tbuckley/cabot-search huggingface dataset:
Zoledronic acid inhibits the earliest stages of vasculogenesis: blockage of the transdifferentiation of monocytes into endothelial cells induced by pleiotrophin and mCSF
Authors: Haiming Chen, Mingjie Li, Richard Campbell, Dror Shalitin, Cathy Wang, Eric Sanchez, Jeffrey Steinberg, James Wang, Y. Chang, Benjamin Bonavida, Thomas Deuel, James Berenson
Journal: Cancer Research (2007)

4651  We have discovered a novel mechanism leading to blood vessel formation that involves the transdifferentiation of monocytes into endothelial cells by tumor cell production of pleiotrophin (PTN), a protein highly produced by myeloma (Chen et al, Blood 2005; Yeh et al, Br J Haematol 2006) and breast cancer (Zhang et al, JBC 1997) cells. The nitrogen-containing bisphosphonate zoledronic acid has been shown to inhibit bone loss and recent studies also demonstrate profound anti-angiogenic effects of this drug. The inhibitory effects of zoledronic acid on blood vessel formations remain unknown. We purified human monocytes (CD14+) and cultured these cells on collagen I-coated dishes. mCSF was added to the cells after 1 hour of culture. PTN was added twice to the culture, once after 24 hoursand again after 5 days with or without zoledronic acid or bortezomib. FLK-1 expression (VEGFR-2) showed that the cells incubated on collagen I without drugs formed tube-like structures in the presence of PTN and mCSF. However, the tube-like structures disappeared after adding zoledronic acid at either 1.5 or 0.15 uM. In order to examine whether zoledronic acid also reduces the expression of endothelial genes and proteins when monocytes are induced to transdifferentiate in the presence of these cytokines, we used RT-PCR and Western blot analysis on the endothelial cell markers Flk-1 Tie-2 and von Willebrand factor (vWF). The results of both RT-PCR and Western blot analysis showed that the expression of endothelial markers was blocked at zoledronic acid concentrations of 15uM, 1.5uM and 0.15uM. We further examined the effects of zoledronic acid on early stage angiogenesis in vivo using the chorioallantoic membrane (CAM) assay. Fertilized chick eggs were incubated horizontally at 38°C in a humidified incubator, windowed by day 3 of incubation and processed by day 8. The tested micro-sponge with zoledronic acid (1.5uM) or control reagents was implanted on the CAM. The eggs were sealed with adhesive tape and returned to the incubation for 48 hours. The assay scored positive when two independent observers reported a significant reduction of vessels in the treated area. The results of the CAM assay showed that compared to saline, zoledronic acid significantly reduced new macroscopic and microscopic vessel formation. These experiments define a previously unrecognized novel mechanism by which zoledronic acid may inhibit new blood vessel formation in cancer patients_preventing the transdifferentiation of monocytes into endothelial cells induced by PTN. They also suggest a specific new mechanism through which zoledronic acid has anti-angiogenic effects which provides further support for the potential anti-cancer effects of this agent.
Abstract 15975: sGCStimulation is Efficacious in a Novel Canine Model of Resistant Hypertension
Authors: Julia Vogel, Philip Boehme, Peter Sandner, Lena Schramm, Jessica Hoffmann, Katharina Boden, Peter Kolkhof, Wilfried Dinh, Jörg Hüser, Hubert Truebel, Thomas Mondritzki
Journal: Circulation (2018)

Introduction: Hypertension (HtN) is one of the major cardiovascular risk factors. Studies have shown that therapy resistant hypertension (rHtN), i.e. elevated blood pressure despite the concurrent ...
A polypoidal ‘non-polyp’ in the colon
Authors: John Joseph McGoran, Sudarshan R Kadri, Catherine Moreman, Peter Wurm
Journal: Gut (2019)

A 42-year-old Caucasian man presented with increased stool frequency and dyspeptic symptoms for which he had been prescribed lansoprazole. At colonoscopy he was found to have a 4-cm smooth polypoidal lesion in the transverse colon, adjacent to the hepatic flexure (figure 1). It was determined not to represent an adenoma and a CT colonogram was arranged, which found no extracolonic invasion but shed little further detail on the nature of the lesion in question.



Figure 1 
A sizeable smooth lesion arising from the epithelium at the transverse colon.



