tbuckley/cabot-search huggingface dataset:
Reactive Oxygen Species: A Breath of Life or Death?
Authors: John P. Fruehauf, Frank L. Meyskens
Journal: Clinical Cancer Research (2007)

Abstract New insights into cancer cell–specific biological pathways are urgently needed to promote development of rationally targeted therapeutics. Reactive oxygen species (ROS) and their role in cancer cell response to growth factor signaling and hypoxia are emerging as verdant areas of exploration on the road to discovering cancer's Achilles heel. One of the distinguishing and near-universal hallmarks of cancer growth is hypoxia. Unregulated cellular proliferation leads to formation of cellular masses that extend beyond the resting vasculature, resulting in oxygen and nutrient deprivation. The resulting hypoxia triggers a number of critical adaptations that enable cancer cell survival, including apoptosis suppression, altered glucose metabolism, and an angiogenic phenotype. Ironically, recent investigations suggest that oxygen depletion stimulates mitochondria to elaborate increased ROS, with subsequent activation of signaling pathways, such as hypoxia inducible factor 1α, that promote cancer cell survival and tumor growth. Because mitochondria are key organelles involved in chemotherapy-induced apoptosis induction, the relationship between mitochondria, ROS signaling, and activation of survival pathways under hypoxic conditions has been the subject of increased study. Insights into mechanisms involved in ROS signaling may offer novel avenues to facilitate discovery of cancer-specific therapies. Preclinical and clinical evaluation of agents that modify ROS signaling in cancer offers a novel avenue for intervention. This review will cover recent work in ROS-mediated signaling in cancer cells and its potential as a target for developmental therapeutics.
Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients
Authors: J. Baselga, A. Llombart-Cussac, M. Bellet, V. Guillem-Porta, N. Enas, K. Krejcy, E. Carrasco, L. Kayitalire, M. Kuta, A. Lluch, P. Vodvarka, P. Kerbrat, M. Namer, L. Petruzelka
Journal: Annals of Oncology (2003)
Selective depletion of myelin–reactive T cells with the anti–OX–40 antibody ameliorates autoimmune encephalomyelitis
Authors: A.D. Weinberg, D.N. Bourdette, T.J. Sullivan, M. Lemon, J.J. Wallin, R. Maziarz, M. Davey, F. Palida, W. Godfrey, E. Engleman, R.J. Fulton, H. Offner, A.A. Vandenbark
Journal: Nature Medicine (1996)
Satisfaction Guaranteed — “Payment by Results” for Biologic Agents
Authors: Alan M Garber, Mark B McClellan
Journal: New England Journal of Medicine (2007)

As increasing numbers of promising but expensive biologic agents are introduced for use as medical treatments, drug pricing has become a high-profile issue. Earlier this year, pricing practices took a new turn in Britain, when the National Institute for Health and Clinical Excellence (NICE), the evaluative agency that applies cost-effectiveness analysis in making recommendations concerning drug coverage, declined to support coverage of the proteasome inhibitor bortezomib (Velcade) by the British National Health Service (NHS) for the treatment of multiple myeloma. It concluded that the price was too high relative to NICE's estimates of its average benefits for the population to . . .
Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells
Authors: Simona Taverna, Valeria Amodeo, Laura Saieva, Antonio Russo, Marco Giallombardo, Giacomo De Leo, Riccardo Alessandro
Journal: Molecular Cancer (2014)

Recent findings indicate that exosomes released from cancer cells contain microRNAs (miRNAs) that may be delivered to cells of tumor microenvironment. To elucidate whether miRNAs secreted from chronic myelogenous leukemia cells (CML) are shuttled into endothelial cells thus affecting their phenotype, we first analysed miRNAs content in LAMA84 exosomes. Among the 124 miRNAs identified in LAMA84 exosomes, we focused our attention on miR-126 which was found to be over-overexpressed in exosomes compared with producing parental cells. Transfection of LAMA84 with Cy3-labelled miR-126 and co-culture of leukemia cells with endothelial cells (EC) confirmed that miR-126 is shuttled into HUVECs. The treatment of HUVECs with LAMA84 exosomes for 24 hours reduced CXCL12 and VCAM1 expression, both at the mRNA and protein level, and negatively modulated LAMA84 motility and cells adhesion. Transfection in HUVECs of miR-126 inhibitor reversed the decrease of CXCL12 and restored the motility and adhesion of LAMA84 cells while the over-expression of miR-126, showed opposite effects. Our results show that the miR-126 shuttled by exosomes is biologically active in the target cells, and support the hypothesis that exosomal miRNAs have an important role in tumor-endothelial crosstalk occurring in the bone marrow microenvironment, potentially affecting disease progression.
Stimulated mobilization of monocyte Mac-1 and p150,95 adhesion proteins from an intracellular vesicular compartment to the cell surface.
Authors: L J Miller, D F Bainton, N Borregaard, T A Springer
Journal: Journal of Clinical Investigation (1987)

