tbuckley/cabot-search huggingface dataset:
Abstract 2564: The anticancer molecule TPEN induces DNA damage in human colon cancer cells
Authors: Hala Gali-Muhtasib, Omar Rahal, Maamoun Fatfat, Carla Hankache, Bassam Osman, Hala Khalife, Khaled Machaca
Journal: Cancer Research (2015)

Abstract The maintenance of optimal metal levels is an essential aspect of cell homoeostasis. However, in many types of cancer these metal levels especially iron, zinc and copper diverge from normal levels. We have recently shown that the zinc chelator TPEN increases the generation of reactive oxygen species (ROS) which selectively kills colon cancer cells. We have also provided evidence that the redox cycling of copper is responsible for TPEN anticancer effects. In this study, we aimed to further decipher the mechanism of TPEN-induced cell death in colon cancer cells through studying its effect on DNA damage. HCT116 p53+/+ human colon cancer cells were seeded were treated with 5μM TPEN at 50% confluence The inhibition of cell growth was measured by MTT, while ROS production was measured by the DCFH Assay using flow cytometry. siRNAs against DNApk and Chk2 was used to investigate the involvement of these DNA damage sensors in TPEN activity. DNA damage was assessed by the comet assay. Phosphorylation of ATM, ATR, Chk1, Chk2 and H2AX by TPEN were detected immunocytochemically by multiparameter cytometry. Expression levels of Chk1/2, ATR and DNApK were determined by western blotting. We show that cell death by TPEN is associated with significant DNA damage, an effect that was dependent on ROS generation and on the redox cycling of copper, as evidenced by reversal of DNA damage in the presence of antioxidants (NAC, CAT) or the copper chelator neocuproine (Neo). DNA damage was associated with increased expression of p-H2AX and a significant activation of ATM/ATR signaling molecules, specifically p-ATM, p-ATR and p-Chk1. Interestingly, silencing DNApk and Chk2 reversed DNA damage caused by TPEN, suggesting the involvement of DNApk and ATM/ATR pathways in TPEN-mediated effects. This study shows for the first time the involvement of DNApk and Chk2 in TPEN-induced DNA damage and confirms our previous findings that the redox cycling of copper is the main mechanism by which TPEN induces cell death in human colon cancer cells. Citation Format: Hala Gali-Muhtasib, Omar Rahal, Maamoun Fatfat, Carla Hankache, Bassam Osman, Hala Khalife, Khaled Machaca. The anticancer molecule TPEN induces DNA damage in human colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2564. doi:10.1158/1538-7445.AM2015-2564
29. Clinical Trial Showing EPO-Independence for 7 Months by Prolonged Secretion of Autologous EPO by TARGT™
Authors: Shany Blum, Nir Shapir, Reem Miari, Atar Liran, Benny Lerner, Keren Doenyas-Barak, Shai Efrati, Doron Schwartz, Gil Chernin, Garry A. Neil
Journal: Molecular Therapy (2015)

