tbuckley/cabot-search huggingface dataset:
Perioperative docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophageal and gastric adenocarcinoma: Safety and response results from a multicenter phase II trial.
Authors: L. E. Ferri, S. Ades, T. Alcindor, V. Marcus, M. Hickeson, G. Artho, M. R. Chasen, M. P. Thirlwell
Journal: Journal of Clinical Oncology (2010)

4075 Background: Docetaxel, cisplatin, and 5FU (DCF) has been shown to be an effective regimen for metastatic adenocarcinoma (ADC) of the foregut. We have completed accrual to a phase II trial of perioperative DCF in operable locally advanced ADC of the esophagus, gastro-esophageal junction (GEJ), and stomach with a focus on safety and tolerability, response, and resectability. Methods: Following staging with EUS, CT, PET, and diagnostic laparoscopy, eligible pts with ADC of the foregut (AJCC stage II or greater) received DCF (docetaxel 75 mg/m2 IV day 1, cisplatin 75 mg/m2 IV day 1, 5-FU 750 mg/m2 CIV for 120 hrs, every 3 weeks) for 3 cycles prior to and 3 cycles after resection. Primary outcome was complete resection (R0) with target accrual of 43 pts at 2 centers. Results: From 3/07-8/09, 43 pts (64 [24-80] years: M 39/F 4) with ADC (cN0/1 = 9/34) of the esophagus (11), GEJ (25), and stomach (7) were enrolled. In the pre-op phase, 37/43 (86%) completed all 3 cycles. There were 23 grade 3 toxicities (neutropenia [3], fatigue [3], and mucositis [8]) in 16 pts, and 5 grade 4 toxicities (neutropenia [3], myocardial infarction [1] and sepsis [1]) during the pre-op phase. CT after pre-op cycles showed a 36% decrease in tumour length. PET showed a 49 % decrease in maxSUV, with 26/34 (74%) achieving metabolic response (> 35 % reduction in maxSUV). Surgery was performed in 41/43 (95%) by esophagectomy (34) or gastrectomy (7). There were major post-op complications (Clavien grade > 2) in only 3/41 patients (all leaks) and no post-op deaths. Complete resection (R0) was achieved in all 41 pts with pathologic CR in 3/41 (7%), a good response (> 50% tumor regression) in 16 (39%), and moderate response (25%-50% regression) in 11 (27%). Of the 36 pts who are sufficiently post-op to have completed adjuvant treatment, 20 (55%) received all 3 cycles. At follow-up of 13.5 (5-28) months, 29/43 (67%) remain disease-free. 7/43 (16%) have died of disease progression. Conclusions: Perioperative DCF is a tolerable and highly effective regimen for the peri-operative treatment of locally advanced adenocarcinoma of the esophagus and stomach. No significant financial relationships to disclose.
Abstract 1088: Efficient detection of germ cell cancer related miRNAs in serum using the TaqMan miRNA ABC purification bead kit in combination with the Taqman advanced miRNA assays
Authors: Leendert HJ Looijenga, Ton Van Agthoven, Ad Gillis
Journal: Cancer Research (2016)

