tbuckley/cabot-search huggingface dataset:
Targeting survivin and p53 in pediatric acute lymphoblastic leukemia
Authors: J W Tyner, A M Jemal, M Thayer, B J Druker, B H Chang
Journal: Leukemia (2011)

Despite advances in treatment and outcomes for patients with pediatric acute lymphoblastic leukemia (ALL), there continue to be subsets of patients who are refractory to standard chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. RNA interference technology has identified survivin as a potential therapeutic target. Survivin, a member of the inhibitor of apoptosis (IAP) proteins and chromosome passenger complex, is expressed in hematologic malignancies and overexpressed in relapsed pediatric ALL. Our studies show that survivin is uniformly expressed at high levels in multiple pediatric ALL cell lines. Furthermore, silencing of survivin expression in pediatric ALL cell lines as well as primary leukemic blasts reduces viability of these cells. This includes cell lines derived from patients with relapsed disease featuring cytogenetic anomalies such as t(12;21), Philadelphia chromosome t(9;22), t(1;19) as well as a cell line carrying t(17;19) from a patient with de novo ALL. Furthermore, inhibition of survivin increases p53-dependent apoptosis that can be rescued by inhibition of p53. Finally, a screen of randomly selected primary patient samples confirms that survivin-specific small interfering RNA and survivin-targeted drug, YM155, effectively reduce viability of leukemic blasts.
6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance
Authors: Natalia Issaeva, Huw D. Thomas, Tatjana Djurenovic, Janneke E. Jaspers, Ivaylo Stoimenov, Suzanne Kyle, Nicholas Pedley, Ponnari Gottipati, Rafal Zur, Kate Sleeth, Vicky Chatzakos, Evan A. Mulligan, Cecilia Lundin, Evgenia Gubanova, Ariena Kersbergen, Adrian L. Harris, Ricky A. Sharma, Sven Rottenberg, Nicola J. Curtin, Thomas Helleday
Journal: Cancer Research (2010)

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy.
Synovial membrane immunohistology in early untreated juvenile idiopathic arthritis: differences between clinical subgroups
Authors: Sorcha Finnegan, Susan Clarke, David Gibson, Catherine McAllister, Madeleine Rooney
Journal: Annals of the Rheumatic Diseases (2011)

Objective Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of inflammatory disorders, within which there are a number of clinical subgroups. Diagnosis and assignment to a particular subgroup can be problematical and more concise methods of subgroup classification are required. This study of the synovial membrane characterises the immunohistochemical features in early untreated, newly diagnosed JIA and compares findings with disease subgroup at 2 years. Methods 42 patients with newly diagnosed untreated JIA underwent synovial biopsy before the administration of steroids or disease-modifying antirheumatic drugs. Patients were classified as either polyarticular, persistent oligoarticular or extended-to-be oligoarticular. The location and semiquantitative analysis of T-cell subsets, B cells, macrophages and blood vessels were determined using immunohistochemistry. Results Synovial hyperplasia varied significantly between the three groups (p&lt;0.0001). There was a significant difference in the CD3 T-cell population between the three groups (p=0.004) and between the extended-to-be and persistent group (p=0.032). CD4 expression was significantly higher in the poly and extended-to-be oligo groups (p=0.002), again the extended-to-be group had more CD4 T cells than the persistent group (p=0.008). B-cell infiltrates were more marked in the polyarticular group and were significantly higher in the extended-to-be group compared with the persistent group (p=0.005). Vascularisation was more pronounced in the polyarticular and extended-to-be oligoarticular groups, the extended-to-be group had significantly more vascularisation than the persistent group (p=0.0002). Conclusions There are significant differences in the histomorphometric features of synovial tissue between patient subgroups. Immunohistological examination of synovial membrane biopsies may provide further insight into early disease processes in JIA.
Short-Term Treatment With Anti-CD3 Antibody Reduces the Development and Progression of Atherosclerosis in Mice
Authors: Sabine Steffens, Fabienne Burger, Graziano Pelli, Yann Dean, Greg Elson, Marie Kosco-Vilbois, Lucienne Chatenoud, François Mach
Journal: Circulation (2006)