Recombinant human EPO (rHuEPO) along with iron supplementation corrects anemia in most patients with End Stage Renal Disease (ESRD) but is associated with supra-physiological peak serum concentration (Cmax) of EPO and may cause thromboembolic complications. The Transduced Autologous Restorative Gene Therapy system (TARGT™) is an ex-vivo gene therapy that provides autologous, continuous proteins or peptide therapy in the physiological range. The system consists of several 2 × 30 mm pieces of dermal tissue (Micro-Organ, MO), extracted under local anesthetic in which its fibroblasts cells are transduced with a Helper-Dependent Adenoviral Vector (HDAd) containing the EPO gene expression cassette. After culture, and measurement of EPO production, one or more transduced MOs (TARGTs) are re-implanted as required for delivering the target dose. Patients are treated with local steroid injection to stabilize secretion. The system allows dose flexibility and the TARGTs may be removed or added according to the in-vivo secretion levels. We present here initial results from an-ongoing open label ascending dose clinical study of TARGTEPO in patients with anemia due to ESRD. We have completed the enrollment of patients in the first out of 3 cohorts (the low dose) with 6 EPO-dependent patients treated with a total of up to 3 TARGTepo units each, secreting a total of 25 IU/Kg/day of autologous EPO. All patients continued their previous regimen of intravenous supplemental iron. Patients follow-up post implantation is still ongoing with one patient being followed with stable EPO secretion and resulting stable Hb for over 7 months. Results obtained suggest stabilization of serum EPO levels at the physiological range of £20 mIU/ml and the resulting Hb levels between 9-12 g/dL without rHuEPO or transfusion while TARGTs are still functioning. Comparative analysis of serum EPO levels revealed significantly lower Cmax with TARGTepo compared to rHuEPO. Also, comparison of extrapolated Area Under the Curve (AUC) of rhEPO vs. actual TARGTepo AUC, revealed that TARGTepo maintained Hb within the desired range in patients with an order of magnitude smaller exposure to EPO compared to rHuEPO. This observation may have significant clinical benefits. No treatment related serious adverse events have been reported. TARGTEPO is a promising novel therapy for anemia and potentially for other protein deficient diseases.
OC-009 Characterisation and outcome of patients with infliximab induced lupus erythematosus and retreatment with a second anti-tumour necrosis factor agent:
Authors: S Subramanian, V Yajnik, B Sands, G Cullen, J R Korzenik
Journal: Gut (2010)

<h3>Introduction</h3> Drug induced lupus erythematosus (DILE) due to infliximab therapy for inflammatory bowel diseases (IBD) is an uncommon occurrence. It remains uncertain whether patients with infliximab induced DILE could benefit from another anti-tumour necrosis factor (TNF) agent without recurrent DILE. <h3>Methods</h3> We reviewed the case records of patients with infliximab induced DILE diagnosed at Massachusetts General Hospital and noted details of their clinical and immunological profile at presentation. Case notes of patients who were treated with a second anti-TNF agent were examined for evidence of recurrent DILE. <h3>Results</h3> Thirteen patients with infliximab therapy induced DILE were identified with a female to male ratio of 11:2 (Abstract 009). Symmetric large joint arthralgias were noted in all patients; fever and malar rash were noted in 2 and 3 patients, respectively. All patients had high titers of anti-nuclear and anti-double stranded DNA antibody. Median peak ANA titer was 1 in 2560 and 7 out of 13 (53.8%) patients had a titer of 1 in 2560 or greater. Anti-histone antibodies were positive in 4/7 patients tested; human anti-chimeric antibody was negative in the two tested patients. Eight patients were retreated with a second anti-TNF agent (6 certolizumab pegol and 2 adalimumab) of whom two patients (1 adalimumab and certolizumab pegol) developed recurrent DILE. One patient self-discontinued therapy after 2 months despite no recurrence of DILE. Five patients remain well with no recurrence of DILE after a median of 5 months (range 2–6) therapy. <h3>Conclusion</h3> Re-challenge with a further anti-TNF agent in patients who have developed DILE with infliximab is associated with a 25% recurrence rate during short-term follow-up implying that DILE may be drug specific rather than class specific, permitting ongoing treatment with an anti-TNF agent in some patients with infliximab induced DILE.
429. Optimizing Intratumoral Oncolytic Virus Delivery Using Hemodynamic Manipulations
Authors: Amber C. Miller, Rebecca Nace, Lukkana Suksanpaisan, Kah-Whye Peng, Stephen J. Russell
Journal: Molecular Therapy (2015)

