tbuckley/cabot-search huggingface dataset:
Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1α Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor
Authors: Yang Wang, Maha Saad, Refika I. Pakunlu, Jayant J. Khandare, Olga B. Garbuzenko, Alexandre A. Vetcher, Viatcheslav A. Soldatenkov, Vitaly P. Pozharov, Tamara Minko
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1α (HIF1A). Experimental Design: The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis. Results: The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy. Conclusions: The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.
Cancer Stem Cells: An Old Idea—A Paradigm Shift
Authors: Max S. Wicha, Suling Liu, Gabriela Dontu
Journal: Cancer Research (2006)

Abstract Although the concept that cancers arise from “stem cells” or “germ cells” was first proposed about 150 years ago, it is only recently that advances in stem cell biology have given new impetus to the “cancer stem cell hypothesis.” Two important related concepts of this hypothesis are that (a) tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of self-renewal. As a result of this, (b) tumors contain a cellular subcomponent that retains key stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation albeit aberrant that contributes to cellular heterogeneity. Recent experimental evidence in a variety of tumors has lent strong support to the cancer stem cell hypothesis that represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology. This hypothesis has fundamental implications for cancer risk assessment, early detection, prognostication, and prevention. Furthermore, the current development of cancer therapeutics based on tumor regression may have produced agents that kill differentiated tumor cells while sparing the rare cancer stem cell population. The development of more effective cancer therapies may thus require targeting this important cell population. (Cancer Res 2006; 66(4): 1883-90)
Long-Term Follow-Up After Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia/Myelodysplastic Syndrome: Late CNS Relapses Despite Graft-Versus-Host Disease
Authors: Jeffrey K. Davies, David C. Taussig, Heather Oakervee, Andrew J. Davies, Samir G. Agrawal, John G. Gribben, T. Andrew Lister, Jamie D. Cavenagh
Journal: Journal of Clinical Oncology (2006)
Mechanisms of traumatic shoulder injury in elite rugby players
Authors: James Crichton, Doug R Jones, Lennard Funk
Journal: British Journal of Sports Medicine (2012)

Shoulder injuries in rugby players are common, but the mechanisms of injury are less well understood. This study aims to elucidate common mechanisms of injury and identify the patterns of injury they produce.Twenty-four elite rugby players, referred to the senior author for diagnosis and management of shoulder injuries, were selected. Videos of the injuries were independently reviewed by rugby-medical experts to describe the mechanisms of injury. The mechanisms reported were collated and analysed to determine the level of agreement between reviewers and conclude an overall description of injury mechanisms.The authors identified three mechanisms of shoulder injury from the video analysis. These are the 'Try-Scorer', characterised by hyperflexion of the outstretched arm such as when scoring a try; the 'Tackler', extension of the abducted arm behind the player while tackling; and the 'Direct Impact', a direct blow to the arm or shoulder when held by the side in neutral or slight adduction. The Try Scorer and Tackler mechanisms both involve a levering force on the glenohumeral joint (GHJ). These mechanisms predominantly cause GHJ dislocation, with Bankart, reverse Bankart and superior labrum anterior-posterior tears. The Try-Scorer Mechanism also caused the majority (83%) of rotator cuff tears. The Direct Hit mechanism resulted in GHJ dislocation and labral injury in 37.5% of players and was most likely to cause acromioclavicular joint dislocation and scapula fractures, injuries that were not seen with the other mechanisms.Greater understanding of the mechanisms involved in rugby shoulder injury is useful in understanding the pathological injuries, guiding treatment and rehabilitation and aiding the development of injury-prevention methods.
Molecular mechanisms of glucocorticoid action: what is important?
Authors: R. Newton
Journal: Thorax (2000)

