tbuckley/cabot-search huggingface dataset:
Abstract 5513: Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase (PDI) for ovarian cancer treatment.
Authors: Shili Xu, Alexey N. Butkevich, Roppei Yamada, Yu Zhou, Bikash Debnath, Roger Duncan, Ebrahim Zandi, Nicos A. Petasis, Nouri Neamati
Journal: Cancer Research (2013)

Abstract Protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) chaperone protein, catalyzes disulfide bond breakage, formation and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective and safe small-molecule inhibitors of PDI. Here, we report a new class of novel propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and mass spectrometry, we established that PACMA 31, one of the most active analogues, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with PDI's active site cysteines. We also demonstrated that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent a new approach for the development of targeted anticancer agents for ovarian cancer therapy, and can also serve as useful probes for investigating the biology of PDI-implicated pathways. Citation Format: Shili Xu, Alexey N. Butkevich, Roppei Yamada, Yu Zhou, Bikash Debnath, Roger Duncan, Ebrahim Zandi, Nicos A. Petasis, Nouri Neamati. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase (PDI) for ovarian cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5513. doi:10.1158/1538-7445.AM2013-5513
Abstract 1555: <i>In vitro</i> and <i>in vivo</i> evaluation of analogs of <i>N</i>-(<i>o</i>-carboxybenzoyl)glutamic acid imide, an active thalidomide metabolite
Authors: Kaveshree Pather, Nuala A. Helsby, Brian D. Palmer, Lai-Ming Ching
Journal: Cancer Research (2010)

Abstract Thalidomide, with its ability to inhibit angiogenesis and to inhibit the production of survival factors in the bone marrow, has proven to be very effective for the treatment of multiple myeloma. Previous studies from our laboratory identified 3 metabolites in the blood and urine of myeloma patients who were responding to thalidomide therapy (Lu et al, Clin Cancer Res. 9, 1680; 2003). One hydrolysis product, N-(O-carboxybenzoyl)glutamic acid imide (CGI) was as potent as lenalidomide in inhibiting angiogenesis and in inhibiting cytokine production in vitro. Structurally related molecules of CGI have been synthesised in an effort to produce analogs with improved potency, stability and activity. Analogs were each tested for activity for inhibition of tube formation by endothelial cells on matrigel and for inhibition of IL-6 production by RPMI-8226 myeloma cells stimulated by lipopolysacharide (LPS). Analogs with significantly improved potency compared to CGI in inhibiting tube formation and with less cytotoxicity have been synthesized. A tetra-fluorinated analog (SN 29900) was 17-fold and a morpholide-analog (SN 31721) was 8-fold more potent than CGI. SN 29900 was also better in inhibiting LPS-induced IL-6 production by RPMI-8226 cells provided 50% inhibition whilst SN 31721 provided only 15% inhibition at 10 µg/ml. SN 31721 and SN 29900 were both more stable than CGI at low pH levels. These analogs were well-tolerated in mice, with no signs of toxicity seen after an intra-peritoneal dose of 1000 mg/kg. Nor were toxicities observed following daily gavage at 200 mg/kg for 30 days. Plasma pharmacokinetics of SN 29900 and SN 31721 after an intra-peritoneal injection of 100 mg/kg was measured and the results indicated that the analogs were absorbed and cleared more rapidly than lenalidomide. The AUC0-∞ for SN 29900 and SN 31721 in mice was 41.1 µM.h and 162 µM.h respectively compared to 338 µM.h for lenalidomide at the same dose. Lenalidomide potentiates the activity of DMXAA, a vascular disrupting agent in phase III trials, against subcutaneous murine tumours. This was not observed with SN 29900, perhaps because of its poorer pharmacokinetic profile. Development of more lipophilic analogs that may have slower rates of clearance and improved pharmacokinetics are currently under development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1555.
The burden of visceral leishmaniasis in Italy from 1982 to 2012: a retrospective analysis of the multi-annual epidemic that occurred from 1989 to 2009
Authors: M Gramiccia, A Scalone, T Di Muccio, S Orsini, E Fiorentino, L Gradoni
Journal: Eurosurveillance (2013)