Monocytes were stimulated to increase their cell surface quantity of leukocyte adhesion proteins p150,95 and Mac-1 by the chemoattractant formyl-methionyl-leucyl-phenylalanine, or other mediators such as platelet-derived growth factor, tumor necrosis factor, C5a, and leukotriene B4. Dose-response curves indicated variations in the sensitivity of monocytes and granulocytes to these mediators. These increases were independent of protein synthesis and half-maximal at 2 min. Human alveolar and murine peritoneal macrophages, cells that had previously diapedised, could not be induced to upregulate Mac-1 or p150,95. Detergent permeabilization studies in monocytes indicated that these proteins were stored in internal latent pools, which were reduced upon stimulation. Electron microscopy utilizing rabbit antiserum against p150,95 revealed these proteins on the plasma membrane, and in intracellular vesicles and peroxidase negative granules. Together with other functional studies, these findings suggest that the mobilization of Mac-1 and p150,95 from an intracellular compartment to the plasma membrane regulates the monocyte's ability to adhere and diapedese.
3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation
Authors: KM Wahidur Rahman, Sanjeev Banerjee, Shadan Ali, Aamir Ahmad, Zhiwei Wang, Dejuan Kong, Wael A. Sakr
Journal: Cancer Research (2009)

Abstract Survivin, a member of inhibitor of apoptosis family, is associated with both prostate cancer progression and drug resistance. Therefore, we hypothesized that survivin may play a potentially important role in hormone-refractory prostate cancer (HRPC) and bone metastatic disease; thus, targeting of survivin signaling could enhance therapeutic efficacy in prostate cancer. 3,3′-Diindolylmethane (DIM) has been known to have cancer chemoprevention activity. However, no information is available regarding the down-regulation of survivin by DIM, which could result in the chemosensitization of HRPC cells to Taxotere-induced killing. We investigated the effect of DIM alone or in combination with Taxotere using LNCaP and C4-2B prostate cancer cells. We observed that DIM enhanced Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in survivin expression as well as androgen receptor and nuclear factor-κB (NF-κB) DNA-binding activity. We also found that knockdown of survivin expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both prostate cancer cells. Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-κB-Luc activity in prostate cancer cells exposed to DIM and Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone tumor growth, and the results were correlated with the down-regulation of survivin. From these results, we conclude that inactivation of survivin by DIM enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of HRPC and metastatic prostate cancer. [Cancer Res 2009;69(10):4468–75]
Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation
Authors: Arian Laurence, Cristina M. Tato, Todd S. Davidson, Yuka Kanno, Zhi Chen, Zhengju Yao, Rebecca B. Blank, Françoise Meylan, Richard Siegel, Lothar Hennighausen, Ethan M. Shevach, John J. O'Shea
Journal: Immunity (2007)
Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab
Authors: Werner Wenning, Aiden Haghikia, Jörg Laubenberger, David B. Clifford, Peter F. Behrens, Andrew Chan, Ralf Gold
Journal: New England Journal of Medicine (2009)

We describe the clinical and therapeutic course of a 52-year-old patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML) developed after 12 months of therapy with natalizumab. The patient was hospitalized 2 months after the onset of neurologic and psychiatric symptoms and was treated with plasma exchange and immunoadsorption to eliminate natalizumab. After a brief improvement, he became critically ill with an apparent episode of immune reconstitution inflammatory syndrome. Steroid-pulse therapy led to stabilization of the patient's condition and clinically significant recovery. This case illustrates that prompt diagnosis and treatment may improve the outcome in patients with severe PML associated with natalizumab therapy.
MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells
Authors: Sergey Filippov, Gerald C. Koenig, Tae-Hwa Chun, Kevin B. Hotary, Ichiro Ota, Thomas H. Bugge, Joseph D. Roberts, William P. Fay, Henning Birkedal-Hansen, Kenn Holmbeck, Farideh Sabeh, Edward D. Allen, Stephen J. Weiss
Journal: The Journal of Experimental Medicine (2005)

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
Diagnostic Imaging Use for Patients With Cancer
Authors: Samuel Swisher-McClure, Justin Bekelman
Journal: JAMA Oncology (2015)