Inflammatory diseases such as asthma and rheumatoid arthritis are characterised at the molecular level by chronically increased expression of multiple cytokines, chemokines, kinins and their receptors, adhesion molecules, and inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the inducible cyclooxygenase (COX-2).1 At the cellular level, inflamed regions show a substantial influx of various inflammatory cells, arterial dilation, increased blood flow, plasma protein leakage, and oedema whilst, in the case of chronic asthma, substantial remodelling of the airways is observed involving excessive smooth muscle proliferation. However, these parameters of inflammation are effectively reduced by treatment with glucocorticoids by both direct and indirect mechanisms.2 3 For example, the reduced eosinophilia following glucocorticoid treatment in asthmatic subjects arises by direct promotion of eosinophil apoptosis and indirectly by suppressing receptor expression and production of cytokines or growth factors.4 These include factors such as interleukin (IL)-3, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF), and eotaxin which are involved in eosinophil maturation, recruitment, and survival. Similarly, glucocorticoids reduce T cell proliferation and increase T cell apoptosis via mechanisms that are at least partly the result of inhibition of the T cell growth factor, IL-2.5-8 Likewise, monocyte apoptosis is increased and influx of other infiltrating inflammatory cells is also repressed.2 9 Again, this is partly caused by reduced expression of adhesion molecules, both on migrating and target cells, as well as reduced expression of cytokines and chemokines from sites of inflammation.

Therapeutically, the ability to suppress a number of inflammatory indices makes glucocorticoids among the most potent anti-inflammatory agents currently available for the treatment of chronic inflammatory diseases such as asthma.2 3 The clinical efficacy of synthetic glucocorticoids such as prednisolone or dexamethasone stems from their ability to mimic natural glucocorticosteroids. Bodily insults, including inflammation, pain, infection or even mental …
Kupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion injury in rats
Authors: N Hisama
Journal: Hepatology (1996)

We investigated the role of hepatic macrophages in the inflammatory response following reperfusion injury by blocking Kupffer cell phagocytosis with gadolinium chloride (GdCl3). Liver ischemia was induced in rats by occluding the portal vein for 30 minutes. A bolus of GdCl3 (7 mg/kg) was injected intravenously 1 and 2 days before surgery. The serum levels of cytokine-induced neutrophil chemoattractant (CINC) in untreated rats increased following reperfusion, peaked after 6 hours, and then gradually decreased. GdCl3 or heparin alone significantly decreased the serum levels of CINC (P < .05). In addition, pretreatment with GdCl3/heparin further inhibited the rise in the serum levels of CINC following reperfusion compared with those in untreated animals (P < .01). The in vitro production of CINC by Kupffer cells, obtained from animals pretreated with heparin or GdCl3, was significantly lower than that of cells isolated from untreated animals. Pretreatment with GdCl3/heparin further decreased CINC production by Kupffer cells compared with that of cells from animals that were pretreated with heparin or GdCl3 alone. The expression of CINC transcripts in Kupffer cells or in liver tissue peaked 3 hours after reperfusion in untreated animals. Pretreatment with heparin, GdCl3, or both significantly decreased the levels of CINC messenger RNA (mRNA) transcripts. Pretreatment with heparin, GdCl3, or GdCl3/heparin significantly decreased the number of neutrophils that accumulated in the liver 24 hours following reperfusion, compared with those in untreated animals. These results suggest that Kupffer cells release CINC and may play an important role in early neutrophil infiltration into the liver following ischemia/reperfusion.
The Paradoxical Expression of Maspin in Ovarian Carcinoma
Authors: Anil K. Sood, Mavis S. Fletcher, Lynn M. Gruman, Jeremy E. Coffin, Sarvenaz Jabbari, Zhila Khalkhali-Ellis, Nancy Arbour, Elisabeth A. Seftor, Mary J C Hendrix
Journal: Clinical Cancer Research (2002)