Starting from 1989 Italy experienced an increase of visceral leishmaniasis (VL) cases over a baseline of 10 to 30 cases reported annually. The number of cases peaked in 2000 and 2004 with more than 200 cases/year, and subsequently declined to reach on average one third of the 2000 peak value in the period after 2010. A retrospective analysis from 1982 to 2012 showed that the multi-annual epidemic consisted of major components including (i) an outbreak involving infants and immunocompetent adults in parts of the Campania region (southern peninsular Italy) and that appears to have declined naturally, (ii) a second outbreak affecting human immunodeficiency virus (HIV)-infected individuals throughout the country, that declined owing to the use of highly active antiretroviral therapies (HAART), (iii) a generalised increase of VL cases in immunocompetent individuals and patients affected by associated conditions other than HIV from endemic regions of peninsular and insular Italy (other than Campania), which was due to a geographical spreading of VL foci, with no major case-clusters or outbreak features. A minor component consisted in the appearance of a few autochthonous cases in formerly non-endemic areas, starting from the early 1990s. Epidemic determinants and reasons for VL decline in the Campania region remain largely unexplained, despite the information available on canine reservoir and phlebotomine vectors in Italy.
Abstract 1565: Mesoporous silicon particle mediated dendritic cell based vaccine formulation showed stronger immunoresponse for the presentation of tumor antigens and adjuvant
Authors: Ismail M. Meraz, Jianhua Gu, Rita Serda
Journal: Cancer Research (2012)

Abstract Dendritic cell (DC) based immunotherapy is being used for cancer therapy in various clinical trials. During evaluation of recent clinical studies, it became apparent that efficient DC-based immunotherapy is dependent on a number of factors, such as the mode of antigen presentation, maturation of DC, injection site, and vaccination dosing. Major limiting factors for DC-based vaccines are insufficient loading of antigens by DC and poor migratory capacity of DC to lymph nodes. Nanotechnology provides tools to load large payloads of antigens and adjuvants in particles for uptake by DC. Toll-like receptor (TLR) ligands have been proposed as vaccine adjuvants for boosting adaptive immunity in cancer therapy. TLR signaling induces DC activation that is characterized by enhanced expression of costimulatory molecules and increased secretion of cytokines necessary for activation and differentiation of naive T cells. In this study, we have used porous silicon (pSi) microparticles to create a novel vaccine. We have demonstrated that porous silicon particles can be decorated with TLR-ligands using lipopolysaccharide (LPS) or monophosphoryl lipid (MPL). This decorated particles are substrates for bone marrow-derived DC internalization, leading to cellular uptake and activation and enhanced migration of DC to lymph nodes. Confocal and scanning electron microscopy, as well as flow cytometry studies supported higher uptake of LPS and MPL conjugated particles as compared to unlabeled particles. TLR ligands induced morphological changes in GM-CSF-stimulated bone marrow cells during particle uptake consistent with classical DC dentron formation. Stimulated antigen presenting cells also expressed elevated levels of costimulatory (e.g. CD80, CD86) and major histocompatibility molecules (MHC), and secreted pro-inflammatory cytokines both in vitro and in vivo. Ex-vivo processed DC loaded with TLR ligand coated pSi showed enhanced migration to lymph node as compared with empty DC when injected mice subcutaneously. As expected, LPS conjugation to particles showed toxicity towards DC whereas MPL conjugated pSi showed little or no toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1565. doi:1538-7445.AM2012-1565
A reduced qRT-PCR-based gene expression signature with prognostic value in early breast cancer.
Authors: E Espinosa, A Gámez, I Sánchez, [ Pinto, D Hardisson, R Madero, P Zamora, A Redondo, M González Barón, J Fresno Vara
Journal: Cancer Research (2009)