A repeat colonoscopy, carried …
Respiratory specimens and the diagnostic accuracy of Aspergillus lateral flow assays (LFA-IMMY™): real-life data from a multicentre study
Authors: C. Lass-Flörl, G. Lo Cascio, M. Nucci, M. Camargo dos Santos, A. Lopes Colombo, M. Vossen, B. Willinger
Journal: Clinical Microbiology and Infection (2019)
Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNβ-Driven Antitumor Immunity
Authors: Prabhani U. Atukorale, Shruti P. Raghunathan, Vanitha Raguveer, Taylor J. Moon, Carolyn Zheng, Peter A. Bielecki, Michelle L. Wiese, Amy L. Goldberg, Gil Covarrubias, Christopher J. Hoimes, Efstathios Karathanasis
Journal: Cancer Research (2019)

Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I IFNβ. Using a murine model of metastatic triple-negative breast cancer, systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immune-potentiating cargoes for effective APC-driven local and systemic antitumor immunity. SIGNIFICANCE: Systemic administration of an immuno-nanoparticle in a murine breast tumor model drives a robust tumor site-specific APC response by delivering two synergistic immune-potentiating molecules, highlighting the potential of nanoparticles for immunotherapy.
The androgen receptor regulates PSA expression and cell growth by two different mechanisms
Authors: Paramita M. Ghosh, Margarita Mikhailova, Roble G. Bedolla, Yu Wang, Naveen K. Krishnegowda, Jeffrey I. Kreisberg
Journal: Cancer Research (2006)

935  Prostate cancer is almost universally detected by increased levels of prostate specific antigen (PSA) in the serum and expression of this serum marker is also used to determine tumor recurrence. However, over the last few years, clinicians have remarked about the lack of correlation between serum PSA levels and tumor volume or progression. The aim of these studies was to compare the pathways leading to PSA expression and proliferation in androgen-dependent LNCaP prostate cancer cells and its androgen-independent clone C4-2, which exhibit increased PSA expression. In androgen dependent cells, both PSA expression and growth is regulated by the activation of the androgen receptor (AR), a ligand activated transcription factor. Casodex, a competitive inhibitor of androgen binding to the AR, inhibited the growth of LNCaP but not C4-2 cells, but decreased PSA levels in both thus suggesting a dissociation between PSA expression and growth in C4-2 cells. Based on these results, we investigated whether signal transduction pathways known to regulate cell proliferation also affected PSA expression. The two best-known pathways regulating growth are those downstream of Ras and phosphatidylinositol 3-kinase (PI3K). Ras activates the mitogen activated protein kinases (MAPK) while the downstream effectors of PI3K include Akt and mTOR. In turn mTOR regulates the activation of p70S6 kinase, 4E-BP1 and e1F4G. The effect of these kinases on PSA expression and proliferation were evaluated by inhibition of the individual components with pharmacological inhibitors and small interfering RNA (siRNA). Proliferation rates were determined by MTT assay and by flow cytometry while protein expression was determined by immunoblotting. Treatment of LNCaP and C4-2 cells with PD98059, which inhibits p42/44MAPK activation, significantly decreased PSA expression but not proliferation. In contrast, the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin, inhibited cell growth but caused an increase in PSA expression, indicating that activation of PI3K and mTOR mediates proliferation but inhibit PSA expression. Downregulation of Akt by an Akt1-specific siRNA, decreased both growth and PSA expression. The downstream effectors of mTOR were also downregulated by specific siRNA. Inhibition of 4E-BP1, but not p70S6 kinase or e1F4G significantly decreased proliferation rates whereas e1F4G inhibition, but not that of p70S6 kinase or 4E-BP1, caused a significant upregulation of PSA expression, thereby indicating that mTOR9s effects on proliferation are mediated by 4E-BP1 while its effect on PSA expression are mediated by e1F4G. These results demonstrate for the first time that PSA expression and cell proliferation are differentially regulated downstream of AR activation - whereas PSA expression is mediated by Akt and p42/44MAPK activation and is inhibited by e1F4G, proliferation in prostate cancer cells is mediated by Akt and 4E-BP1.
Immune checkpoint inhibitor-based combinations: is dose escalation mandatory for phase I trials?
Authors: V. Simmet, L. Eberst, A. Marabelle, P.A. Cassier
Journal: Annals of Oncology (2019)

