bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of tissue factor pathway inhibitor release and interactions with growth factors on the antitumor effects of ultra low molecular weight heparin semuloparin.
Authors: Fareed Jawed , Gray Angel , Kahn Daniel , Cunanan Josephine , Khan Hussein , Viskov Christian , Hoppensteadt Debra 
Published: March 2020

e13117 Background: Heparins are known to produce anti-tumor effects beside other pharmacologic actions. More recently an ultra LMWH has been developed for the prevention of thrombosis in cancer patients. Initial studies demonstrated that this agent also exhibits anti-tumor effects in animal models. To understand the mechanism of anti-tumor effects of this agent studies were designed to fractionate this ULMWH in to various AT affinity fractions. Methods: An ULMWH (semuloparin, Sanofi-aventis) and its high (HAF) and low (LAF) affinity fractions were prepare by AT affinity chromatography. These agents were administered at 1 mg/kg to primates via intravenous route. Blood samples were collected for a period of up to 6 hours. TFPI release and anti-Xa activities were measured. The interactions of ULMWH and its fractions with various growth factors such as FGF, VEGF, EGF and beta TGF were measured using a mass spectral method employing SELDI technique. The anti-tumor effects of each of these agents were measured using the mouse model of Lewis lung carcinoma. Results: In comparison to ULMWH the LAF showed minimal anti Xa activity whereas HAF exhibited a higher activity. All agents exhibited a similar release of the TFPI; however, HAF exhibited slightly higher release. All agents also showed varying degrees of binding to growth factors as measured by peak intensities. All agents produce anti-tumor effects in the mouse model resulting in a significant reduction in tumor size. Conclusions: Semuloparin has been clinically proven to prevent venous thromboembolism in patients with cancer (SAVE ONCO). These effects are attributable to the inhibition of factor Xa and the generation of thrombin. The fact that LAF mediates its anti-tumor effects without producing anti Xa effects suggest that these may be related to the release of TFPI. Furthermore the ULMWH, HAF and LAF all interact with growth factors suggest that these interactions may also contribute to anti-tumor effects of semuloparin, therefore, beside antithrombotic effects this agent also exhibits oncostatic effects.
A study of denileukin diftitox to treat refractory ovarian cancer.
Authors: Czerlanis Cheryl M. , Drakes Maureen , Elmishad Amira , Kosik Kelly , Parthasarathy Mala , Potkul Ronald , Smith Donna M. , Yu Zheng , Zakrzewski Sandra , Stiff Patrick J. 
Published: March 2020

e13121 Background: The number of circulating CD4+ regulatory T-cells (Tregs) has been correlated with outcome in advanced ovarian cancer. A prior report (Barnett, et al; AACR Abstracts 2006: 1148) suggested that denileukin diftitox, a fusion toxin containing interleukin-2 fused to diphtheria toxin, may be of therapeutic value in this disease acting via Treg depletion. As part of a larger study of denileukin diftitox with dendritic cell-based vaccination, we treated patients with the agent alone to determine if it depletes circulating CD4+CD25HiFoxP3+CD127Low Tregs and induces clinical responses. Methods: Patients with relapsed/refractory ovarian or primary peritoneal carcinoma were eligible. No chemotherapy or immunotherapy was allowed for the preceding 4 weeks. Denileukin diftitox 18 μg/kg IV was given every 28 days for up to 4 cycles. Weekly monitoring of CD4 Tregs and CD8+CD28- Tregs was done by monoclonal antibody labeling of PBMC and flow cytometry studies. Clinical responses were measured by standard methods of disease assessment including CA125 testing. Results: Seven women were treated, of whom 3 had minimal residual disease (MRD). No Grade III-IV toxicities were seen. Unlike the prior report, no clinical responses were seen in 4 patients with bulky measurable disease. Median progression free survival was 5.5 months (range 0.5-20.5) and median overall survival will exceed 21.6 months (range 1.4-26.5+) with MRD a marker for prolonged remissions and survival. We saw no Treg depletion after the 1st cycle; i.e., no patient had ≥25% reduction in Tregs at the expected nadir at day 14. Mean CD4+CD25HiFoxP3+CD127Low Tregs/CD4 cells for controls was 1.16% (range .35-2.13) at baseline, with no significant temporal variation. Mean Tregs/CD4 cells for treated subjects was 2.89% (range 1.06-5.40) at baseline and 3.11% (range .81-5.13) at day 14. For 6 patients who received ≥2 cycles, mean Tregs/CD4 cells dropped to 1.95% (range .71-3.74) at day 42 and 1.65% (range .78-2.36) at day 70. CD8+CD28- Tregs were only increased (>50% of CD8 T-cells) in 2 patients and not correlated with remission duration. Conclusions: These data suggest that denileukin diftitox depletes Tregs in relapsed ovarian cancer only with repeated dosing and may be of clinical value in MRD.
Effect of cryopreservation, type of antigen, and route of administration on in vivo migration of human monocyte-derived dendritic cells.
Authors: Nicol Andrew John , Tazbirkova Andrea , Macfarlane David , Nieda Mie 
Published: March 2020

