tbuckley/cabot-search huggingface dataset:
Treatment With G-CSF Reduces Acute Myeloid Leukemia (AML) Blasts Viability In Presence Of Bone Marrow Stroma
Authors: Meritxell Nomdedeu, Marta Pratcorona, Marina Díaz-Beyá, Xavier Calvo, Mari Carmen Lara-Castillo, Daniel Esteban, Maria Rozman, Dolors Costa, Jordi Esteve, Ruth M. Risueño
Journal: Blood (2013)
Abstract 2356: Erythrocytes used as tumor antigen delivery system to target antigen-presenting cells embody an innovative approach for <i>in situ</i> cancer immunotherapy
Authors: Magali Cremel, Nathalie Guerin, Quitterie Barthe, Vanessa Bourgeaux, Willy Berlier, Françoise Horand, Yann Godfrin
Journal: Cancer Research (2016)

Abstract Introduction: In current vaccine therapy, efficient delivery of tumor antigens (TA) to antigen-presenting cells (APC) represents a major step toward the development of strong TA-specific immune response including cytotoxic T lymphocyte (CTL) induction. Our innovative approach is to use the property of erythrocytes to be naturally phagocytosed by APC when senescent. Indeed, TA can be encapsulated into erythrocytes that will be used as carrier to specifically deliver the TA to APC, which will ensure their degradation and presentation to T cells. Materials and Methods: The proof of concept was established with Ovalbumin (OVA), tyrosinase-related protein 2 (TRP2 (melanoma TA) and prostate specific antigen (PSA, prostate TA). These TA were encapsulated into erythrocytes by a hypotonic lysis process. To stimulate the erythrophagocytosis by APC, the membranes of erythrocytes were coated with antibodies. Then, erythrocytes containing TA were intravenously injected to mice concomitantly with Poly(I:C) adjuvant. The CTL response was analyzed by IFNγ ELISPOT and in vivo lysis of TA-expressing target cells injected to immunized mice. Humoral response was assessed by the determination of TA-specific immunoglobulin titer in mouse serum. Results: All TA were efficiently encapsulated in erythrocytes in a dose-dependent manner. A strong T-cell response was induced after 2 injections of TA encapsulated in erythrocytes: 2μg of OVA and 20μg of TRP2 induced the in vivo lysis of 97% and 96% of TA-target cells, respectively. By comparison, injections of free antigen induced less than 5% of lysis. Furthermore, a significant number of TA-specific IFNγ-secreting cells was generated (1585 and 286 cells / 106 cells for TRP2 and PSA, respectively) compared to the free TA (&amp;lt; 80 cells / 106 cells for both TA). In addition, we established a dose-dependent PSA-specific humoral response. Finally, a significant delay of tumor growth was obtained in mice more than twenty days after the subcutaneous implantation of EG7-OVA or B16F10 (melanoma) tumor cell lines, compared to injections with free antigen or control vehicle. Conclusion: The use of erythrocytes as TA carrier to specifically deliver antigen to APC and induce efficient immune response against tumor can be a very promising strategy in cancer immunotherapy. Citation Format: Magali Cremel, Nathalie Guerin, Quitterie Barthe, Vanessa Bourgeaux, Willy Berlier, Françoise Horand, Yann Godfrin. Erythrocytes used as tumor antigen delivery system to target antigen-presenting cells embody an innovative approach for in situ cancer immunotherapy. [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 2356.
Abstract 2228: Cbl-b inhibitors as novel intra-cellular checkpoint inhibitors for cancer immunotherapy
Authors: Saket Agarwal, Jian Wu, Chris Riling, Matthew Kodrasov, Joseph Weinstock, Ivan Sokirniy, Michael Mattern, Taku Kambayashi, Suresh Kumar
Journal: Cancer Research (2016)