Maspin is a noninhibitory member of the serpin family that is down-regulated in breast carcinoma but overexpressed in pancreatic carcinoma. There are no published data regarding the role of maspin in ovarian carcinoma, which is the focus of the present study. Ovarian cell lines (normal and cancer) and tumors (80 invasive, 14 benign, and 10 low malignant potential) were evaluated for maspin expression and localization. Normal ovarian surface epithelial cells had low levels of maspin. Two of four ovarian cancer cell lines (OVCAR3 and SKOV3) expressed maspin, whereas the cell line EG had weak expression, and 222 had no detectable maspin. Subcellular fractionation studies revealed that the two maspin-positive ovarian cancer cell lines contained maspin in both the nuclear and cytosolic compartments. Wild-type maspin was transfected into the aggressive ovarian cancer cell lines SKOV3 and 222. The in vitro invasive activity of the maspin-transfected cell lines was 44-68% lower than respective controls. The histopathology analysis revealed that among the ovarian tumors examined, 57 (71%) were ranked positive for maspin. Thirty (37%) of the invasive tumors overexpressed maspin. Invasive cancers were more likely to have predominantly cytoplasmic staining compared with benign and low-malignant-potential tumors. Maspin overexpression was significantly associated with a high tumor grade (P = 0.004), the presence of ascites (P = 0.02), a lower likelihood of optimal surgical cytoreduction (P = 0.04), and a shorter duration of overall survival (median survival, 6.33 versus 2.67 years; P = 0.003). The Cox proportional hazards multivariate model revealed that maspin overexpression and high stage were independent predictors of survival. Thus, maspin was found to be overexpressed in a substantial proportion of ovarian tumors, which may serve as an adverse prognostic factor; however, its localization may provide new clues as to its activity and function. These paradoxical results may offer new insights regarding the role of maspin in ovarian cancer progression that may also impact diagnosis and treatment strategies.
miR-29b Participates in Early Aneurysm Development in Marfan Syndrome
Authors: Denis R. Merk, Jocelyn T. Chin, Benjamin A. Dake, Lars Maegdefessel, Miquell O. Miller, Naoyuki Kimura, Philip S. Tsao, Cristiana Iosef, Gerald J. Berry, Friedrich W. Mohr, Joshua M. Spin, Cristina M. Alvira, Robert C. Robbins, Michael P. Fischbein
Journal: Circulation Research (2011)

Rationale: Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined. Objective: We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. Methods and Results: Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan ( Fbn1 C1039G/+ ) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1 C1039G/+ aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1 C1039G/+ ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1 C1039G/+ aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1 C1039G/+ mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. Conclusions: We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.
Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch
Authors: Tian Zhang, Andrew J. Armstrong
Journal: Clinical Cancer Research (2015)

Abstract Notch signaling is implicated in prostate cancer progression and docetaxel resistance. Cui and colleagues describe the additive efficacy and mechanisms of a γ-secretase inhibitor, PF-03084014, and docetaxel in preclinical models of prostate cancer, suggesting the need for further clinical development of Notch pathway modulators in men with metastatic prostate cancer. Clin Cancer Res; 21(20); 4505–7. ©2015 AACR. See related article by Cui et al., p. 4619
Complications of Multiple Myeloma Therapy, Part 1: Risk Reduction and Management of Peripheral Neuropathy and Asthenia
Authors: Paul G. Richardson, Jacob P. Laubach, Robert L. Schlossman, Constantine Mitsiades, Kenneth Anderson
Journal: Journal of the National Comprehensive Cancer Network (2010)

Peripheral neuropathy (PN) and asthenia (fatigue) occur as both disease- and treatment-related complications in patients with multiple myeloma (MM). Risk factors for treatment-related PN, which has an estimated incidence of 37% to 83% among patients with MM, include therapy duration, dose intensity, cumulative dose, and the presence of preexisting neuropathy. Asthenia is the most common adverse effect of treatment, occurring in approximately 76% to 96% of patients receiving therapy. The severity of PN and asthenia can range from mild to potentially debilitating. These conditions can be dose limiting; they may interfere with optimizing duration of therapy and may also substantially affect patient quality of life. Regular screening and monitoring, combined with patient education and effective management strategies, can reduce the risk of these treatment-related complications, as well as their consequences.
Survey on Use of Palliative Radiotherapy in Hospice Care
Authors: Stephen Lutz, Carol Spence, Edward Chow, Nora Janjan, Stephen Connor
Journal: Journal of Clinical Oncology (2004)

Radiation oncologists and hospice professionals both provide end-of-life care for oncology patients, and little has been written about the interface between these two groups of specialists. Hospice professionals were surveyed to assess the perceived need for palliative radiotherapy in the hospice setting, to investigate factors that limit the access of hospice patients to radiotherapy, and to suggest areas of future collaboration on education, research, and patient advocacy.Members of the National Hospice and Palliative Care Organization (NHPCO) and American Society for Therapeutic Radiology and Oncology jointly authored a questionnaire to investigate the beliefs of hospice professionals toward the use of radiotherapy for oncology patients in hospice. The questionnaire was distributed to all NHPCO member institutions, and the results were compiled and statistically analyzed.Four hundred eighty of more than 1,800 surveyed facilities responded to the questionnaire. The findings suggest that the majority of hospice professionals feel that radiotherapy is important in palliative oncology and that radiotherapy is widely available in the United States. Yet less than 3% on average of hospice patients served by hospices responding to the survey actually received radiotherapy in 2002. The most common barriers to radiotherapy in hospice care include radiotherapy expense, transportation difficulties, short life expectancy, and educational deficiencies between the specialties.Multiple barriers act to limit the use of palliative radiotherapy in hospice care. Finding ways to surmount these obstacles will provide opportunity for improvement in the end-of-life care of cancer patients.
Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response
Authors: Y. N. Kallis, A. J. Robson, J. A. Fallowfield, H. C. Thomas, M. R. Alison, N. A. Wright, R. D. Goldin, J. P. Iredale, S. J. Forbes
Journal: Gut (2010)