Oncolytic virotherapies like vesicular stomatitis virus (VSV) are experimental cancer therapies wherein naturally evolved or engineered viruses selectively infect tumor cells, inducing tumor cell death (oncolysis), immunotherapeutic responses, and tumor regression. Our mathematical model predicts increasing delivery, distribution, and size of intratumoral infectious centers will increase the probability of achieving tumor cure from direct oncolysis. However, currently intratumoral infection is heterogeneously distributed, resulting in intratumoral infection voids. These voids are predicted to be a result of barriers to intratumoral virus that have the potential to be targeted in order to optimize current oncolytic regimens consistent with mathematical predictions. Optimization requires the ability to accurately visualize and analyze intratumoral infection noninvasively in animals. Here we have used dynamic radiohistology in which noninvasive SPECT/CT imaging after the administration of recombinant virus expressing the sodium-iodide symporter (NIS) reporter gene is used to visualize radiotracer uptake at centers of active NIS expression correlating with intratumoral infectious centers. The SPECT/CT data was analyzed using distributive distance transformation algorithms that quantitatively assess changes in intratumoral distribution and infection voids, allowing for testing of the mathematical model predictions. This technique has proven to be valuable in observing location, size, and evolution of intratumoral infectious centers in three dimensions, and quantitative analysis of infection distribution using SPECT/CT data has the potential to increase understanding of barriers to therapeutic success. Hemodynamic changes are thought to alter tumoral perfusion pressure, a barrier to intratumoral virus delivery. Indeed, we show that increasing intratumoral perfusion pressure through an increase in systemic blood pressure results in an increase in survival matched with an increase in delivery shown using the above analytical methods. Conversely, intratumoral delivery decreases with a decrease in blood pressure. This confirms the ability to use a mathematically guided approach to inform and analyze increases in oncolytic virus therapeutic efficacy and highlights the importance of hemodynamic regulation during therapeutic administration.
Bone Marrow Stem Cells Infusion in Treatment of Patients with Acute Myocardial Infarction.
Authors: Lidia Gil, Anna Czyz, Krzysztof Sawinski, Maria Kozlowska-Skrzypczak, Mieczyslaw Komarnicki, Stefan Grajek, Maciej Lesiak, Malgorzata Popiel, Piotr Breborowicz, Andrzej Cieslinski, Rafal Czepczynski, Jerzy Sowinski, Jan Styczynski
Journal: Blood (2006)
MultiplexKRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction
Authors: F. Janku, H.J. Huang, T. Fujii, D.N. Shelton, K. Madwani, S. Fu, A.M. Tsimberidou, S.A. Piha-Paul, J.J. Wheler, R.G. Zinner, A. Naing, D.S. Hong, D.D. Karp, G. Cabrilo, E.S. Kopetz, V. Subbiah, R. Luthra, B.K. Kee, C. Eng, V.K. Morris, G.A. Karlin-Neumann, F. Meric-Bernstam
Journal: Annals of Oncology (2016)
Geographic Variations and Temporal Trends in Cesarean Delivery Rates in China, 2008-2014
Authors: Hong-Tian Li, Shusheng Luo, Leonardo Trasande, Susan Hellerstein, Chuyun Kang, Jia-Xin Li, Yali Zhang, Jian-Meng Liu, Jan Blustein
Journal: JAMA (2017)

<h3>Importance</h3> The increasing use of cesarean delivery is an emerging global health issue. Prior estimates of China's cesarean rate have been based on surveys with limited geographic coverage. <h3>Objective</h3> To provide updated information about cesarean rates and geographic variation in cesarean use in China. <h3>Design, Setting, and Data Sources</h3> Descriptive study, covering every county (n = 2865) in mainland China's 31 provinces, using county-level aggregated information on the number of live births, cesarean deliveries, maternal deaths, and perinatal deaths, collected by the Office for National Maternal &amp; Child Health Statistics of China, from 2008 through 2014. <h3>Exposures</h3> Live births. <h3>Main Outcomes and Measures</h3> Annual rate of cesarean deliveries. <h3>Results</h3> Over the study period, there were 100 873 051 live births, of which 32 947 229 (32.7%) were by cesarean delivery. In 2008, there were 13 160 634 live births, of which 3 788 029 (28.8%) were by cesarean delivery and in 2014 there were 15 123 276 live births, of which 5 280 124 (34.9%) were by cesarean delivery. Rates varied markedly by province, from 4.0% to 62.5% in 2014. Despite the overall increase, by 2014 rates of cesarean delieries in 14 of the nation's 17 "super cities" had declined by 4.1 to 17.5 percentage points from their earlier peak values (median, 11.4; interquartile range, 6.3-15.4). In 4 super cities with the largest decreases, there was no increase in maternal or perinatal mortality. <h3>Conclusions and Relevance</h3> Between 2008 and 2014, the overall annual rate of cesarean deliveries increased in China, reaching 34.9%. There was major geographic variation in rates and trends over time, with rates declining in some of the largest urban areas.
Heparin-Induced Thrombocytopenia in Patients with Coronary Artery Disease: A Common but Underdiagnosed Syndrome.
Authors: Min Ju Kim, Se Hoon Park, Tae Hoon Ahn, Eak Kyun Shin, Soo-Mee Bang, Eun Kyung Cho, Dong Bok Shin, Jae-Hoon Lee
Journal: Blood (2004)
539. Clinical LV Design Incorporating Human-Derived Cell-Fate Control (Suicide) Elements
Authors: William M. McKillop, Bryan C.Y. Au, Cesar Moncada, Nadejda Andreev, Carolyn A. Keever-Taylor, William R. Drobyski, Mark D. Minden, Christopher J. Paige, Jeffrey A. Medin
Journal: Molecular Therapy (2015)