e13128 Background: Immunotherapy strategies using antigen loaded dendritic cells are being widely utilized in clinical trials for patients with malignancies. To induce effective immune responses against tumors, dendritic cells need to traffic into areas rich in immune effector cells such as T cells and natural killer T cells. In our study, we investigated localization of monocyte derived dendritic cells (MoDC) following different routes of administration, and whether cryopreservation or type of antigen has an impact on MoDC trafficking properties. Methods: Twelve patients with metastatic malignancies received 111Indium-oxine labeled MoDC pulsed with peptide/protein based antigen or glycolipid antigen, which was administered intradermally, subcutaneously or intravenously, and fresh or after a cryopreservation step. Results: Following intravenous administration, MoDC rapidly distributed into lungs, followed by liver and spleen. In nine of twelve cases intradermally administered MoDC migrated to regional lymph nodes but this was true only for one of nine MoDC injections administered subcutaneously. Cryopreservation and type of antigen did not influence migration capabilities of MoDC. Conclusions: Our data confirms that MoDC trafficking is markedly dependent on the mode of delivery. There is no difference in trafficking of MoDC administered fresh or after cryopreservation and the type of antigen does not have impact on MoDC distribution in the human body.
Association between elevated blood pressure and clinical response in patients treated with anti-vascular endothelial growth factor (anti-VEGF) therapy in phase I clinical trials.
Authors: Bilen Mehmet Asim , Naing Aung , Hong David S. , Falchook Gerald Steven , Fu Siqing , Wen Sijin , Wheler Jennifer J. , Durand Jean-Bernard , Ewer Michael , Kurzrock Razelle 
Published: March 2020

e13506 Background: Relationship between elevated blood pressure and clinical response in patients with advanced cancers treated with anti-VEGF treatment was evaluated. Methods: We performed an analysis of 438 consecutive patients from 19 clinical trials treated with therapy that included an anti-VEGF agent starting January, 2006. Clinical response was determined by RECIST 1.0. Blood pressures (BP) were scored as shown in Table. BP scores were calculated from an average mean BP of all BP readings for each patient, taken at each visit, and then divided into time points: baseline, 4, 8 and 12 months. Other factor included number of medication. Scores at each time point were compared to baseline value and divided into: increasing, decreasing and stable. Chi-square was used to correlate increased BP scores with clinical response. Additional analysis was also done by using CTCAE v4.02 for grading of BP. Results: The median age was 57 years (13 to 88) and 54% were male; 10% of patients received more than one anti-VEGF therapy. The median number of anti-VEGF therapies was 2 (1 to 3). Within the first four months, 52% of patients who achieved partial response (PR) had increased BP scores from baseline compared to 18% of those with progressive disease (PD) and 25% of those with stable disease (SD) (p <0.0001) (CTCAE; p=0.004) but there was no difference between SD and PD (p = 0.11) (CTCAE; p=0.31). The elevation in BP scores was significantly higher in the PR+SD group (31%) compared to PD group (18%) within 4 months (p=0.008) (CTCAE; p=0.07). There is a significant difference in increased BP scores among PR to SD groups within 8 months and 12 months (p=0.04 and p=0.028) (CTCAE; p=0.04 and p=0.107). Conclusions: Increasing BP scores is a positive prognostic indicator for favorable clinical response in patients who received anti-VEGF treatment. [Table: see text]
Use of PTEN status to determine the functional outcome of combined MEK and mTOR inhibition.
Authors: Ciuffreda Ludovica , Falcone Italia , Cesta Incani Ursula , Sette Giovanni , Eramo Adriana , Del Curatolo Anais , De Maria Ruggero , Cognetti Francesco , Milella Michele 
Published: March 2020