Danil V. Makarov, MD, MHS; Pamela R. Soulos, MPH; Heather T. Gold, PhD; James B. Yu, MD, MHS; Sounok Sen, MD; Joseph S. Ross, MD, MHS; Cary P. Gross, MD
Development and characterization of a high-throughput in vitro cord formation model insensitive to VEGF inhibition
Authors: Beverly L Falcon, Belinda O’Clair, Don McClure, Glenn F Evans, Julie Stewart, Michelle L Swearingen, Yuefeng Chen, Kevin Allard, Linda N Lee, Kuldeep Neote, Dyke P McEwen, Mark T Uhlik, Sudhakar Chintharlapalli
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Anti-VEGF therapy reduces tumor blood vessels, however, some vessels always remain. These VEGF insensitive vessels may help support continued tumor growth and metastases. Many in vitro assays examining multiple steps of the angiogenic process have been described, but the majority of these assays are sensitive to VEGF inhibition. There has been little focus on the development of high-throughput, in vitro assays to model the vessels that are insensitive to VEGF inhibition. Methods Here, we describe a fixed end-point and kinetic, high-throughput stem cell co-culture model of cord formation. Results In this system, cords develop within 24 hours, at which point they begin to lose sensitivity to VEGF inhibitors, bevacizumab, and ramucirumab. Consistent with the hypothesis that other angiogenic factors maintain VEGF-independent vessels, pharmacologic intervention with a broad spectrum anti-angiogenic antagonist (suramin), a vascular disrupting agent (combretastatin), or a combination of VEGF and Notch pathway inhibitors reduced the established networks. In addition, we used our in vitro approach to develop an in vivo co-implant vasculogenesis model that connects with the endogenous vasculature to form functional blood vessels. Similar to the in vitro system, over time these vessels become insensitive to VEGF inhibition. Conclusion Together, these models may be used to identify novel drugs targeting tumor vessels that are not sensitive to VEGF inhibition.
Single Nucleotide Polymorphisms, Apoptosis, and the Development of Severe Late Adverse Effects After Radiotherapy
Authors: David Azria, Mahmut Ozsahin, Andrew Kramar, Sheila Peters, David P. Atencio, Nigel E.A. Crompton, Françoise Mornex, André Pèlegrin, Jean-Bernard Dubois, René-Olivier Mirimanoff, Barry S. Rosenstein
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, ≥3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. Experimental Design: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). Results: Overall, 13 and 21 patients were found to possess a total of &amp;lt;4 and ≥4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had ≥4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had ≥4 SNPs (P &amp;lt; 0.001). Conclusions: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.
Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance
Authors: Rajat Singh, Yongjun Wang, Youqing Xiang, Kathryn E. Tanaka, William A. Gaarde, Mark J. Czaja
Journal: Hepatology (2008)

Activation of c-Jun N-terminal kinase (JNK) has been implicated as a mechanism in the development of steatohepatitis. This finding, together with the reported role of JNK signaling in the development of obesity and insulin resistance, two components of the metabolic syndrome and predisposing factors for fatty liver disease, suggests that JNK may be a central mediator of the metabolic syndrome and an important therapeutic target in steatohepatitis. To define the isoform-specific functions of JNK in steatohepatitis associated with obesity and insulin resistance, the effects of JNK1 or JNK2 ablation were determined in developing and established steatohepatitis induced by a high-fat diet (HFD). HFD-fed jnk1 null mice failed to develop excessive weight gain, insulin resistance, or steatohepatitis. In contrast, jnk2(-/-) mice fed a HFD were obese and insulin-resistant, similar to wild-type mice, and had increased liver injury. In mice with established steatohepatitis, an antisense oligonucleotide knockdown of jnk1 decreased the amount of steatohepatitis in concert with a normalization of insulin sensitivity. Knockdown of jnk2 improved insulin sensitivity but had no effect on hepatic steatosis and markedly increased liver injury. A jnk2 knockdown increased hepatic expression of the proapoptotic Bcl-2 family members Bim and Bax and the increase in liver injury resulted in part from a Bim-dependent activation of the mitochondrial death pathway.JNK1 and JNK2 both mediate insulin resistance in HFD-fed mice, but the JNK isoforms have distinct effects on steatohepatitis, with JNK1 promoting steatosis and hepatitis and JNK2 inhibiting hepatocyte cell death by blocking the mitochondrial death pathway.
Roles of Fas and Fas ligand during mammary gland remodeling
Authors: Joon Song, Eva Sapi, Wendi Brown, Jon Nilsen, Karrie Tartaro, Barry M. Kacinski, Joseph Craft, Frederick Naftolin, Gil Mor
Journal: Journal of Clinical Investigation (2000)

