bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of clinical follow-up and diagnostic testing on intervention for tetralogy of Fallot
Authors: House Aswathy Vaikom , Danford David A , Spicer Robert L , Kutty Shelby 
Published: May 2015

ObjectiveOur purpose was to evaluate yield of tools commonly advocated for surveillance of tetralogy of Fallot (TOF).MethodsAll patients (pts) with TOF, seen at any time from 1/2008 to 9/2013 in an academic cardiology practice were studied. At the first and each subsequent outpatient visit, the use of tools including history and physical (H&P), ECG, Holter (HOL), echocardiogram (Echo), MR or CT (MR-CT) and stress testing (STR) were noted. Recommendations for intervention (INT) and for time to next follow-up were recorded; rationale for each INT with attribution to one or more tools was identified.ResultsThere were 213 pts (mean 11.5 years, 130 male) who had 916 visits, 123 of which (13.4%) were associated with 138 INTs (47 surgical, 54 catheter-mediated, 37 other medical). Recommended follow-up interval was 9.44±6.5 months, actual mean follow-up interval was 11.7 months. All 916 (100%) patient visits had a H&P which contributed to 47.2% of INT decisions. Echo was performed in 652 (71.2%) of visits, and contributed to 53.7% of INTs. MR-CT was obtained in 129 (14.1%) of visits, and contributed to 30.1% of INTs. ECG was applied in 137 (15%) visits, and contributed to 1.6% of INTs. HOL was obtained in 188 (20.5%) visits, and contributed to 11.3% of INTs. STR was performed at 101 (11%) of visits, and contributed to 8.9% of INTs.ConclusionsINTs are common in repaired TOF, but when visits average every 11–12 months, most visits do not result in INT. H&P, Echo and HOL were the most frequently applied screens, and all frequently yielded relevant information to guide INT decisions. STR and MR/CT were applied as targeted testing and in this limited, non-screening role had high relevance for INT. There was low utilisation of ECG and major impact on INT was not demonstrated. Risk stratification in TOF may be possible, and could result in more efficient surveillance and targeted testing.
Biological treatment in systemic juvenile idiopathic arthritis: achievement of inactive disease or clinical remission on a first, second or third biological agent
Authors: Woerner A , Uettwiller F , Melki I , Mouy R , Wouters C , Bader-Meunier B , Quartier P 
Published: May 2015

ObjectivesTo analyse the effect of biological agents (BAs) in terms of achieving inactive disease (ID) or clinical remission (CR) in patients with systemic juvenile idiopathic arthritis (SJIA), to describe effects of switching or discontinuing a BA and to assess the proportion of patients able to maintain ID or CR off steroids and after withdrawing BA therapy.MethodsRetrospective study in a French paediatric rheumatology reference centre using the CEMARA (CEntre des MAladies RAres) register.ResultsSeventy-seven patients were included with a cumulative follow-up of 245.5 patient-years (median 1.1, range 0.5–8.0). On a first BA, ID was achieved in 37 patients, including 1 patient out of 12 patients on etanercept, 26 patients out of 51 on anakinra and 7 out of 10 on canakinumab. One patient on abatacept and two patients on tocilizumab also achieved ID. Switching of BA was common. The switch to a second (n=34), third (n=18) or fourth (n=4) BA resulted in ID in a further 13 patients, either on canakinumab (n=6) or tocilizumab (n=7). At last follow-up, 40 patients were in CR (27 patients off steroids, 5 patients having never received steroid treatment), either on (n=29) or off (n=11) BA.ConclusionsIn this series of patients with SJIA, interleukin-1 inhibitors were associated with a higher proportion of ID than tumour necrosis factor inhibitors when used as first BA. Switching allowed some patients to achieve ID when treated with canakinumab or tocilizumab. CR was eventually achieved in more than half of the patients.
ACPA-positive primary Sjögren's syndrome: true primary or rheumatoid arthritis-associated Sjögren's syndrome?
Authors: Payet J , Belkhir R , Gottenberg J E , Bergé E , Desmoulins F , Meyer O , Mariette X , Seror R 
Published: May 2015

ObjectivesAnticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5–10% of primary Sjögren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA.Patients and methodsACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria.ResultsAt inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5–10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA.ConclusionsMedian term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.
Rho Kinase Inhibitor Fasudil Suppresses the Vasculogenic Mimicry of B16 Mouse Melanoma Cells Both In Vitro and In Vivo
Authors: Xia Yun , Cai Xian-Yi , Fan Ji-Quan , Zhang Li-Ling , Ren Jing-Hua , Chen Jing , Li Zhen-Yu , Zhang Rui-Guang , Zhu Fang , Wu Gang 
Published: May 2015