Abstract Malignant germ cell tumors, also known as germ cell cancers (GCC), are the most frequent cancer in young Caucasian males, with an increasing incidence during the last decades. They are clinically and histologically subdivided into seminomas and nonseminomas. The last can be composed of different elements, including embryonal carcinoma (the stem cell component), teratoma (TE) (somatic lineage) as well as yolk sac tumor (YST) and choriocarcinoma (CHC) (extra-embryonic lineages). The currently used serum markers, informative for both diagnosis as well as follow-up are AFP and hCG, predominantly indicative for the presence of the YST and CHC components. Recently, we reported that a selected set of miRNAs are highly expressed in all histological elements of GCC, with the exception of TE, including the miR 371-3 cluster. In addition to the presence in the primary cancers, they can also be identified in the serum of patients with such a malignancy, outperforming the classical markers AFP and hCG (Gillis and Rijlaarsdam et al. Molec. Oncol. 2013; Rijlaarsdam et al. Andrology, 2015). Here we demonstrate the power of the TaqMan Advanced miRNA Assays (PN 478007, Applied Biosystems) in combination with the use of the TaqMan miRNA ABC Purification Kit (PN 4473087, Applied Biosystems), starting with 50 μL human serum. The protocol includes polyadenylation of the miRNA targets at the 3’ end, followed by an adapter ligation at the 5’ end. Universal forward and reverse primers are used for amplification, followed by detection using the Applied Biosystems 7500 RealTime PCR System. Quality controls were added using dilution experiments of the cell lines, also included as inter-plate control, as well as for cDNA synthesis and RT-PCR efficiency. The non-human spike-ins ath-miR159a and cel-miR-39-3p were added as exogenous controls, while hsa-miR-30b-5p was used as endogenous control for normalization (reference). In total 30 GCC-related sera as well as 10 normal controls proved the informativity as well as efficiency of the developed pipeline in a standardized laboratory setting. Citation Format: Leendert HJ Looijenga, Ton Van Agthoven, Ad Gillis. Efficient detection of germ cell cancer related miRNAs in serum using the TaqMan miRNA ABC purification bead kit in combination with the Taqman advanced miRNA assays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1088.
Des infections à Salmonella enterica de sérotype Oranienburg associées à un fromage de production locale au Tyrol
Authors: F Allerberger, P Kreidl, M P Dierich, E Klingsbichel, D Jenewein, C Mader, D Khaschabi, M Schönbauer, C Berghold
Journal: Eurosurveillance (2000)

Seize cas d’infections a Salmonella enterica de serotype Oranienburg ont ete detectes entre le 10 aout et le 29 septembre 1999 au Tyrol (Autriche). Dix d’entre eux presentaient une diarrhee sanglante et six etaient porteurs asymptomatiques. A l’issue des interviews realisees aupres de 11 des 16 cas, l’epidemie a ete associee a une ferme alpine et a la consommation d’un fromage au lait de vache produit localement. Les analyses microbiologiques ont revele la presence de S. Oranienburg dans le fromage et le poulailler. Dans cette ferme, le poulailler etait proche de la zone de production du fromage et les poulets y circulaient librement.
Prevalence and Epitope Specificity of Non-Neutralizing Antibodies in Haemophilia A Patients without Inhibitors Using a Multiplex x-MAP Technology.
Authors: Aurélien Lebreton, Priscilla Lapalud, Hervé Chambost, Christine Biron-Andréani, Elodie Boissier, Catherine Pouymayou, Alain Marquès-Verdier, Claude Granier, Jean-Francois Schved, Géraldine Lavigne-Lissalde
Journal: Blood (2009)
Outcome of Head Start III multinational protocol for newly diagnosed central nervous system (CNS) primitive neuroectodermal tumors (pnet) of young children.
Authors: T. B. Davidson, L. Ji, K. Haley, G. Dhall, J. P. Grimm, F. H. Gilles, S. L. Gardner, J. C. Allen, A. A. Bedros, M. M. Etzl, R. S. Olshefski, A. Cornelius, J. Torkildson, G. A. Kennedy, J. R. Fangusaro, S. R. Rassekh, M. J. Joyce, S. J. Bertolone, R. Sposto, J. L. Finlay
Journal: Journal of Clinical Oncology (2011)