<h3>Background and methods</h3> In advanced liver damage, hepatic regeneration can occur through proliferation of a resident hepatic progenitor cell (HPC) population. HPCs are located within a designated niche in close association with myofibroblasts and bone marrow (BM) derived macrophages. Extra-cellular matrix (ECM) laminin invariably surrounds HPCs, but the functional requirement of this matrix-cell association is untested in vivo. Using the collagen Iα1<sup>(r/r)</sup> mouse (r/r), which produces mutated collagen I resistant to matrix metalloproteinase degradation and has an exaggerated fibrotic response to liver injury, we test the relationship between collagen degradation, laminin deposition, and the HPC response. <h3>Results</h3> Chronic fibrotic carbon tetrachloride (CCl<sub>4</sub>) injury can induce a florid HPC response associated with dense laminin deposition. In the recovery phase after chronic CCl<sub>4</sub> injury, r/r mice have a markedly attenuated HPC response compared to wild-types, together with persistence of collagen I and failure to deposit ECM laminin. Similar results were found in r/r mice given the choline-deficient ethionine supplemented diet, another model of the HPC response. In cross-over sex-mismatched BM transplantation (BMT) experiments between r/r mice and wild-types, the blunted HPC response of r/r mice was not rescued by wild-type BMT and likewise not conferred on to wild-type recipients by r/r BMT, demonstrating that the attenuated HPC response in r/r mice is a property intrinsic to the liver. <h3>Conclusion</h3> Failure of ECM remodelling after chronic fibrotic liver injury hinders the ability of the liver to activate HPCs. Laminin-progenitor cell interactions within the HPC niche are a critical for HPC mediated regeneration.
Expression of an Exogenous Human Oct-4 Promoter Identifies Tumor-Initiating Cells in Osteosarcoma
Authors: Padraic P. Levings, Sean V. McGarry, Thomas P. Currie, David M. Nickerson, Steven McClellan, Steven C. Ghivizzani, Dennis A. Steindler, C. Parker Gibbs
Journal: Cancer Research (2009)

We explored the nature of the tumor-initiating cell in osteosarcoma, a bone malignancy that predominately occurs in children. Previously, we observed expression of Oct-4, an embryonal transcriptional regulator, in osteosarcoma cell cultures and tissues. To examine the relationship between Oct-4 and tumorigenesis, cells from an osteosarcoma biopsy (OS521) were stably transfected with a plasmid containing the human Oct-4 promoter driving a green fluorescent protein (GFP) reporter to generate the transgenic line OS521Oct-4p. In culture, only approximately 24% of the OS521Oct-4p cells were capable of activating the transgenic Oct-4 promoter; yet, xenograft tumors generated in NOD/SCID mice contained approximately 67% GFP(+) cells, which selectively expressed the mesenchymal stem cell-associated surface antigens CD105 and ICAM-1. Comparison of the tumor-forming capacity of GFP-enriched and GFP-depleted cell fractions revealed that the GFP-enriched fractions were at least 100-fold more tumorigenic, capable of forming tumors at doses of <300 cells, and formed metastases in the lung. Clonal populations derived from a single Oct-4/GFP(+) cell were capable of forming tumors heterogeneous for Oct-4/GFP expression. These data are consistent with the cancer stem cell model of tumorigenesis in osteosarcoma and implicate a functional link between the capacity to activate an exogenous Oct-4 promoter and tumor formation. This osteosarcoma tumor-initiating cell appears highly prolific and constitutes a majority of the cell population in a primary xenograft tumor, which may provide a biological basis for the particular virulence of this type of cancer.