Abstract The approval by the FDA and clinical use of immune checkpoint inhibitors, such as anti-PD1 and anti-CTLA4 antibodies, that activate cytotoxic T lymphocyte (CTL) mediated anti-tumor immune responses against advanced solid tumors has resulted in a paradigm shift in cancer therapy. Antitumor activity of CTLs and NK cells is tightly regulated by intracellular signaling events orchestrated by the ubiquitin signaling system. In particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), a RING finger E3-ubiquitin ligase primarily expressed in immune cells, acts as an intracellular checkpoint and a master negative regulator of both CTLs and NK cells. Accordingly, Cbl-b-/- mice have been observed to reject a variety of implanted metastatic and non-metastatic tumors and to delay significantly the outgrowth of spontaneous tumors; these observed antitumor effects were seen to be mediated by activated CD8+ T cells and NK cells. Based on the overwhelming evidence supporting the role of Cbl-b in immune suppression, this ubiquitin conjugating enzyme is considered a novel target for developing small molecule cancer immunotherapy agents. Using proprietary high throughput screening technologies, Progenra identified novel, selective Cbl-b inhibitors that were shown to decrease ubiquitination of substrates such as TAM receptor kinases (Tyro3) and to activate T cells (as judged by increased IL-2 production) and NK cells (as judged by increased IFNγ production and degranulation) in ex vivo functional assays. ADME/DMPK evaluation and in vivo efficacy of selected Cbl-b inhibitors will be discussed in relation to the therapeutic utility of this class of small molecule agent, which is expected to potentiate the anticancer effects of approved immunotherapy agents. Citation Format: Saket Agarwal, Jian Wu, Chris Riling, Matthew Kodrasov, Joseph Weinstock, Ivan Sokirniy, Michael Mattern, Taku Kambayashi, Suresh Kumar. Cbl-b inhibitors as novel intra-cellular checkpoint inhibitors for cancer immunotherapy. [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 2228.
Abstract 4811: Global demethylation with decitabine increases DNA repair and sensitizes melanoma to carboplatin
Authors: Timothy Budden, Ryan J. Davey, Ricardo E. Vilain, Katie A. Ashton, Stephen Braye, Andre van der Westhuizen, Nikola A. Bowden
Journal: Cancer Research (2016)

Abstract Global genome repair (GGR) is critical for recognizing DNA damage by the chemotherapy agent carboplatin, and triggering apoptotic signalling. XPC is a critical gene in the GGR pathway but in melanoma XPC is not induced in response to carboplatin resulting in extreme resistance. Despite low global methylation levels across the melanoma genome, there is evidence methylation plays a role in suppression of XPC. 5-aza-2’-deoxycytidine (decitabine), is a DNA methyltransferases inhibitor used as a chemotherapy agent that results in global loss of methylation and re-expression of silenced genes. We hypothesised that restoring expression of XPC in melanoma using decitabine could overcome resistance to carboplatin. To confirm low XPC in melanoma tumour tissue, transcript and protein expression from 196 advanced primary and metastatic melanomas was quantified and compared to normal tissue and other cancer types. Melanoma cell lines with low baseline XPC were treated with pharmacological doses of decitabine or carboplatin alone, or in sequential combination. XPC transcript, apoptosis, proliferation, senescence, global and CpG island shore demethylation was quantified. XPC transcript and protein was low in a proportion of melanoma tumours and expression correlated with overall survival. Treatment of melanoma cells with carboplatin alone did not significantly induce XPC expression or increase apoptosis in the majority of melanoma cell lines. Decitabine decreased global methylation (average 44.67% decrease) and increased XPC expression (0.9-3.0 fold increase). Hotspots of demethylation after decitabine treatment in the XPC CpG island shore were detected and could be responsible for the increase in XPC expression. When carboplatin was administered following decitabine, a greater XPC induction (1.5-7.6 fold increase) occurred with significantly increased levels of apoptosis (1.6-2.2 fold increase). This was coupled with a decreased proliferation and the presence of markers of senescence. Knocking down XPC expression with siRNA significantly reduced the effects of combination treatment. The outcomes of this study are evidence that silencing of XPC by methylation is a mechanism of carboplatin resistance in melanoma and sequential combination of decitabine followed by carboplatin may be used to restore GGR function and overcome resistance. Citation Format: Timothy Budden, Ryan J. Davey, Ricardo E. Vilain, Katie A. Ashton, Stephen Braye, Andre van der Westhuizen, Nikola A. Bowden. Global demethylation with decitabine increases DNA repair and sensitizes melanoma to carboplatin. [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 4811.
Case 21-2016
Authors: Andrew Z. Fenves, Pamela W. Schaefer, Jay Luther, Virginia M. Pierce
Journal: New England Journal of Medicine (2016)