Abstract Abstract #2030 Background: Gene profiling may improve prognostic accuracy in patients with early breast cancer, but this technology is not widely available. We used commercial assays for qRT-PCR to measure the expression of 83 genes previously found to determine breast cancer prognosis. The objective of our study was to develop a simple molecular signature predicting relapse in early breast cancer with positive hormonal receptors.&amp;#x2028; Methods: 153 patients (age 29-82 years-old) with early breast cancer and a minimum follow-up of 5 years were included. All tumours were positive for hormonal receptors and 38% had positive lymph nodes; 64% of patients received adjuvant chemotherapy (with anthracycline if N+ or high-risk N0). RNA was isolated from tissue slices of formalin-fixed paraffin-embedded samples using the MasterPure RNA Purification Kit (Epicentre Biotech). qRT-PCR amplifications were performed with TaqMan Gene Expression Assays products in an ABI PRISM 7900 HT Sequence Detection System (Applied Biosystems). The reactions were carried out using the TaqMan Low Density Arrays (Applied Biosystems). A supervised analysis was done to identify a prognostic expression signature using BRB Array Tools software. Survival curves were derived from Kaplan-Meier estimates and compared by log-rank test. The association of gene expression and clinical variables with distant metastasis-free survival (DMFS) was analyzed by Cox regression models. SAS 9.1 software package was used for statistical analyses.&amp;#x2028; Results: After a median follow-up of 92 months, 28% of patients relapsed. We defined an 8-gene prognostic signature. The distant metastasis-free survival at 5 years was calculated for this profile. DMFS was 97% -good risk- versus 60% -poor risk, HR 20.3 (95% CI 6.17-67.2), p&amp;lt;0.001. This gene expression profile was highly informative in identifying patients with distant metastasis, even when corrected for traditional prognostic factors in Cox multivariate analysis (HR 20, 95% CI 5.9-67.4). Performance was similar to that of three validated gene profiles. The validity of this signature was verified in an independent cohort obtained at the GEO database.&amp;#x2028; Conclusions: This study identifies a new molecular signature with prognostic utility that outperforms traditional histopathologic prognostic factors. Our 8-gene qRT-PCR assay is suitable for analyzing routine formalin-fixed paraffin-embedded samples in the clinical setting. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2030.
Abstract 617: Apigenin intake regulates Fox ‘O’ signaling in an autochthonous mouse model of prostate cancer
Authors: Sanjeev Shukla, Natarajan Bhaskaran, Gregory T. MacLennan, Pingfu Fu, Sanjay Gupta
Journal: Cancer Research (2012)

Abstract Forkhead transcription factors of ‘O’ class (FoxOs) are involved in a paradigm that supports proliferation, survival, longevity during multiple cellular environments, and tumor development. Perturbation of FOXO activity leads to altered cellular response which results in cancer development and progression. We previously showed that FOXO signaling is deregulated in human prostate adenocarcinoma and in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model that mimics progressive forms of human disease. In the present study we aimed to demonstrate the potential role of apigenin, a common dietary flavonoid present in fruits and vegetables, in modulating FoxO signaling and its downstream events to suppress cancer progression using in vivo and in vitro models. Apigenin was fed to TRAMP mice at 20- and 50- μg/mouse/day (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) for six days in a week for 20 weeks; whereas control animals received vehicle only. Apigenin intake by TRAMP mice from 8-28 weeks of age exhibited marked reduction in tumor growth with no signs of metastasis. Apigenin feeding to TRAMP resulted in a significant dose-dependent reduction in Foxo3a, but not Foxo1a protein observed in the dorso-lateral prostates. Foxo3a protein was redistributed more in nuclear than the cytosolic compartments after apigenin feeding. Simultaneously, decreased Foxo3a phosphorylation (Ser253) was observed in the dorso-lateral prostate, which correlated with decreased cytoplasmic retention of Foxo3a with no significant change in 14-3-3 chaperone protein in the cytosol after apigenin feeding. Conversely, TRAMP mice have higher 14-3-3 expression than non-transgenic mice and this higher level accounted for nuclear retention of Foxo3a. A subsequent decrease in p-Akt (Ser473) was noted after apigenin feeding demonstrating that the decreased nuclear presence of p-Akt (ser473) may be restricting Foxo3a phosphorylation and its retention in the nucleus. Furthermore, an increase in the levels of MnSOD and Cu/ZnSOD was observed in TRAMP mice after apigenin intake. Similar findings were recorded in cell culture studies where apigenin treatment to human prostate cancer LNCaP and PC-3 cells resulted in the restoration of FOXO3a in the nucleus. This increase in Foxo3a protein levels in the nucleus may be a decisive factor resulting in the inhibition of prostate cancer. These finding suggests that apigenin has potential role in regulating the FOXO signaling cascade and may be a major therapeutic target in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 617. doi:1538-7445.AM2012-617
Extensive small-bowel diverticulosis identified with the newly introduced On Demand Enteroscopy system
Authors: Gian Tontini, Martin Grauer, Hakan Akin, Michael Vieth, Hüseyin Tasdelen, Maurizio Vecchi, Markus Neurath, Helmut Neumann
Journal: Endoscopy (2013)