Mammary involution is associated with degeneration of the alveolar structure and programmed cell death of mammary epithelial cells. In this study, we evaluated the expression of Fas and Fas ligand (FasL) in the mammary gland tissue and their possible role in the induction of apoptosis of mammary cells. FasL-positive cells were observed in normal mammary epithelium from pregnant and lactating mice, but not in nonpregnant/virgin mouse mammary tissue. Fas expression was observed in epithelial and stromal cells in nonpregnant mice but was absent during pregnancy. At day 1 after weaning, high levels of both Fas and FasL proteins and caspase 3 were observed and coincided with the appearance of apoptotic cells in ducts and glands. During the same period, no apoptotic cells were found in the Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice. Increase in Fas and FasL protein was demonstrated in human (MCF10A) and mouse (HC-11) mammary epithelial cells after incubation in hormone-deprived media, before apoptosis was detected. These results suggest that the Fas-FasL interaction plays an important role in the normal remodeling of mammary tissue. Furthermore, this autocrine induction of apoptosis may prevent accumulation of cells with mutations and subsequent neoplastic development. Failure of the Fas/FasL signal could contribute to tumor development.
Daylight photodynamic therapy for actinic keratoses: a randomized double‐blinded nonsponsored prospective study comparing 5‐aminolaevulinic acid nanoemulsion ( <scp>BF</scp> ‐200) with methyl‐5‐aminolaevulinate
Authors: N. Neittaanmäki‐Perttu, T.T. Karppinen, M. Grönroos, T.T. Tani, E. Snellman
Journal: British Journal of Dermatology (2014)

Daylight-mediated photodynamic therapy (DL-PDT) using methyl-5-aminolaevulinate (MAL) is effective for thin, grade I, actinic keratoses (AK). There are no published studies of other photosensitizers used in DL-PDT.To compare the efficacy and adverse effects of 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) with MAL in DL-PDT of grade I-III AKs.In 13 patients, 177 AKs were randomized symmetrically for a split-face prospective observer-blinded study and received either BF-200 ALA or MAL DL-PDT. Grade I AKs were treated once and grade II-III AKs twice with a 0·25-mm layer of photosensitizer precursors. Pain was assessed during and after the daylight exposure. Efficacy at 3 months was assessed clinically and histologically.BF-200 ALA cleared 71/84 (84·5%) and MAL 69/93 (74·2%) of the AKs (P = 0·099), all grades responding equally, but with new AKs appearing during follow-up (n = 4, BF-200 ALA; n = 8, MAL). In per patient half-face analysis BF-200 ALA showed significantly higher clearance rates for grade I AKs than did MAL (P = 0·027), but for thicker grades, clearance was equal (P = 0·564). BF-200 ALA and MAL treatments resulted in 61·5% and 38·5% complete histological clearance (P = 0·375), respectively. p53 expression decreased by 54·4% and 33·7%, respectively (P = 0·552). Both treatments were nearly painless with similar adverse reactions and no difference in patient preference.BF-200 ALA showed a trend towards improved efficacy results compared with MAL. Thicker lesions in both groups responded when treated repeatedly. Importantly, a thin 0·25-mm layer of the photosensitizer precursors was sufficient, which may lead to lower expense.
Parent and Physician Perspectives on Quality of Care at the End of Life in Children With Cancer
Authors: Jennifer W. Mack, Joanne M. Hilden, Jan Watterson, Caron Moore, Brian Turner, Holcombe E. Grier, Jane C. Weeks, Joanne Wolfe
Journal: Journal of Clinical Oncology (2005)

Purpose To ascertain parents' and physicians' assessments of quality of end-of-life care for children with cancer and to determine factors associated with high-quality care as perceived by parents and physicians. Methods A survey was conducted between 1997 and 2001 of 144 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital (Boston, MA) or Children's Hospitals and Clinics of St Paul and Minneapolis, MN, between 1990 and 1999 (65% of those located and eligible) and 52 pediatric oncologists. Results In multivariable models, higher parent ratings of physician care were associated with physicians giving clear information about what to expect in the end-of-life period (odds ratio [OR] = 19.90, P = .02), communicating with care and sensitivity (OR = 7.67, P &lt; .01), communicating directly with the child when appropriate (OR = 11.18, P &lt; .01), and preparing the parent for circumstances surrounding the child's death (OR = 4.84, P = .03). Parent reports of the child's pain and suffering were not significant correlates of parental ratings of care (P = .93 and .35, respectively). Oncologists' ratings of care were inversely associated with the parent's report of the child's experience of pain (OR = 0.15, P = .01) and more than 10 hospital days in the last month of life (OR = 0.24, P &lt; .01). Parent-rated communication factors were not correlates of oncologist-rated care. No association was found between parent and physician care ratings (P = .88). Conclusion For parents of children who die of cancer, doctor-patient communication is the principal determinant of high-quality physician care. In contrast, physicians' care ratings depend on biomedical rather than relational aspects of care.