A 32-year-old man was admitted to this hospital after being found in an unresponsive state in his jail cell. He had jaundice and encephalopathy; results of liver-function tests were abnormal, and CT revealed cerebral edema. Diagnostic tests were performed.
Abstract 4: Hyper activation of poly(ADP-ribose) polymerase 1 initiates large-scale metabolic changes in a cellular model of glioblastoma
Authors: Anna M. Wilk, Elise Fouquerel, Bobbie Johnston, Samuel A.J. Trammell, Lindsay Schambeau, Joel F. Andrews, Lewis Pannell, Sara J. Cooper, Charles Brenner, Robert W. Sobol
Journal: Cancer Research (2016)

Abstract PARP1 is a key enzyme of the Base Excision Repair (BER) pathway, facilitating the repair of base damage and single-strand DNA breaks. Activated PARP1 synthesizes poly (ADP-ribose) (PAR), triggering chromatin de-condensation to facilitate recruitment of BER proteins to complete repair. PARP1 activation is attenuated upon successful repair of the DNA lesion. However, unrepaired DNA breaks lead to continuous PARP1 activation and cell death. The molecular mechanism underlying PARP1 activation induced cell death was recently revealed as independent from NAD+ depletion. We have shown that PARP1 activation and PAR synthesis affect glycolysis by directly inhibiting the glycolytic enzyme, hexokinase 1 (HK1). Following on these discoveries, we decided to investigate global metabolic changes triggered by hyperactivation of PARP1. For this study, we used gas chromatography mass spectrometry (GC-MS) to quantify over 150 cellular metabolites and Multiple-Reaction Monitoring Liquid Chromatography Mass Spectrometry (MRM LC-MS) to measure NAD+ metabolites. As a model, we tested glioblastoma cells overexpressing methylpurine DNA glycosylase (MPG) to enhance the PARP1-activation response to DNA damage induced by the alkylating agent MNNG. Simultaneously, to monitor independence from the DNA damaging effect of NAD+ depletion, we utilized an inhibitor of NAD+ biosynthesis, FK866. We found that PARP1 activation leads to a strong accumulation of glucose, likely as a secondary effect of HK1 inhibition. In addition, we observed a significant change in the level of other metabolites including an increase in inosine, inosine monophosphate (IMP), cytidine and uridine levels upon PARP1 activation, suggesting an indirect effect of PARP1 activation on purine and pyrimidine metabolism. Ongoing studies will use these global approaches to unravel the complete metabolic response of cancer cells to genotoxic treatment. Citation Format: Anna M. Wilk, Elise Fouquerel, Bobbie Johnston, Samuel A.J. Trammell, Lindsay Schambeau, Joel F. Andrews, Lewis Pannell, Sara J. Cooper, Charles Brenner, Robert W. Sobol. Hyper activation of poly(ADP-ribose) polymerase 1 initiates large-scale metabolic changes in a cellular model of glioblastoma. [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 4.
Characterization of Lentiviral Vector Derived Anti-Bcma CAR T Cells Reveals Key Parameters for Robust Manufacturing of Cell-Based Gene Therapies for Multiple Myeloma
Authors: Graham Lilley, Alden Ladd, Daniel Cossette, Laura Viggiano, Gregory Hopkins, John W. Evans, Mingli Li, Howard J. Latimer, Sara M. Miller, Michael Kuczewski, Wendy Bakeman, Kayla MacLeod, Kevin M. Friedman, Dawn A Maier, Michael Paglia, Richard A. Morgan, Mark D Angelino
Journal: Blood (2015)
Abstract 3954: Prospective evaluation of circulating tumor cells (CTCs) in head and neck cancer patients receiving definitive radiotherapy with a nanotechnology based system
Authors: Joseph M. Caster, Michael J. Eblan, Kyle Wang, Ja Hye Myung, Bhishamjit Chera, Seungpyo Hong, Andrew Z. Wang
Journal: Cancer Research (2016)