The recently introduced On Demand Enteroscopy system (ODE; NaviAid AB, Smart Medical Systems, Ra'anana, Israel) enables deep small-bowel enteroscopy using standard endoscopic equipment. The ODE device consists of a disposable balloon that is advanced through the working channel of a standard endoscope equipped with a working channel of at least 3.8 mm ([Fig. 1]). To the best of our knowledge, there are currently no published reports on the use of this new technique.
Abstract P4-11-21: Dosimetric Comparison of Radiotherapy for Left Sided Breast Cancer: Breath-Hold Versus Free-Breathing
Authors: TM Zagar, M Palta, S Catalano, L O'Neill, S Yoo, J Horton, LR. Prosnitz
Journal: Cancer Research (2010)

Abstract Background: Radiotherapy for left sided breast cancer potentially increases risk for late toxicity to the heart. The simple technique of breath-hold (BH) can be instituted in an attempt to reduce volume of lung and heart irradiated in tangential fields. We report on patients with left sided breast cancer that were planned both with conventional free-breathing (FB) and BH radiation techniques from a single institution. Methods: From 10/2006 to 5/2010, 20 patients with node-negative, early stage breast cancer underwent CT simulation for left sided breast cancer and were selected for analysis in this report. FB and BH CT scans were obtained and treatment plans using opposed tangential fields were created to compare various dosimetric indices. Results: BH plans resulted in lower doses to the heart (max dose 1774 vs. 4560cGy, P&amp;lt;0.0001; mean dose 175 vs. 296cGy, p=0.0178; V25 0 vs. 1.85%, P&amp;lt;0.0001; volume in tangential field 0 vs. 10.11cc p=0.0002) compared to FB. The ipsilateral lung received lower doses but a larger volume of lung was encompassed in the tangential fields (V20 13.32 vs. 20.32%, P&amp;lt;0.0001; mean dose 741 vs. 1025cGy, p=0.0003; volume in tangential field 198.8 vs. 256.8cc P&amp;lt;0.0001) compared to FB. Conclusions: Treatment of early stage left sided breast cancer with BH technique is a simple method for minimizing cardiac and ipsilateral lung dose. Long term follow-up is necessary to demonstrate if these dosimetric differences translate into clinically meaningful differences. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-21.
Abstract 2379: Rap1 regulates angiogenesis in prostate tumors
Authors: Jyotsana Menon, Robert S. Doebele, Frank T. Schulze-Hoepfner, Marsha Rich Rosner
Journal: Cancer Research (2010)