Numerous phase I trials testing immune checkpoint inhibitors (CPI)-based combinations are currently being conducted to improve response rates observed with single agents. However, methodology varies across studies, especially regarding the use of dose escalation.
Higher self‐reported severity of atopic dermatitis in adults is associated with poorer self‐reported health‐related quality of life in France, Germany, the U.K. and the U.S.A.
Authors: L. Andersen, M.E. Nyeland, F. Nyberg
Journal: British Journal of Dermatology (2019)

BackgroundBetter understanding of the relationship between atopic dermatitis (AD) severity and health‐related quality of life (HRQoL) could help improve knowledge of a more effective treatment for people with AD.
Donor Telomere Length Influences Engraftment and Outcome in Aplastic Anemia Patients Undergoing Matched Related Stem Cell Transplantation
Authors: Aruna Barade, Anu Korula, Nisham Pn, Kavitha M Lakshmi, Uday Prakash Kulkarni, Anup Devasia, Aby Abraham, Alok Srivastava, Vikram Mathews, Eunice Sindhuvi Edison, Biju George
Journal: Blood (2017)
US opioid prescribing: the federal government advisers with recent ties to big pharma
Authors: Tim Schwab
Journal: BMJ (2019)

With the US facing an epidemic of opioid deaths linked to overprescribing, <b>Tim Schwab</b> finds that the influential National Academies of Science, Engineering and Medicine has not disclosed that one of its presidents, and members of a panel it convened to advise on prescribing opioids, had recent links to the drug industry
Prescription Drug Monitoring Programs — Friend or Folly in Addressing the Opioid-Overdose Crisis?
Authors: Rebecca L. Haffajee
Journal: New England Journal of Medicine (2019)

Virtually every U.S. state has implemented a PDMP to address high-risk opioid-prescribing and opioid-seeking behaviors. Many stakeholders, however, have expressed doubts about their utility and concerns regarding their potential unintended consequences.
Multiscale Computational Modeling: Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir (Adv. Healthcare Mater. 16/2019)
Authors: Reyhaneh Neghabat Shirazi, Shahrin Islam, Fiona M. Weafer, William Whyte, Claudia E. Varela, Agnes Villanyi, William Ronan, Peter McHugh, Ellen T. Roche
Journal: Advanced Healthcare Materials (2019)

In article number 1900228 by Ellen T. Roche and co-workers, an in silico model of therapy delivery from an implantable epicardial reservoir is developed with input from experimental characterization to help elucidate the factors that govern epicardial drug delivery. The model can be used to inform future epicardial drug delivery device design.
Maturation of the infant rhesus macaque gut microbiome and its role in the development of diarrheal disease
Authors: Nicholas Rhoades, Tasha Barr, Sara Hendrickson, Kamm Prongay, Andrew Haertel, Leanne Gill, Laura Garzel, Katrine Whiteson, Mark Slifka, Ilhem Messaoudi
Journal: Genome biology (2019)

Diarrhea is the second leading cause of death in children under 5 years of age. Enhanced understanding of causal pathways, pathogenesis, and sequelae of diarrhea is urgently needed. Although the gut microbiota is believed to play a role in susceptibility to diarrheal diseases, our understanding of this association remains incomplete. Infant rhesus macaques (Macaca mulatta) are susceptible to diarrhea making them an ideal model to address this question. The maturation of the infant rhesus macaque gut microbiome throughout the first 8 months of life occurs in a similar pattern as that described for human infants. Moreover, the microbiome of the captive reared infant rhesus macaque more closely resembles that of human infants in the developing world than in the western world. Importantly, prior to disease onset, the gut microbiome of infants that later develop diarrhea is enriched in pathways of immunomodulatory metabolite synthesis, while those of infants that remain asymptomatic are enriched in pathways for short-chain fatty acid production. We identify Prevotella strains that are more abundant at 1 month in infants that later develop diarrhea. At 8 months, the microbiomes of animals that experience diarrhea show increased abundance of Campylobacter and a reduction in Helicobacter macacae. The composition of the microbial community could provide a phenotypic marker of an infant’s susceptibility to diarrheal disease. Given the significant physiological and immunological similarities between human and nonhuman primates, these findings provide potential markers of susceptibility to diarrhea that could be modulated to improve infant health, especially in the developing world.
Using Multiple Financial Incentive Structures to Promote Sustainable Changes in Health Behaviors
Authors: Pasquale E. Rummo, Brian Elbel
Journal: JAMA Network Open (2019)