We have previously reported on cell-fate control or 'suicide' transgenes based on the human enzymes deoxyCytidine Kinase (dCK) and Thymidylate Kinase (tmpK). These cell-fate control systems are based on modified human kinases, which convert exogenous non-toxic pro-drugs into toxic products. Modified dCK activates bromovinyldeoxyuridine (BVdU), l-deoxythymidine (LdT), l-deoxyuridine (LdU), etc., to become cytotoxic compounds that induce apoptosis. Modified tmpK specifically acts on metabolites of azidothymidine (AZT). It converts AZT-MP to AZT-DP. Subsequent conversion to AZT-TP results in inducible-programmed cell death of tmpK-transduced cells. Recently we have fused these 'suicide' transgenes to a cytoplasmic tail-truncated human LNGFR (CD271), a cell surface marker, enforcing a one-to-one correlation between components. Both the trLNGFRdCK and trLNGFRtmpK constructs follow an IRES element in bicistronic lentivectors (LVs) ensuring transfer of the therapeutic construct and the cell-fate control element into the same target cells. This system offers a robust method to eradicate transduced cells at the end of treatment or upon observation of adverse events. It also provides a facile method for vector tracking, and facilitates the evaluation of vector transduction efficiency and selection of expanded transduced cells ex vivo. Currently, we are engineering these cell-fate control elements into 3 independent LVs for clinical application: 1) in an IL-12-based construct to generate anti-tumor vaccines in AML, 2) to engineer overexpression of a lysosomal hydrolase to treat Fabry disease, and 3) to mitigate the graft-versus-host disease response resulting from adoptive T cell transfers. Pre-clinical data suggests significant expression of IL-12 in ex vivo transduced patient AML blasts and near complete AZT-responsive cell death. Our LV designed for treatment of Fabry disease restores stable alpha-galactosidase A activity in ex vivo-transduced CD34+ HSCs and provides a mechanism for their death upon AZT addition if needed. The trLNGFRtmpK construct will provide a marker for ex vivo expansion of T cells carrying the cell-fate control cassette and allow for selective ablation of those cells if graft-versus-host disease occurs. Indeed, we have observed significant transduction frequencies and inducible death of transduced human T cells upon AZT addition. The trLNGFRdCK and trLNGFRtmpK constructs are novel human-derived cell-fate control ('suicide') elements for use in clinical vector design.
Abstract 2153: Kinome inhibitor screen identifies kinase inhibitors that inhibit selectively the survival of mutant K-Ras-dependent human cancer cells
Authors: Norbert Berndt, Xiaolei Zhang, Rays H.Y. Jiang, Said M. Sebti
Journal: Cancer Research (2015)