Background— Atherosclerosis is a chronic inflammatory disease of the large arteries that is the primary cause of heart disease and stroke. Anti-CD3–specific antibodies suppress immune responses by antigenic modulation of the CD3 antibody/T-cell receptor complex. Their unique capacity to restore self-tolerance in a mouse model of diabetes and, importantly, in patients with recent-onset type 1 diabetes involves transforming growth factor-β–dependent mechanisms via expansion and/or activation of regulatory T cells. We hypothesized that treatment with anti-CD3–specific antibodies might inhibit atherosclerosis development and progression in mice. Methods and Results— Low-density lipoprotein receptor–deficient mice were fed a high-cholesterol diet for 13 or 24 weeks. Anti-CD3 antibody was administered on 5 consecutive days beginning 1 week before or 13 weeks after the high-cholesterol diet was initiated, respectively. Control mice were injected in parallel with phosphate-buffered saline. Anti-CD3 antibody therapy reduced plaque development when administered before a high-cholesterol diet and markedly decreased lesion progression in mice with already established atherosclerosis. We found increased production of the antiinflammatory cytokine transforming growth factor-β in concanavalin A–stimulated lymph node cells and enhanced expression of the regulatory T-cell marker Foxp3 in spleens of anti-CD3 antibody–treated mice. A higher percentage of apoptotic cells within the plaques of anti-CD3 antibody–treated mice was also observed. Conclusions— Altered disease progression, combined with the emergence of this particular cytokine pattern, indicates that short-term treatment with an anti-CD3 antibody induces a regulatory T-cell phenotype that restores self-tolerance in a mouse model of atherosclerosis.
Connexin 37 Limits Thrombus Propensity by Downregulating Platelet Reactivity
Authors: Anne Angelillo-Scherrer, Pierre Fontana, Laurent Burnier, Isabelle Roth, Rocco Sugamele, Anne Brisset, Sandrine Morel, Séverine Nolli, Esther Sutter, Alexandra Chassot, Claude Capron, Delphine Borgel, François Saller, Marc Chanson, Brenda R. Kwak
Journal: Circulation (2011)

Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed gap junctional intercellular communication.In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the Cx37 gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine Cx37(-/-) platelets or in murine Cx37(+/+) and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in Cx37(-/-) platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37-1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37-1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37-1019C channels for neurobiotin.We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.
The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo.
Authors: B Johnston, T B Issekutz, P Kubes
Journal: The Journal of Experimental Medicine (1996)

A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.
Impaired potassium-induced dilation in hypertensive rat cerebral arteries does not reflect altered Na+,K(+)-ATPase dilation.
Authors: J G McCarron, W Halpern
Journal: Circulation Research (1990)

We have recently demonstrated that K(+)-induced dilation of cerebral resistance-sized vessels has two independent components, only one of which seemed sodium pump dependent. In our current investigation, potassium-induced dilation of spontaneous tone was compared in cerebral arteries from normotensive Wistar-Kyoto rats and age-matched stroke-prone spontaneously hypertensive rats. Branches of the posterior cerebral artery were cannulated and pressurized, and these vessels developed spontaneous tone. After a 5-minute period in K(+)-free physiological saline solution, K+ was increased in 1-mM increments to a final concentration of 15 mM. In the normotensive arteries, K+ concentrations between 0 and 5 mM K+ resulted in dilations that had a transient (sodium pump-dependent) component, and K+ concentrations in excess of 7 mM produced dilations that lacked a transient (sodium pump-independent) component. Similar branches from the hypertensive rat also responded with transient dilations to K+ (less than 5 mM), and these were significantly greater at 3 mM K+. However, the maintained dilations to K+ (greater than 7 mM), noted in preparations from Wistar-Kyoto rats, were absent in seven of eight preparations. Thus, the impaired dilations, in the hypertensive vessels, to K+ described here is a consequence of altered function of some sodium pump-independent component rather than altered Na+,K(+)-ATPase activity.
Laparoendoscopic Single-Site Upper Urinary Tract Surgery: Assessment of Postoperative Complications and Analysis of Risk Factors
Authors: Francesco Greco, Luca Cindolo, Riccardo Autorino, Salvatore Micali, Robert J. Stein, Giampaolo Bianchi, Caterina Fanizza, Luigi Schips, Paolo Fornara, Jihad Kaouk
Journal: European Urology (2011)
Antioxidative, Antinitrative, and Vasculoprotective Effects of a Peroxisome Proliferator–Activated Receptor-γ Agonist in Hypercholesterolemia
Authors: Ling Tao, Hui-Rong Liu, Erhe Gao, Zhi-Ping Teng, Bernard L. Lopez, Theodore A. Christopher, Xin-Liang Ma, Ines Batinic-Haberle, Robert N. Willette, Eliot H. Ohlstein, Tian-Li Yue
Journal: Circulation (2003)