e13512 Background: PTEN is a lipid phosphatase couteracting the activity of the PI3K pathway. PTEN mutations and deficiencies are prevalent in many types of human cancers and are associated with poor prognosis and therapeutic resistance. MAPK is another key cellular network that works independently from, in parallel to, and/or through interconnections with PI3K to promote cancer development. Here we investigated whether a strategy combining MEK and mTOR inhibition may be effective in preclinical models of human cancer and the role of PTEN loss in determining sensivity/resistance to single and combined pathway inhibition. Methods: We employed in vitro assays (cell proliferation assays, cell cycle and apoptosis analysis, WB, and ELISA assays) to determine functional and molecular drug effects. Pharmacologic interactions between MEK and mTOR inhibitors were analyzed by conservative isobologram analysis using a fixed dose-ratio experimental design. Results: In cell lines with wt-PTEN (including melanoma, breast, lung, and colon cancer), combined MEK and mTOR blockade achieves synergistic effects at suboptimal drug concentrations but becomes frankly antagonistic in the presence of complete inhibition of MEK-to-ERK signaling (combination index - CI: 1.2->1000). This, in turn, led to the identification of a novel crosstalk mechanism by which MEK blockade restores PTEN expression and cross-inhibits the PI3K/AKT/mTOR pathway, thus bypassing the need for double pathway blockade. Conversely, in cancer cell lines with PTEN loss, combined MEK and mTOR blockade resulted in strongly synergistic effects (CI: 0.0005-0.4), due to cooperative induction of apoptosis. A similar synergistic growth inhibition was also observed in a patient-derived lung cancer stem cell line, which displayed low to undetectable PTEN protein levels. Conclusions: Our results suggest that combined MEK and mTOR inhibition exerts strongly synergistic effects in cancer models with PTEN loss. This notion may be helpful in selecting appropriate cellular (and possibly clinical) contexts for the design rational therapeutic strategies based on concomitant inhibition of the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.
Sorafenib in the treatment of metastatic paraganglioma: A case report.
Authors: Gunaldi Meral , Kara Ismail Oguz , Usul Afsar Cigdem , Duman Berna Bozkurt 
Published: March 2020

e13523 Background: Paragangliomas (extra-adrenal pheochromocytomas) are rare chromaffin cell tumors that can often be cured by resection. Excess release of catecholamines is characteristic for paragangliomas. Paragangliomas are mostly benign if diagnosed and treated early. Overall 0–36% of paraganglioma patients develop metastatic disease, depending on the type of tumor. Methods: We present a case of a 43-year-old woman who admitted to our department with a history of episodic headaches, diaphoresis and weakness. Hypertension and tachycardia were diagnosed. She had elevated plasma catecholamine levels and a right paraaortic mass (9x9.5cm) was visualized on CT. The mass was excised and the diagnosis of paraganglioma was confirmed. In postoperative follow-up the patient's blood pressure and catecholamine levels were normalized. After twenty months follow up, local recurrence and metastases were detected in thorax, abdomen, and skeletal system. Plasma catecholamine levels were high. Results: Chemotherapy with CVD (adriamycine (7mg/m2), dacarbazine (400mg/m2), cyclophosphamide (500mg/m2), vincristine (1.4mg/m2) on day 1 and 2, repeated every 21 days; were administered and no improvement was observed in PET-CT following a treatment of three cycles. Sorafenib (800mg/m2/day) was applied for three-months. Finally the patient’s plasma catecholamine levels and metastatic lesions regressed. Conclusions: Treatment options of metastatic paragangliomas (MP) are removal by excision or ablation, chemotherapy, or targeted pharmaceuticals. Benefits of CVD chemotherapy for MP appears to be short-term and do not include an increase in patient survival. As targeted therapy, treatment of MP with everolimus or imatinib were attempted with no significant benefit, and thus are not recommended. However partial response was reported with Sunitinib some cases. We used sorafenib as another multiple TKI and detected complete response. So far, sorafenib has not been applied in the treatment of MP in literature. Sorafenib can be preferred in the treatment of MP. Therefore, more comprehensive clinical trials are needed.
Transcriptional inhibition of Notch signaling using cell penetrating fusion proteins.
Authors: Epenetos Agamemnon A. , Colucci Silvia , Deonarain Mahendra , Stylianou Spyros 
Published: March 2020