9519 Background: Outcomes for children with newly diagnosed CNS PNET remain poor compared to medulloblastoma. Head Start I and II improved survival for these patients, demonstrating a role for intensified induction chemotherapy followed by autologous hematopoietic cell rescue (AuHCR). Head Start III was developed to further improve outcomes for these children. Methods: Between April 2003 and December 2009, 52 children with newly diagnosed CNS PNET were enrolled among 22 institutions. Patients were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, and high dose methotrexate in cycles 1, 3, and 5; vincristine, cyclophosphamide, oral etoposide and temozolomide in cycles 2 and 4) followed by (in children without tumor progression) consolidation with myeloablative chemotherapy (thiotepa, carboplatin and etoposide) with AuHCR. Induction Regimen D was replaced midway through the study by D2, with reduced cyclophosphamide and methotrexate doses due to toxicities. Patients with residual tumor at end of induction and patients older than 6 years were to receive irradiation (RT) after consolidation. Results: The 3 year event-free (EFS) and overall survival (OS) rates (± SE) for all patients were 35 ± 7%. The 3 year EFS and OS (± SE) for the 3 subtypes, non-pineal supratentorial (ST) PNET, pineal PNET and other PNET were 52 ± 10 % and 52 ±11%, 10 ± 9% and 10 ± 9%, 28 ± 11% and 29 ± 13%, respectively (p=0.027 and p=0.011). The 2 year OS (± SE) for patients treated with Regimens D and D2 were 55 ± 10% and 24 ± 10%, respectively. In multivariate Cox regression analyses, disease subtype (p=0.045) and regimen (p=0.014) were the only significant predictors of EFS after adjusting for metastatic status, initial extent of resection, age and sex. RT-free EFS at 3 years was 29 ±7%. Conclusions: Reduction of cyclophosphamide and methotrexate in Induction Regimen D2 produced inferior outcomes. Patients with ST non-pineal PNET have a superior outcome to those with PNET of other tumor sites or subtypes. 29% of children survive event-free without irradiation. Innovative strategies need to be incorporated to improve further the outcome for such high-risk children.
Abstract 3830: Synthesis and anticancer activity of novel prodigiosin analogs
Authors: Xiaobing Tian, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Abstract We recently reported that Prodigiosin is a potent p53 pathway restoring small molecule that acts through p73 and by interfering with p73:mutant p53 protein interaction (Hong et al., Cancer Research, 2014). Prodigiosin is the parent member of the tripyrrole alkaloid family of natural products that shows potent anti-cancer activity against tumors with mutated p53. To improve pharmacological and medicinal properties of Prodigiosin including p73 induction and restoration of the p53 pathway in tumors with mutated p53, two new series of analogs were synthesized. We introduced carboxylic group substituents either directly on the C-ring or on the side-chain of the C-ring. Carboxylic group allowed for further derivatization of Prodigiosin. A number of new analogs have been prepared and tested for their anticancer activity. Preliminary biological activity assay showed that new compounds inhibited cancer cell proliferation from 0.1 μM to 10 μM both in p53 mutated SW480 and wild-type HCT116 colorectal cancer cell lines. Some of the newly synthesized compounds can induce p53 transcriptional reporter activity in p53 mutated SW480 colorectal cancer cells. Our ongoing experiments are focused on the signaling mechanism of apoptosis induced by the new analogs, identification of molecular targets of the compounds, and in vivo studies of Prodigiosin analogues as single agents or in combination with chemotherapy or targeted therapy. Citation Format: Xiaobing Tian, Shengliang Zhang, Wafik S. El-Deiry. Synthesis and anticancer activity of novel prodigiosin analogs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3830.
miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1)
Authors: Jaekwang Kim, Fabienne C. Fiesel, Krystal C. Belmonte, Roman Hudec, Wang-Xia Wang, Chaeyoung Kim, Peter T. Nelson, Wolfdieter Springer, Jungsu Kim
Journal: Molecular Neurodegeneration (2016)