Chethan Bachireddy, MD, MSc; Andrew Joung, BA; Leslie K. John, PhD; Francesca Gino, PhD; Bradford Tuckfield, PhD; Luca Foschini, PhD; Katherine L. Milkman, PhD
Exploring ceramide metabolism as a potential target in dedifferentiated liposarcoma.
Authors: Bryce Demoret, Andrew Patt, Colin W Stets, Mindy Hoang, John L. Hays, Ewy Mathe, James Lin Chen
Journal: Journal of Clinical Oncology (2019)

e22558 Background: Dedifferentiated liposarcomas (DDLPS) are highly aggressive mesenchymal tumors characterized by MDM2 amplification. Elevated MDM2 amplification levels are associated with tumor growth, chemoresistance, and changes in cellular metabolism. Previous work from our laboratory has demonstrated that lipid metabolism, particularly increased glycosylated ceramides (Gly-Cer), is profoundly altered as a function of MDM2 amplification. Importantly, ceramides have been identified to play a key role in proliferation arrest and apoptosis or autophagy by stabilizing p53 through the binding and disrupting the MDM2-p53 interaction. Gly-Cer clears out ceramides, thereby preventing the ceramides from performing their anti-proliferative activity. We hypothesized that restoring Gly-Cer levels would induce anti-proliferative effects in DDLPS. Methods: 6 DDLPS cell lines (MDM2-high: Lipo224, Lipo141, Lipo224B, Lipo246; MDM2-low: Lipo815, Lipo863) were selected for in vitro assessment. MDM2 levels were ascertained via Western blot and RNA-sequencing. Metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling were conducted on all cell lines. Inhibitory concentration 50% (IC50) of the C 6 -ceramide (C 6 C) and nanoliposomal C 6 -Ceramides (C 6 CNL) were tested in vitro by XTT . Adjusted t-tests were used to determine metabolite relevance. Results: Metabolomic/lipidomic analyses identified a correlation between MDM2 amplification status and elevated levels of glycosylated ceramides (nom: Pval &lt; 0.001), including GlcCer_NS(d18:1/24:1), GlcCer_NS(d19:1/24:1), GlcCer_NS(d18:1/25:0), glycosyl-N-palmitoyl-sphingosine, and glycosyl-N-stearoyl-sphingosine. Further, the ratio of glycosylated to un-glycosylated ceramides in DDLPS cell was also associated with MDM2 status for Cer(d19:1/24:1) (Pval &lt; 0.01) and borderline associated for Cer(d18:1/16:0) and Cer(d18:1/25:0) (Pval &lt; 0.2). In vitro treatment of DDLPS cell lines with C 6 C resulted in a reduction of cellular viability most prominent in MDM2-high cell lines (IC50: 17 vs. 55 µM). When treated with C 6 CNL, all DDLPS cell lines exhibited equal sensitivity (IC50: ~9 µM). Western blots demonstrate C 6 CNL treatment resulted in a reduction in MDM2 expression and restoration of p53 function. Conclusions: Exogenous ceramide treatment reduces MDM2 expression, restores TP53 status, and manifests anti-proliferative activity in DDLPS. C 6 CNL exhibited lower effective concentrations relative to free C 6 ceramide. Prospective in vivo studies are underway to confirm these findings.
Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation
Authors: Samuel A. Stoner, Ming Yan, Katherine Tin Heng Liu, Kei-Ichiro Arimoto, Takahiro Shima, Huan-You Wang, Daniel T. Johnson, Rafael Bejar, Catriona Jamieson, Kun-Liang Guan, Dong-Er Zhang
Journal: Blood (2019)
IVUS Guided PCI Results in a larger Lumen and Improved Clinical and Functional Parameters at 6 Months Follow-Up and Continued Lower tvr and Mace rate at 2.5 year Follow-Up. Abstracts of original contributions: The 14th World Congress of Cardiology, Sydney, NSW, Australia May 5-9, 2002
Authors: A.L. Gaster, C. von Birgelen, L. Korsholm, S. Jensen, P. Thayssen, K.E. Pedersen, T.H. Haghfelt
Journal: Journal of the American College of Cardiology (2002)
A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma
Authors: Y.N. Vashisht Gopal, Seth Gammon, Rishika Prasad, Barbara Knighton, Federica Pisaneschi, Jason Roszik, Ningping Feng, Sarah Johnson, Snigdha Pramanik, Jessica Sudderth, Dawen Sui, Courtney Hudgens, Grant M. Fischer, Wanleng Deng, Alexandre Reuben, Weiyi Peng, Jian Wang, Jennifer L. McQuade, Michael T. Tetzlaff, Maria E. Di Francesco, Joe Marszalek, David Piwnica-Worms, Ralph J. DeBerardinis, Michael A. Davies
Journal: Clinical Cancer Research (2019)