e13525 Background: Notch signalling is deregulated in a number of cancers and is possibly involved in cancer stem cell development. It is postulated that cancers such as breast can become addicted to Notch signalling presenting opportunities for tumour-specific intervention. Due to the presence of at least 4 cell surface receptors that mediate Notch signalling, conventional targeting agents such as monoclonal antibodies cannot inhibit them all. As all the signalling cascades converge on the Notch transcriptional complex (NTC) in the nucleus, inhibition of gene expression by disrupting this machinery is an attractive strategy to overcome this redundancy. Methods: Towards this, we have developed a fusion protein based on the potent cell penetrating protein (CPP) antennapedia (Antp) recombinantly fused to a dominant-negative truncated mastermind-like protein (DN-MAML) called TR4. We have also developed a method of incorporating CPP to deliver intracellular antibody fragments against nuclear targets such as Notch and mastermind. Results: The Antp-DN-MAML protein (TR4) has similar potency to many of the gamma-secretase inhibitors being developed against this pathway but more specific for the NTC.TR4 can inhibit tumour cells in vitro and in vivo and provide some insight into the mechanism of action. Also such intracellular targets are accessible to antibodies, provided they are delivered using CPP such as antennapedia. Conclusions: .As a model system, scFvs have been raised to key epitopes in the NTC which can lead to complex inhibition and the same downstream effects as TR4.In addition, we further demonstrate that there is a more general approach to trascription factor inhibition using single-chain Fvs fused to Antp
Antitumor effect of Chinese herb oridonin on human non-small cell lung cancer (NSCLC).
Authors: Chen Siyu , Tian Wei , Ma Ai-Hong , Desai Sonal , Tolentino Krysteena , Guo Yantong , Li Tianhong 
Published: March 2020

e13526 Background: Oridonin, a diterpenoid purified from the Chinese herb Rabdosia rubescens, has anti-inflammatory and potentially anti-tumor property. We aimed to study the antitumor effect of oridonin on a panel of human non-small cell lung cancer (NSCLC) cell lines. Methods: Human NSCLC cell lines with a wild-type EGFR gene and a RAS gene mutation were treated with escalating dose concentration of oridonin (from 2.5 to 50 µM). Antitumor effect was measured by 72-hr growth inhibition by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Ongoing experiments will identify potential drug target(s) by assessing changes in global gene expression. Results: Oridonin exhibited a dose-dependent and time-dependent cytotoxic effect on a panel of NSCLC cell lines. Table 1 summarizes the molecular and histological features of these NSCLC cells, and their cytotoxicity to oridinin, erlotinib and pemetrexed. In those NSCLC cells that were sensitive to oridonin, morphological changes were consistent with autophagy and apoptosis. Potential drug targets will be verified by RT-PCR and immunoblotting. Conclusions: Oridonin exerts a distinct cytotoxicity that is independent of the sensitivity of NSCLC cells to erlotinib or pemetrexed. Further mechanistic and animal studies are warranted to understand its anti-tumor property and toxicity profile in preclinical evaluation. [Table: see text]
A pipeline to detect antibody-targetable cancer stem cell proteins.
Authors: Calogero Raffaele A , Lanzardo Stefania , Conti Laura , Cavallo Federica 
Published: March 2020

e13527 Background: Monoclonal antibody represents an ideal tool to develop highly specific drugs. However, the efficacy of antibody-based drugs is strongly dependent by the effect that the protein targeted will have on the disease cell. Particularly interesting, as target for antibody therapy, are oncoantigens (OAs), i.e., surface tumor antigen that supports tumor growth. Methods: We have developed a two steps pipeline that allows identifying moAbs directed against e.g., cancer stem cells (CSC) OAs. First step: we compare transcription profiles, derived by tumor cell line grown as epithelial monolayer, with those derived by spheroids generated using the same cell line. Since spheroids are enriched in CSCs, genes up-modulated in spheroids are putative targets for antibody-targeting. Putative targets are ranked on the basis of their oncological potential and low expression in normal tissues. Top ranking targets are then tested in animal model. If vaccination inducing antibody response is able to reduce tumour growth and/or metastasis formation targets are proficient for the second step: they are used to vaccinate BALB/c mice. IgG expressing cells are isolated and libraries of the heavy (HV) and light variable (LV) chains are sequenced. Bioinformatics is then used to detect enriched VH and VL, which are transformed in single-chain antibodies to test target binding efficacy. Results: Using our pipeline we have identified, as associated to HER2+ breast cancer cell, TMPRSS4. This protein is involved in metastasis and invasion and, in hepatocellular carcinoma, it is over-expression leads to epithelial-mesenchymal transition. We are now evaluating if antibodies raised against TMPRSS4 are able to inhibit metastasis formation in BALB/c mice. On the basis of these results we will move to the second step of the pipeline. Conclusions: We have designed a pipeline that allows identification of CSC associated proteins suitable as targets for antibody-driven therapy.
Docetaxel followed by temsirolimus in suppression of mTOR pathway.
Authors: Huang Chao H , Van Veldhuizen Peter J. , Gadashova Ayten , Williamson Stephen K. , Farassati Faris 
Published: March 2020