Abstract
The aim of this study was to investigate the biologic role of the Rho kinase inhibitor fasudil in the vasculogenic mimicry (VM) of B16 mouse melanoma cells. It was previously reported that RhoA plays a critical role in angiogenesis by coordinating endothelial cell cytoskeleton remodeling and promoting endothelial cell motility. Although RhoA has been implicated in the regulation of angiogenesis, little has been described regarding its control of these tumor cell–lined channels. In this study, we established an in vitro model of VM using 3-dimensional cell culturing of mouse B16 melanoma cells and studied VM in vivo by transplanting B16 cells into C57/BL mice. Next, we explored the effect of RhoA and Rho-associated, coiled-coil containing protein kinase (ROCK) on VM formation using the Rho kinase inhibitor fasudil. We provide direct evidence that fasudil leads to reduced vascular-like channels in Matrigel. Additional experiments suggested that fasudil prevents both initial cellular architecture changes and cell migration in vitro. Finally, we provide in-depth evidence for the underlying mechanisms of fasudil-induced VM destruction using the Rho-GTPase agonist lysophosphatidic acid. In vivo studies revealed that fasudil reduced B16 melanoma cell xenograft tumor growth without causing significant toxicity in mice. Fasudil-treated tumors also displayed fewer VM channels. These results suggest that fasudil may be an emerging therapeutic option for targeting cancer VM. Mol Cancer Ther; 14(7); 1582–90. ©2015 AACR.
Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
Authors: Zahonero Cristina , Aguilera Pilar , Ramírez-Castillejo Carmen , Pajares Marta , Bolós Maria Victoria , Cantero Diana , Perez-Nuñez Angel , Hernández-Laín Aurelio , Sánchez-Gómez Pilar , Sepúlveda Juan Manuel 
Published: May 2015

Abstract
Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified ± EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell–related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. Mol Cancer Ther; 14(7); 1548–58. ©2015 AACR.
Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer
Authors: Kazim Sabiha , Malafa Mokenge P. , Coppola Domenico , Husain Kazim , Zibadi Sherma , Kashyap Trinayan , Crochiere Marsha , Landesman Yosef , Rashal Tami , Sullivan Daniel M. , Mahipal Amit 
Published: May 2015

Abstract
Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage–dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Mol Cancer Ther; 14(7); 1570–81. ©2015 AACR.
Abstract 3637: Targeted inhibition of MER tyrosine kinase in the tumor microenvironment decreases tumor growth in a mouse model of breast cancer
Authors: Jacobsen Kristen M. , DeRyckere Deborah , Zhang Weihe , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K. 
Published: May 2015

Abstract
Tumor-associated macrophages (TAMs) and other tumor-infiltrating myeloid-derived cells are known to support tumor growth, proliferation and metastasis. Increased numbers of TAMs are also associated with poor prognosis in many solid tumors, including breast cancer. Previous studies have shown that targeting TAMs, either by re-programming or depletion, is an effective method to reduce solid tumor growth. MER, a receptor tyrosine kinase, is expressed on macrophages. MER-dependent signaling upon recognition and ingestion of apoptotic material (efferocytosis) suppresses proinflammatory cytokine production and increases secretion of immunosuppressive, wound healing cytokines. Recently we have identified MER as a potential therapeutic target in the tumor microenvironment utilizing polyoma middle T (PyVmT) orthotopic and transgenic models of breast cancer in Mertk-/- mice. Genetic deletion of MER in the tumor microenvironment led to a reduction in tumor growth, as well as increased proinflammatory cytokines and decreased IL-10 production.
To further investigate the utility of MER inhibition in the tumor microenvironment as a therapeutic strategy, the efficacy of a first in class MER-selective, orally bioavailable, small molecule tyrosine kinase inhibitor (UNC TKI) was evaluated in immunocompetent C57Bl/6 mice implanted orthotopically with PyVmT mammary gland tumor cells. These PyVmT tumors cells do not express MER, AXL or TYRO3. Treatment with UNC TKI inhibited phosphorylation of MER in mouse macrophages in vitro, but did not affect survival of macrophages or MER-negative PyVmT tumor cells. However, after four weeks of daily treatment with UNC TKI, primary tumor growth was reduced two-fold compared to vehicle-treated tumor bearing mice. Serum IL-10 and IL-4 levels were reduced by 20% and 30%, respectively, in UNC TKI treated tumor-bearing mice compared to vehicle-treated tumor-bearing mice. Taken together, these data suggest that MER inhibition in the tumor microenvironment reduces tumor growth by altering the immunosuppressive environment and stimulating anti-tumor immunity. Moreover, these data validate UNC TKI as a promising strategy for immune-mediated treatment of breast cancer.
Citation Format: Kristen M. Jacobsen, Deborah DeRyckere, Weihe Zhang, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham. Targeted inhibition of MER tyrosine kinase in the tumor microenvironment decreases tumor growth in a mouse model of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2014-3637
Abstract 3774: Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake
Authors: Lee Chen-Ting , Blackley Aaron , Landon Chelsea , Spasojevic Ivan , Kirkpatrick John P. , Dewhirst Mark W. 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. Current standard treatment for GBM following maximum safe resection includes temozolomide (TMZ) with concurrent radiotherapy. Despite the improvement of survival by TMZ and radiation, the overall prognosis remains poor for GBM patients. This is partially attributed to drug resistance. Expression of DNA repair protein O6-methylguanine methyltransferase (MGMT) in gliomas confers TMZ resistance and a worse prognosis. Therefore, development of novel therapy to suppress MGMT expression and overcome TMZ resistance is highly desired. Hyperthermia has been shown to increase TMZ sensitivity in melanoma and this provides a good rationale to evaluate whether hyperthermia overcomes TMZ resistance in glioblastoma cells.
In this study, we investigated the effect of hyperthermia treatment (43
°C) on TMZ sensitivity of four human glioblastoma cell lines using clonogenic assays. Our results showed that hyperthermia treatment increased TMZ-induced cell death in TMZ-resistant glioma cells, but had no additional beneficial effect in the TMZ-sensitive cells. Hyperthermia in combination with radiation further overcame TMZ resistance. To study the molecular targets, we found that hyperthermia downregulated MGMT expression through increasing proteasome-mediated MGMT degradation, which can be reversed by the proteasome inhibitor bortezomib. Hyperthermia had no effects on p53 expression and MGMT promoter methylation which was responsible for MGMT gene silencing. In addition, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed an increase of TMZ and its downstream product 5-aminoimidazole-4-carboxamide (AIC) in hyperthermia-treated cells, indicating an increase of TMZ drug uptake and breakdown.
In conclusion, these results suggest that hyperthermia overcomes MGMT-mediated resistance of glioblastoma cell lines to TMZ and increases TMZ drug uptake. This study suggests a potential benefit of using hyperthermia in the treatment of GBM, particularly those with more adverse prognosis.
This work was supported by Debrule Research Fund.
Citation Format: Chen-Ting Lee, Aaron Blackley, Chelsea Landon, Ivan Spasojevic, John P. Kirkpatrick, Mark W. Dewhirst. Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3774. doi:10.1158/1538-7445.AM2014-3774
Abstract 3885: ITGA6 (CD49F) is directly regulated by hypoxia-inducible factors
Authors: Peacock Danielle L. , Schwab Luciana P. , Seagroves Tiffany N. 
Published: May 2015