Loss-of-function mutations in PINK1 and PARKIN are the most common causes of autosomal recessive Parkinson's disease (PD). PINK1 is a mitochondrial serine/threonine kinase that plays a critical role in mitophagy, a selective autophagic clearance of damaged mitochondria. Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Therefore, identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD. Although post-translational stabilization of PINK1 upon mitochondrial damage has been extensively studied, little is known about the regulation mechanism of PINK1 at the transcriptional or translational levels. Here, we demonstrated that microRNA-27a (miR-27a) and miR-27b suppress PINK1 expression at the translational level through directly binding to the 3′-untranslated region (3′UTR) of its mRNA. Importantly, our data demonstrated that translation of PINK1 is critical for its accumulation upon mitochondrial damage. The accumulation of PINK1 upon mitochondrial damage was strongly regulated by expression levels of miR-27a and miR-27b. miR-27a and miR-27b prevent mitophagic influx by suppressing PINK1 expression, as evidenced by the decrease of ubiquitin phosphorylation, Parkin translocation, and LC3-II accumulation in damaged mitochondria. Consequently, miR-27a and miR-27b inhibit lysosomal degradation of the damaged mitochondria, as shown by the decrease of the delivery of damaged mitochondria to lysosome and the degradation of cytochrome c oxidase 2 (COX2), a mitochondrial marker. Furthermore, our data demonstrated that the expression of miR-27a and miR-27b is significantly induced under chronic mitophagic flux, suggesting a negative feedback regulation between PINK1-mediated mitophagy and miR-27a and miR-27b. We demonstrated that miR-27a and miR-27b regulate PINK1 expression and autophagic clearance of damaged mitochondria. Our data further support a novel negative regulatory mechanism of PINK1-mediated mitophagy by miR-27a and miR-27b. Therefore, our results considerably advance our understanding of PINK1 expression and mitophagy regulation and suggest that miR-27a and miR-27b may represent potential therapeutic targets for PD.
VALIDATION OF THE GLOBAL RISK CLASSIFICATION FOR PREDICTION OF LONG-TERM OUTCOME AFTER UNPROTECTED LEFT MAIN CORONARY REVASCULARIZATION
Authors: Yong Kyu Park, Duk-Woo Park, Woo Seok Lee, Chang Hee Kwon, Gyung-Min Park, Hae-Geun Song, Jung-Min Ahn, Won-Jang Kim, Jong-Young Lee, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2012)
Outcomes related to biomarkers in organ preservation for patients with advanced squamous cell carcinoma of the oral cavity (SCCOC).
Authors: F. P. Worden, G. T. Wolf, J. Lee, C. R. Bradford, D. B. Chepeha, M. Prince, A. Eisbruch, J. Moyer, S. Urba, T. Carey
Journal: Journal of Clinical Oncology (2010)

e16009 Background: A previous trial at the University of Michigan was conducted in SCCOC pts using 1 cycle of induction chemotherapy (IC) to select pts for organ preservation. Here we report outcomes related to biomarkers. Methods: Pts with advanced SCCOC received one cycle of cisplatin and 5-fluorouracil. Those who achieved 50% reduction of their tumor received concurrent chemoradiation (CRT); those with less than 50% response underwent salvage surgery. CRT consisted of 70 Gy (2 Gy fraction daily × 7 weeks) with concurrent cisplatin 100 mg/m2 every 3 weeks × 3 cycles. After CRT, pts with a complete histologic response received 2 cycles of paclitaxel 175 mg/m2; those with residual tumor had salvage surgery. Biopsies were obtained and assessed for HPV, p16, p53 mutation, Bcl-xL, and epidermal growth factor receptor (EGFR). Results: Between 7/24/2000 and 3/29/2004, 19 pts were enrolled (11 men; 8 women); 10 were responders to IC, but only 5/10 responded to CRT. 7/19 (37%) were alive at 3 yrs and 4/19 (21%) were alive at ≥ 6 yrs. Three of thirteen tested positive for HPV/p16 and 2/3 were long term survivors. High Bcl-xL expression was associated with local recurrence or a second primary SCC head and neck (p=0.0397). The association between low Bcl-xL expression and disease-specific survival (DSS) approaches significance (p=0.067; HR = 3.768; CI [0.911, 15.582]). Using a Cox regression model to adjust for the effects of smoking, low Bcl-xL expression held prognostic value for better DSS (p =0.0207). Conclusions: In this small sample of pts with SCCOC, no single marker predicted survival or response to therapy. Low Bcl-xL expression may predict better disease-specific survival for organ preservation for pts with SCCOC. Further investigation is warranted. No significant financial relationships to disclose.
Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction
Authors: Yasuko Furumoto, Carolyne K. Smith, Luz Blanco, Wenpu Zhao, Stephen R. Brooks, Seth G. Thacker, Abdalrahman Zarzour, Giuseppe Sciumè, Wanxia L. Tsai, Anna M. Trier, Leti Nunez, Laurel Mast, Victoria Hoffmann, Alan T. Remaley, John J. O'Shea, Mariana J. Kaplan, Massimo Gadina
Journal: Arthritis & Rheumatology (2016)

Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice.Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies.Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.
Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain
Authors: Ling Jin, Yosuke Nonaka, Shin Miyakawa, Masatoshi Fujiwara, Yoshikazu Nakamura
Journal: Molecular Therapy (2016)

Fibroblast growth factor 2 (FGF2) plays a crucial role in bone remodeling and disease progression. However, the potential of FGF2 antagonists for treatment of patients with bone diseases has not yet been explored. Therefore, we generated a novel RNA aptamer, APT-F2, specific for human FGF2 and characterized its properties in vitro and in vivo. APT-F2 blocked binding of FGF2 to each of its four cellular receptors, inhibited FGF2-induced downstream signaling and cells proliferation, and restored osteoblast differentiation blocked by FGF2. APT-F2P, a PEGylated form of APT-F2, effectively blocked the bone disruption in mouse and rat models of arthritis and osteoporosis. Treatment with APT-F2P also exerted a strong analgesic effect, equivalent to morphine, in a mouse model of bone cancer pain. These findings demonstrated dual therapeutic action of APT-F2P in bone diseases and pain, providing a promising approach to the treatment of bone diseases.
Abstract 3571: Targeted suppression of inhibitor of apoptosis proteins amplifies apoptosis and improves response to enzalutamide in prostate cancer
Authors: Amanda Pilling, Ok Hwang, Clara Hwang
Journal: Cancer Research (2016)

Abstract Prostate cancer is the most common malignancy and the 2nd leading cause of cancer death in men worldwide. First-line treatment includes androgen deprivation therapy in addition to androgen receptor (AR) antagonists that work to block androgen signaling. Although most patients respond initially to hormone deprivation therapy, responses are not durable and the disease progresses to a lethal stage, termed castrate resistant prostate cancer (CRPC). Interestingly, most CRPCs are still dependent on AR signaling for growth and survival, therefore more potent AR-antagonists such as enzalutamide have recently been FDA approved for treatment of CRPC. However, response rates to enzalutamide can be limited by emergence of acquired resistance or intrinsic resistance. A universal mechanism of resistance to cytotoxic therapies is upregulation of anti-apoptotic programs that function to override death signals and permit survival of the tumor cell. In prostate cancer, overexpression of the Inhibitor of Apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP has been demonstrated in progression to CRPC. Additionally, aberrant expression of these proteins is reported to contribute to anti-androgen resistance. Therefore, to achieve more robust responses to AR inhibition with enzalutamide, we targeted IAP proteins in order to amplify the apoptotic signal and increase cell death in prostate cancer cells. Using a small-molecule IAP inhibitor, we evaluated response to enzalutamide upon IAP inhibition in prostate cancer cell lines LNCAP and C4-2. Here we demonstrate greater proliferation inhibition, reduced cell survival and synergistic induction of apoptosis signaling in response to combined AR antagonism and IAP inhibition. Furthermore, we demonstrate depletion of cIAP1 protein expression upon enzalutamide treatment indicating a possible role for AR in regulating anti-apoptotic pathways. Taken together these results demonstrate that IAP proteins may be a critical survival pathway in CRPC and antagonism of these proteins through small-molecule inhibition can amplify apoptosis and increase cell death in response to enzalutamide. Targeting a critical survival pathway can lower the apoptotic threshold providing a possible therapeutic opportunity to treat and prevent resistance to enzalutamide and increase benefit to patients with this lethal form of prostate cancer. Citation Format: Amanda Pilling, Ok Hwang, Clara Hwang. Targeted suppression of inhibitor of apoptosis proteins amplifies apoptosis and improves response to enzalutamide in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3571.