e13535 Background: Mammalian target of rapamicin(mTOR) is a downstream regulatory protein of the PI3K/Akt signal transduction pathway. This is a common pathway for a several cell surface receptors including IGFR (Insulin-like Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor). The activation of these receptors through PI3K/Akt pathway is essential in cell proliferation, angiogenesis and anti-apoptosis process. Several therapeutic agents that inhibit these receptors have shown to be active in the treatment of diverse types of cancers. Docetaxel (D) is commonly used in the treatment of lung cancer. We demonstrated previously that the sequence of D followed by mTOR inhibition using temsirolimus (T) in lung cancer cell lines (LCCL) had synergistic effect in suppressing cell proliferation compared with T→D. The exact mechanism of this effect is unknown. We studied the expression of mTOR, Raptor and PI3K in these cell lines treated in different time points to investigate the activity of this pathway when using these sequences of drug treatment. Methods: Adenocarcinoma LCCL H2122 and H1437 were plated and exposed to temsirolimus 1000nM and docetaxel 100nM. The cell viability was measured by optical density (OD) at 24, 48 and 72h. We tested the sequence of D treated for 24h followed by addition of T and the reverse in both LCCL. We then prepared cell lysate at 24h, 48h and 72h time points and studied the expression of mTOR, Raptor and PI3K by western blot using antibody obtained from Cell Signaling. Results: The sequence of D→T had increased suppression of mTOR, Raptor and PI3K at 48 and 72 hours compared with the opposite sequence of T→D. Conclusions: The combination of D → T seems to have synergistic suppression of mTOR and PI3K pathway in 2 LCCL compared with opposite sequence. Further studies in animal models using this sequence and confirmation of mTOR suppression may help determine if this is a feasible combination in the treatment of lung cancer.
Reliability of imaging biomarkers for response assessment in advanced lung cancer: Influence of expertise and automation.
Authors: Beaumont Hubert , Oubel Estanislao , Iannessi Antoine , Wormanns Dag 
Published: March 2020

e13547 Background: Image-based biomarkers play an important role in the assessment of the response to therapy. The value of imaging biomarkers relies on their reproducibility, which depends on the reviewer and on the measuring system. This study aims at evaluating the impact of readers’ expertise and automation of measurements. Methods: A retrospective study was performed on 10 patients with at least one Non-Small Cell Lung Cancer (NSCLC) lesion, and followed over time (7 time points in average) with Computed Tomography (CT). 2 expert radiologists (ERs) and 5 imaging scientists (ISs) measured the Longest Axial Diameter (LAD) and the volume (VOL) of each lesion at each time point. ERs and ISs segmented the lesions by using a proprietary software providing semi-automatic segmentation processing with manual adjustment. ISs performed an additional session using manual segmentation tools only. From each segmentation, VOL and LAD were automatically computed. The variability of the measurements was calculated by using standard statistics. The response to treatment was assessed according to RECIST thresholds for LAD and with +/-30% thresholds for volume. The inter-reader agreement was measured trough the Kappa coefficient. Finally, the reviewing time with and without automation was analyzed. Results: The use of automated tools by ISs reduced the standard deviation of LAD difference from 10.7% to 8.4%. The inter-reader agreement improved Kappa from 0.57 to 0.68 for LAD, and from 0.52 to 0.69 for VOL. The automation reduced the reviewing time by a factor 4 with respect to the manual assessment. No significant differences in variability were found between ISs and the first ER, but significant differences were observed with respect to the second ER. Conclusions: In a RECIST context, automation improved significantly inter-reader agreement. When using volume as a biomarker, automation not only improved the inter-reader agreement, but also decreased notably the reviewing time. No evidence was found about the influence of the expertise on the volume measurement. The difference in the lesions interpretation by the experts is a relevant factor to account for.