Abstract Prostate cancer is the most frequently diagnosed malignancy in men and the second leading cause of cancer related deaths in the United States of America. Advanced stage prostate cancer is associated with poor prognosis since no effective therapies are available when the disease has progressed into a hormone refractory state. This grim prognosis indicates the need for novel approaches to the treatment of advanced stage prostate cancer. One such therapeutic strategy is anti-angiogenic therapy, which interferes with the blood supply of the tumor instead of targeting tumor cells directly. Here we focus on the role of Rap1, a small GTPase homologous to Ras, and its upstream activator, Epac, a guanine nucleotide exchange factor for Rap1, in angiogenesis. In previous studies, we showed that treatment of primary human microvascular endothelial cells (HMVEC) with 8 CPT-2Me-cAMP (8-CPT), a specific agonist of Epac, or introduction of constitutively active Rap1 into these cells blocked VEGF-mediated chemotaxis and inhibited angiogenesis in mice. To test the efficacy of Epac/Rap1 activation in a tumor model, we injected an Epac agonist, 8-CPT, in a PC-3 human prostate tumor xenograft model. Surprisingly, although 8-CPT did not alter tumor growth in PC-3 cells, the drug significantly reduced tumor size in PC-3 cells expressing constitutively active Rap1. Tumor analysis showed an increase in HIF-1α,VEGF and CD31 immunostaining in Rap1-expressing tumors, and a significant decrease in their levels upon treatment of the mice with the Epac agonist 8-CPT. Similar reductions in VEGF and Glut-1 mRNA levels and HIF-1α protein were observed in Rap1-PC-3 cells following 8-CPT treatment when cells were cultured under hypoxic conditions. On the basis of these results, we propose that expression of Rap1 in the PC-3 human prostate tumor cell line promotes hypoxic induction of angiogenesis and increases the susceptibility of the cells to anti-angiogenic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2379.
O3.07 * QUICK, NON INVASIVE AND QUANTITATIVE EVALUATION OF SMALL FIBER NEUROPATHY IN PATIENTS RECEIVING CHEMOTHERAPY
Authors: M. Saad, C. Tafany, D. Ricard
Journal: Neuro-Oncology (2014)

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect of cancer treatment however it is poorly investigated at the early stage due to the lack of simple tool. SUDOSCAN is a quick, non-invasive and quantitative method to assess sudomotor function, based on an electrochemical reaction between sweat chloride and stainless-steel electrodes. It has been validated in small C-Fibers function assessment in diabetes and amylosis. This study aimed to evaluate SUDOSCAN in the detection and follow-up of CIPN in patients treated with neurotoxic chemotherapy even before occurrence of symptoms. 16 patients receiving Oxaliplatin (12 males, mean age: 60 ± 9 years), 8 Carboplatin (4 males, mean age: 67 ± 12 years) and 15 Paclitaxel (5 males, mean age: 64 ± 15 years) were involved in the study. At each chemotherapy infusion accumulated dose of chemotherapy was calculated and the Total Neuropathy Score (TNSc) was performed. To measure small fibre neuropathy patients were assessed by SUDOSCAN (3 minutes exam). The device measures the Electrochemical Sweat Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin (initial mean cumulated dose (MCD): 282 ± 250 mg/m2 and last MCD: 475 ± 238 mg/m2) hands ESC changed from 74 ± 9 to 71 ± 10 and feet ESC from 78 ± 13 to 77 ± 17 µS while TNSc changed from 3 ± 4 to 4 ± 3. In patients receiving Carboplatin (initial MCD: 1296 ± 1304 mg/m2 and last MCD: 1885 ± 1426 mg/m2) hands ESC changed from 57 ± 14 to 46 ± 12 µS and feet ESC from 58 ± 15 to 49 ± 19 µS while TNSc changed from 5 ± 3 to 6 ± 4. In patients receiving Paclitaxel (initial MCD: 1254 ± 1220 mg/m2 and last MCD: 1613 ± 1325 mg/m2) hands ESC changed from 62 ± 18 to 50 ± 20 µS and feet ESC from 72 ± 16 µS to 67 ± 19 µS while TNSc changed from 6 ± 2 to 7 ± 3. For patients receiving Carboplatin which MCD was inferior to Median Cumulated Dose (MeCD) (n = 4), hands ESC changed from 57 ± 9 to 37 ± 6 µS while patients receiving paclitaxel which MCD was inferior to MeCD (n = 7) hands ESC changed from 67 ± 14 to 48 ± 13 µS. When looking at asymptomatic patients mean TNSc was of 2± 2 at initial visit, and 3 ± 2 at last visit. Mean hands ESC changed from 63 ± 21 µS to 52 ± 23 µS, while mean feet ESC changed from 67 ± 22 µS to 63 ± 22 µS at last measure, suggesting that SUDOSCAN could help detecting and quantifying CIPN even in asymptomatic patients. This preliminary study evidenced that small fibre neuropathy can be followed using SUDOSCAN in patients receiving chemotherapy. These preliminary results observed in an on-going chemotherapy must be confirmed in a larger population with measurements performed before the initiation of chemotherapy and during its follow-up.