagnosed after 1/1/14 with at least 2 visits before 8/31/15 were randomly selected from the Flatiron aNSCLC national cohort of &gt; 25,000 patients. Dates of specimen collection, results receipt and treatment start were collected. Results: EGFR/ALK testing was conducted in 75% of non-squamous patients with wide variation across practices (&lt; 20% to 100%). For squamous patients, 15% were tested overall, but with dramatic variation across practices (0% to 100%). For patients with a positive test result available prior to initiation of first line treatment, 79% of EGFR+ and 94% of ALK+ patients received the appropriate targeted therapy. However, for those patients tested after initiation of first line therapy, only 41% of EGFR+ and 65% of ALK+ patients received appropriate targeted first line therapy. EGFR/ALK tests results were received &gt; 4 weeks from aNSCLC diagnosis in 32% and 34% of patients, respectively. Validation testing indicated that delays were attributed to non-lab factors, as test results were returned in &lt; 2 weeks in 95% of cases. Conclusions: Wide variation in real-world practice illustrates the need to improve adherence to ASCO and NCCN biomarker testing guidelines. Educational intervention to improve quality of care in aNSCLC should focus on ensuring testing of almost all non-squamous patients, limiting testing to the non-smoking squamous cell population, and ensuring timely ordering of testing by clinicians.
Influence of prior therapy on breast cancer survivors' preferences for adjuvant systemic therapy in hypothetical scenarios
Authors: N. Love, P. Ravdin, G. Hortobagyi, G. Grana, M. F. Paley, L. Poltorack
Journal: Journal of Clinical Oncology (2004)

591 Background: Breast cancer survivors' (BCS') preferences for adjuvant systemic therapy (AST) have been evaluated through questionnaires, interviews and decision boards. The objective of this educational needs assessment was to evaluate, via electronic keypad polling, the influence of prior therapy on BCS' preferences for AST in hypothetical scenarios. Methods: BCS, more than one year from initial diagnosis, attended one-day meetings in NY (n=199), FL (n=253) and TX (n=273). 67% of the BCS received prior chemotherapy (C), and 55% received prior tamoxifen (T). A research leader panel reviewed the risks and benefits of common ASTs, and electronic keypad responses were obtained about treatment preferences for hypothetical postmenopausal case scenarios. BCS were asked about the magnitude of survival advantage that would make C worthwhile and about scenarios involving a choice between T or anastrozole (A). Responses were analyzed by whether BCS received prior C or T. Results: BCS' prior therapy correlated with their preferences for AST. Specifically, BCS who had received prior C were far more likely to choose adjuvant C for a small survival benefit. BCS who did not receive prior T were more likely to choose adjuvant A than T. Conclusions: BCS who received prior C or T had different perspectives on AST decisions than those who had not received prior therapy. It is not clear if prior experience (or lack of experience) with C or T resulted in these differences or whether this was the result of some other effect, such as differences in baseline risk aversion. To understand BCS' perceptions of the value of therapies, it is important not only to survey BCS who received prior therapy, but also those who did not. These variables should be considered when evaluating similar patient surveys. This project was supported by an education grant from AstraZeneca Pharmaceuticals. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Genentech AstraZeneca AstraZeneca AstraZeneca
Impact of sleep disordered breathing on short-term post-operative outcome after elective coronary artery bypass graft surgery: a prospective observational study
Authors: Sven Rupprecht, Torsten Schultze, Andreas Nachtmann, Ardawan Julian Rastan, Torsten Doenst, Matthias Schwab, Otto W. Witte, Sebastian Rohe, Isabelle Zwacka, Heike Hoyer
Journal: European Respiratory Journal (2017)

Sleep disordered breathing (SDB) is common in patients with coronary disease, but its impact on post-operative recovery after coronary artery bypass graft surgery (CABG) is unclear. We therefore determined the effects of SDB on post-operative outcome after elective CABG. In this prospective two-centre study, 219 patients due to receive elective CABG underwent cardiorespiratory polygraphy for SDB prior to surgery and were monitored for post-operative complications. The primary end-point was a composite of 30-day mortality or major post-operative complications (cardiac, respiratory, surgical, infectious, acute renal failure or stroke). Key secondary end-points were single components of the primary end-point. SDB was present in 69% and moderate/severe SDB in 43% of the CABG patients. There was no difference in the composite of 30-day mortality or major postoperative complications between patients with and without SDB (OR 0.97, 95% CI 0.49–1.96) and between patients with moderate/severe SDB and no/mild SDB (OR 1.07, 95% CI 0.55–2.06). However, moderate/severe SDB was associated with higher rates of mortality (crude OR 10.1, 95% CI 1.22–83.5), sepsis (OR 2.96, 95% CI 1.17–7.50) and respiratory complications (OR 2.85, 95% CI 1.46–5.55). Although SDB was not associated with higher overall morbidity/mortality, moderate/severe SDB may increase the risk of death, and septic and respiratory complications, after elective CABG.
Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery
Authors: Subhash Banerjee, Dominick J. Angiolillo, William E. Boden, Joseph G. Murphy, Houman Khalili, Ahmed A. Hasan, Robert A. Harrington, Sunil V. Rao
Journal: Journal of the American College of Cardiology (2017)
A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC).
Authors: Hongbin Chen, Manuel R. Modiano, Joel W. Neal, Julie R. Brahmer, James R. Rigas, Robert M. Jotte, Natasha B. Leighl, Liming Liu, Julie M. Lisano, Alex A. Adjei, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2012)

7541 Background: AFL is a recombinant human fusion protein that acts as a decoy receptor and prevents the interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors. This study evaluated the efficacy and safety of AFL in combination with first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single arm, open label, multicenter trial in patients with previously untreated, locally advanced, or metastatic NSCLC excluded patients with squamous histology, cavitating lesions, ECOG &gt; 1, uncontrolled hypertension, or brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m 2 , and C 75mg/m 2 , every 3 weeks for up to 6 cycles. For those who completed the combined chemotherapy, Q3W administration of AFL was to continue until disease progression, intolerable toxicity, or any other cause for withdrawal. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Planned sample size was 72 patients. Results: The study was closed prematurely due to 3 confirmed cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 54.8% were male, 85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients with RPLS were Caucasian women. Two had a history of hypertension and both experienced elevated BP and reduced CrCl. Of the 38 patients evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of RPLS observed in this study with AFL + C + P was higher than anticipated. A meta-analysis of safety from three large placebo-controlled studies reported no RPLS among 1333 patient treated with AFL + chemotherapy, and none was reported in prior combination studies of AFL + P or AFL + C + docetaxel. Though the study was stopped early, ORR and PFS were in accordance with most historical first-line NSCLC studies.
Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study
Authors: Andrea B. Apolo, Jeffrey R. Infante, Ani Balmanoukian, Manish R. Patel, Ding Wang, Karen Kelly, Anthony E. Mega, Carolyn D. Britten, Alain Ravaud, Alain C. Mita, Howard Safran, Thomas E. Stinchcombe, Marko Srdanov, Arnold B. Gelb, Michael Schlichting, Kevin Chin, James L. Gulley
Journal: Journal of Clinical Oncology (2017)

Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti–programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1–associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1–positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.