The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)-resistant BRAF-mutant melanomas.Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. 13C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was evaluated noninvasively by [18F]-fluoroazomycin arabinoside (FAZA) PET imaging.OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi in vitro or in vivo. Signaling and growth-inhibitory effects were mediated by LKB1-AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [18F]-FAZA PET uptake in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy.Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.
MYC dysregulation in the progression of multiple myeloma
Authors: Kristine Misund, Niamh Keane, Caleb K. Stein, Yan W. Asmann, Grady Day, Seth Welsh, Scott A. Van Wier, Daniel L. Riggs, Greg Ahmann, Marta Chesi, David S. Viswanatha, Shaji K. Kumar, Angela Dispenzieri, Veronica Gonzalez-Calle, Robert A. Kyle, Michael O’Dwyer, S. Vincent Rajkumar, K. Martin Kortüm, J. Jonathan Keats, Rafael Fonseca, A. Keith Stewart, W. Michael Kuehl, Esteban Braggio, P. Leif Bergsagel
Journal: Leukemia (2019)
A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS 0415).
Authors: Viktor Grünwald, Sebastian Bauer, Barbara Hermes, Philipp Ivanyi, Lars H Lindner, Daniel Pink, Peter Reichardt, Stephan Richter, Armin Tuchscherer
Journal: Journal of Clinical Oncology (2019)

TPS11075 Background: Soft tissue sarcomas (STS) are rare tumors and exhibit substantial histological diversity. Efficacious targeted 1 st line treatment for advanced or metastatic STS is not available, and the standard therapy has been anthracycline-based for decades. This strategy shows poor efficacy, as demonstrated by a median Overall Survival (OS) of 12-20 months. Several STS subtypes, however, have been shown to express PD-L1, and immune checkpoint inhibitors (ICI) have demonstrated principle anti-tumor activity in pretreated STS. Our ongoing clinical trial tests the activity and safety of ICI combination therapy in the first-line setting. We hypothesize that the dual checkpoint blockade with Durvalumab (PD-L1) and Tremelimumab (CTLA-4) improves overall survival in STS when compared to the standard of care doxorubicin. Methods: MEDISARC is a multi-center phase II trial that is enrolling adult treatment-naïve patients with histologically confirmed STS of intermediate or high grade (FNCLCC grade 2 or 3) not amenable to surgery with curative intent and ECOG performance status 0-2. Chemosensitive histologic STS are eligible. 100 patients will be randomized 1:1, stratified by ECOG status (0 vs. 1/2). Patients in the experimental arm are treated with fixed doses of durvalumab (1.5 g Q4W) and tremelimumab (75 mg Q4W for 3 cycles, then Q12W) until Progressive Disease (PD) or for a maximum of 12 months. Doxorubicin treatment in the standard arm is at 75 mg/m 2 Q3W and limited to 6 cycles. OS is the primary endpoint. Secondary endpoints include 2-year OS rate, PFS, ORR according to conventional and modified RECIST 1.1, safety and tolerability and health-related quality of life (EORTC QLQ-C30). OS analysis may be performed when the required number of events (E=70) has been observed. All randomized and treated subjects will be included in the efficacy and safety analysis. The accompanying translational research aims to identify prognostic and predictive biomarkers in blood and tumor tissue. Enrollment of patients started in April 2018 and is ongoing. As of February 2019, 32 patients have been enrolled. The study is sponsored by AIO-Studien-gGmbH, Berlin, Germany. Clinical trial information: 2016-004750-15.