Peroxisome proliferator-activated receptor (PPAR) signaling pathways have been reported to exert anti-inflammatory effects and attenuate atherosclerosis formation. However, the mechanisms responsible for their anti-inflammatory and antiatherosclerotic effects remain largely unknown. The present study tested the hypothesis that a PPARgamma agonist may exert significant endothelial protection by antioxidative and antinitrative effects.Male New Zealand White rabbits were randomized to receive a normal (control) or a high-cholesterol diet and treated with vehicle or rosiglitazone (a PPARgamma agonist) 3 mg x kg(-1) x d(-1) for 5 weeks beginning 3 weeks after the high-cholesterol diet. At the end of 8 weeks of a high-cholesterol diet, the rabbits were killed, and the carotid arteries were isolated. Bioactive nitric oxide was determined functionally (endothelium-dependent vasodilatation) and biochemically (the phosphorylation of vasodilator-stimulated phosphoprotein, or P-VASP). Vascular superoxide production, PPARgamma, gp91phox, and inducible nitric oxide synthase (iNOS) expression, and vascular ONOO- formation were determined. Hypercholesterolemia caused severe endothelial dysfunction and reduced P-VASP, despite a marked increase in iNOS expression and total NOx production. Treatment with rosiglitazone enhanced PPARgamma expression, improved endothelium-dependent vasodilatation, preserved P-VASP, suppressed gp91phox and iNOS expression, reduced superoxide and total NOx production, and inhibited nitrotyrosine formation.The PPARgamma agonist rosiglitazone exerted a significant vascular protective effect in hypercholesterolemic rabbits, most likely by attenuation of oxidative and nitrative stresses. The endothelial protective effects of PPARgamma agonists may reduce leukocyte accumulation in vascular walls and contribute to their antiatherosclerotic effect.
The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin–associated hemolytic uremic syndrome in humans and mice
Authors: Tania N. Petruzziello-Pellegrini, Darren A. Yuen, Andrea V. Page, Sajedabanu Patel, Anna M. Soltyk, Charles C. Matouk, Dennis K. Wong, Paul J. Turgeon, Jason E. Fish, J.J. David Ho, Brent M. Steer, Vahid Khajoee, Jayesh Tigdi, Warren L. Lee, David G. Motto, Andrew Advani, Richard E. Gilbert, S. Ananth Karumanchi, Lisa A. Robinson, Phillip I. Tarr, W. Conrad Liles, James L. Brunton, Philip A. Marsden
Journal: Journal of Clinical Investigation (2012)

Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastrointestinal infection with E. coli O157:H7, which produces Shiga toxins (Stx) that cause hemolytic anemia, thrombocytopenia, and renal injury. Stx-mediated changes in endothelial phenotype have been linked to the pathogenesis of HUS. Here we report our studies investigating Stx-induced changes in gene expression and their contribution to the pathogenesis of HUS. Stx function by inactivating host ribosomes but can also alter gene expression at concentrations that minimally affect global protein synthesis. Gene expression profiling of human microvascular endothelium treated with Stx implicated a role for activation of CXCR4 and CXCR7 by their shared cognate chemokine ligand (stromal cell–derived factor-1 [SDF-1]) in Stx-mediated pathophysiology. The changes in gene expression required a catalytically active Stx A subunit and were mediated by enhanced transcription and mRNA stability. Stx also enhanced the association of CXCR4, CXCR7, and SDF1 mRNAs with ribosomes. In a mouse model of Stx-mediated pathology, we noted changes in plasma and tissue content of CXCR4, CXCR7, and SDF-1 after Stx exposure. Furthermore, inhibition of the CXCR4/SDF-1 interaction decreased endothelial activation and organ injury and improved animal survival. Finally, in children infected with E. coli O157:H7, plasma SDF-1 levels were elevated in individuals who progressed to HUS. Collectively, these data implicate the CXCR4/CXCR7/SDF-1 pathway in Stx-mediated pathogenesis and suggest novel therapeutic strategies for prevention and/or treatment of complications associated with E. coli O157:H7 infection.
Yin and Yang
Authors: Amit X. Garg, Chirag R. Parikh
Journal: Journal of the American Society of Nephrology (2009)

Patients with chronic kidney disease (CKD) have high rates of acute kidney injury (AKI). In the other direction, some AKI does not resolve and a hospitalized patient may be left with CKD. However, most of the time an AKI episode is self-limited, and kidney function returns to a level that predated the acute injury. Two questions then surround the natural history of this latter type of AKI when a patient is discharged from the hospital: Did the AKI identify a group of patients who failed a “stress test,” patients predestined to have high rates of mortality and morbidity including CKD? Did the injury damage the kidney in such a way that there will be a faster rate of decline toward advanced CKD?

Both questions are important for clinical care. The former question guides patient counseling and follow-up and emphasizes the outpatient testing and use of interventions proven to prevent CKD. The latter question also emphasizes the importance of preventing AKI and has particular implications for any intervention that prevents AKI at a high cost or with a possible risk of toxicity. In the current issue of JASN, Ishani and …
Ethnic variation in respiratory morbidity and lung function in childhood.
Authors: I D Johnston, J M Bland, H R Anderson
Journal: Thorax (1987)

In a population of 5689 primary schoolchildren there were few important differences between children of European (n = 5287), African (n = 198), and Indian origin (n = 204) in the prevalence of a history of past respiratory illnesses or current respiratory symptoms. The reported 12 month period prevalence of the symptom "ever wheezy" was 15%, 18%, and 17% respectively in the three ethnic groups (differences not significant). In a subsample of 973 European, 47 African, and 40 Indian children forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were significantly lower by 12% and 13% in Africans and by 8% and 9% in Indians than in Europeans after adjustment to the group mean height of 128 cm. No significant ethnic variation was found for forced mid expiratory flow, FEV1/FVC, or mean transit time. Since the lung function studies were performed on a sample from a large population with little variation in respiratory morbidity, the differences are likely to reflect human biological differences. Separate prediction equations need to be developed for the different ethnic groups in childhood.
Altered Microenvironment Promotes Progression of Preinvasive Breast Cancer: Myoepithelial Expression of αvβ6 Integrin in DCIS Identifies High-risk Patients and Predicts Recurrence
Authors: Michael D. Allen, Gareth J. Thomas, Sarah Clark, Marwa M. Dawoud, Sabarinath Vallath, Sarah J. Payne, Jennifer J. Gomm, Sally A. Dreger, Sarah Dickinson, Dylan R. Edwards, Caroline J. Pennington, Ivana Sestak, Jack Cuzick, John F. Marshall, Ian R. Hart, J. Louise Jones
Journal: Clinical Cancer Research (2013)

This study investigated the functional and clinical significance of integrin αvβ6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS).Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of αvβ6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without αvβ6 expression, were used to measure the effect of αvβ6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFβ signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography.Expression of αvβ6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of αvβ6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of αvβ6-positive myoepithelial cells is dependent on TGFβ-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway.These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of αvβ6 on myoepithelial cells generates a tumor promoter function through TGFβ upregulation of MMP-9. These data suggest that expression of αvβ6 may be used to stratify patients with DCIS.