Abstract
Introduction: In response to hypoxic stress, tumors must adapt to the hostile microenvironment by regulating angiogenesis, cellular metabolism, cell survival and motility. The alpha subunits of the Hypoxia-Inducible Factors (HIF-1α and HIF-2α) are oxygen-responsive, master regulators of the hypoxic response. Over-expression of HIF-1α independently correlates with decreased survival of breast cancer patients, and a hypoxic core gene signature is enriched in triple negative breast cancers (TNBC) and HER2+ cancers relative to luminal tumors (ER+). In a variety of solid tumors, HIF-1α or HIF-2α also directly promotes tumor initiating cell (TIC) activity. Methods: Mammary tumor epithelial cells (MTECs) were established from late-stage tumors of MMTV-PyMT+; Hif1α floxed mice (which model ER-negative, luminal-like tumors), and exposed to either Adenovirus-β-gal or -Cre to create wild-type (WT) and knock-out (KO) cells, respectively. MDA-MB-231 cells (a model of TNBC) were generated in which either HIF1A or HIF2A or both genes (DKD) were knocked down (KD) via shRNA. Results: When PyMT+ MTECs were transplanted into female recipients, HIF-1 deletion reduced primary tumor growth by 60%, lung metastasis by 90% and TIC activity by &gt;35-fold (Schwab et al. 2012). The expression of cell surface markers routinely used to enrich for TICs was assayed in PyMT+ and MDA-MB-231 cells. ITGA6 mRNA and CD49f protein expression were significantly decreased in response to HIF deletion at both normoxia and hypoxia. ChIP assays showed that either HIF-1 or HIF-2 bind to at least two HREs identified within the ITGA6 promoter. When WT PyMT tumors were sorted to enrich for CD49fhi cells, limiting dilution transplantation confirmed that TIC activity was increased relative to CD49low cells. Finally, data mining of breast cancer patient repositories showed that ITGA6 mRNA expression is independently and inversely correlated with overall and recurrence free survival. Conclusions: CD49f is a direct transcriptional target of HIF-1/HIF-2. Because CD49f is known to enrich for breast TICs, we suggest that HIF-dependent regulation of ITGA6 expression contributes at least partially to HIFs promotion of TIC activity in ER-negative breast cancers.
Citation Format: Danielle L. Peacock, Luciana P. Schwab, Tiffany N. Seagroves. ITGA6 (CD49F) is directly regulated by hypoxia-inducible factors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3885. doi:10.1158/1538-7445.AM2014-3885
Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors
Authors: Lindström Lisa , Villoutreix Bruno O. , Lehn Sophie , Hellsten Rebecka , Nilsson Elise , Crneta Enisa , Olsson Roger , Alvarado-Kristensson Maria 
Published: May 2015

Abstract
In addition to its cytosolic function, γ-tubulin is a chromatin-associated protein. Reduced levels of nuclear γ-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased γ-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of γ-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with γ-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogues, such citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or γ-tubulin, and increased by reduced levels of either RB1 or γ-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to γ-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a γ-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of γ-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes.
Implications: The in vivo antitumorigenic activity of γ-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects. Mol Cancer Res; 13(7); 1073–82. ©2015 AACR.