Abstract While mutant (mt) KRas has proven to be difficult to target directly, mt KRas-driven cancer cells may gain dependencies on other signal transduction pathways. Therefore, exploring these dependencies may lead to the discovery of pathways and targets whose inhibition may induce synthetic lethality in cancer cells that depend on mt KRas. We have screened a kinase inhibitor library against 7 human cancer cell lines that harbor mt KRas; 4 mt KRas-dependent (A427 and H358 (lung), SW620 and SK-CO-1 (colon)); and 3 mt KRas-independent (HCT116, DLD-1 and HCT-8 (colon)) to identify kinase inhibitors that selectively inhibit the survival of mt KRas-dependent cancer cells. Our results show that 13 of the kinase inhibitors suppressed potently the survival of all 7 human cancer cell lines, 31 inhibited very weakly and 84 inhibited differentially each cell line, and the remaining compounds showed varied activities across cell lines. Importantly, 7 kinase inhibitors inhibited preferentially (p&amp;lt; 0.01) the viability of mt KRas-dependent over -independent human cancer cell lines. These results suggested that the 7 compounds may target kinases whose inhibition preferentially affects mt KRas-dependent cells. Analysis of the kinases that are targeted by these inhibitors revealed that these compounds target predominantly tyrosine kinases suggesting that at least in these cell lines these compounds may disrupt mt KRas “addiction” by inhibiting tyrosine kinase-dependent signaling. Citation Format: Norbert Berndt, Xiaolei Zhang, Rays H.Y. Jiang, Said M. Sebti. Kinome inhibitor screen identifies kinase inhibitors that inhibit selectively the survival of mutant K-Ras-dependent human cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2153. doi:10.1158/1538-7445.AM2015-2153
Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4
Authors: Stacey A. Ward, Nicole M. Warrington, Sara Taylor, Najla Kfoury, Jingqin Luo, Joshua B. Rubin
Journal: Cancer Research (2016)

Abstract The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416–26. ©2016 AACR.
Abstract CT304: Phase Ib trial of trastuzumab emtansine (TE) in combination with lapatinib (L) plus nab-paclitaxel (A) in metastatic HER2-neu overexpressed breast cancer patients: STELA trial results
Authors: Tejal Patel, Jaime Mejia, Angel Rodriguez, Jenny Chang
Journal: Cancer Research (2015)

Abstract Background: Multiple large randomized clinical trials have demonstrated that dual HER2 targeted therapies are synergistic and result in improved efficacy. We conducted a phase Ib trial of trastuzumab-emtansine (TE) and lapatinib (L), together with Nab paclitaxel (A) in patients with HER2 over-expressed stage IV breast cancer. Methods: Key inclusion criteria are stage IV HER2 positive breast cancer, LVEF ≥ 45%, and Peripheral neuropathy &amp;lt; grade 2. Primary phase Ib objective was to evaluate the maximum tolerated dose (MTD) of TE with L and A using a standard 3+3 dose de-escalation design for up to 9 patients. Safety, tumor response and pharmacokinetics (PK) were also assessed. Dose limiting toxicities (DLTs) were defined as ≥ grade 3 non hematological toxicity attributed to the study drugs. Results: Nine patients, median age 47 (range 44-64) years were enrolled. All patients are currently off the study. The DLTs were grade 3 diarrhea (n = 1) and grade 3 elevated transaminase (n = 1). Grade 3-4 hematological toxicities included neutropenia (N = 6) and thrombocytopenia (N = 1). Other AEs included grade 1-2 mucositis (n = 2), diarrhea (N = 2), and liver function tests abnormality (N = 5). The 24 hour trough levels of each of the drug were within the range of the values reported in the literature. The MTD of TE, L and A was reached at: TE 3.0 mg/kg, Lapatinib 750mg and Abraxane (A) 80 mg/m2. Eight patients, with a median of 1 prior metastatic therapy (range 0-5) were evaluable for response. Five patients, 62.5% derived clinical benefit, including 1 patient with complete response and 4 patients with partial response. Conclusions: TE plus L and A therapy was well tolerated with antitumor activity observed. STELA Ib trial has been expanded to include twelve additional patients for safety and efficacy evaluation. Citation Format: Tejal Patel, Jaime Mejia, Angel Rodriguez, Jenny Chang. Phase Ib trial of trastuzumab emtansine (TE) in combination with lapatinib (L) plus nab-paclitaxel (A) in metastatic HER2-neu overexpressed breast cancer patients: STELA trial results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT304. doi:10.1158/1538-7445.AM2015-CT304