Abstract Background: Circulating tumor cells (CTCs) are an important biomarker in cancer. There has been substantial interest in utilizing CTCs to enable personalized treatment. However, there is limited data on CTCs in patients with head and neck cancers (HNC) where there is growing data that curative treatment needs to be risk-based. The purpose of this prospective, correlative study is to investigate the clinical significance of CTCs, as measured by a highly sensitive CTC capture technology UiChip, in HNC patients undergoing definitive treatment. Methods: HNC patients (M0) undergoing definitive treatment (radiation+/- chemotherapy) were enrolled. Peripheral blood was collected prior to starting RT, at the first week, mid-point, final week of treatment, and every 4 to 12 weeks after completion. Quantification of CTCs was conducted using UiChip. The primary endpoint was change in CTCs pre- and post- RT. Results: 35 patients are included in this analysis (median age 58, 34% non-smokers, 69% HPV/p16 positive, and 17% node (-)) and 90% received chemotherapy. CTCs were detected in all patients pre-RT (100%). There was no association between pre-RT CTC level and tumor or nodal stage. Median CTCs significantly decreased from 71 CTCs/mL (range, 7-849) before RT to 32 (2-209) at completion of RT and 27 (2-78) at 4 to 12 weeks post-treatment. Ten patients had persistent disease and/or distant metastasis at a median follow-up of 10.6 months (range, 3.7-17). CTCs declined throughout treatment in patients with complete clinical and/or radiographic responses, in contrast to an elevation in CTCs at mid or post-RT in the 7 patients with pathologic residual disease/distant failures. Conclusions: We demonstrated that the novel UiChip can capture CTCs in a diverse population of head and neck cancer patients. Our pilot data suggest that individual patient CTC changes during and after treatment may be a predictive biomarker for radiotherapy response and clinical outcomes. Table: Median CTCs/mL Peripheral Blood (Median% of Pre-Treatment Baseline Count)Pre-RTMid-RTPost-RTNumber (%) of CTCs in Complete Responders to RT (N = 18)67 IQR: 39-11737 (38%) IQR: 22-79 (18-94%)21 (18%) IQR: 7-40 (13-42%)Number (%) of CTCs in Partial Responders to RT (N = 7)120 IQR: 36-30366 (123%) IQR: 20-134 (30-172%)51 (45%) IQR: 23-54 (17-63%) Citation Format: Joseph M. Caster, Michael J. Eblan, Kyle Wang, Ja Hye Myung, Bhishamjit Chera, Seungpyo Hong, Andrew Z. Wang. Prospective evaluation of circulating tumor cells (CTCs) in head and neck cancer patients receiving definitive radiotherapy with a nanotechnology based system. [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 3954.
Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor
Authors: C. Cerva, L. Colagrossi, G. Maffongelli, R. Salpini, D. Di Carlo, V. Malagnino, A. Battisti, A. Ricciardi, M. Pollicita, A. Bianchi, A. Picardi, L. Cudillo, R. Cerretti, G. De Angelis, M. Cantonetti, M. Andreoni, C.F. Perno, W. Arcese, V. Svicher, L. Sarmati
Journal: Clinical Microbiology and Infection (2016)
Microvascular and Macrovascular Disease and Risk for Major Peripheral Arterial Disease in Patients With Type 2 Diabetes
Authors: Kamel Mohammedi, Mark Woodward, Yoichiro Hirakawa, Sophia Zoungas, Bryan Williams, Liu Lisheng, Anthony Rodgers, Giuseppe Mancia, Bruce Neal, Stephen Harrap, Michel Marre, John Chalmers
Journal: Diabetes Care (2016)

OBJECTIVE Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD-induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately. RESULTS Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38–2.64], P &amp;lt; 0.0001) and retinal photocoagulation therapy (1.60 [1.11–2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower-limb ulceration (2.07 [1.56–2.75], P &amp;lt; 0.0001) and amputation (1.59 [1.15–2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13–2.73], P = 0.01). CONCLUSIONS Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not.
Lymph Node Count From Neck Dissection Predicts Mortality in Head and Neck Cancer
Authors: Vasu Divi, Michelle M. Chen, Brian Nussenbaum, Kim F. Rhoads, Davud B. Sirjani, F. Christopher Holsinger, Jennifer L. Shah, Wendy Hara
Journal: Journal of Clinical Oncology (2016)

Purpose Multiple smaller studies have demonstrated an association between overall survival and lymph node (LN) count from neck dissection in patients with head and neck cancer. This is a large cohort study to examine these associations by using a national cancer database. Patients and Methods The National Cancer Database was used to identify patients who underwent upfront nodal dissection for mucosal head and neck squamous cell carcinoma between 2004 and 2013. Patients were stratified by LN count into those with &lt; 18 nodes and those with ≥ 18 nodes on the basis of prior work. A multivariable Cox proportional hazards regression model was constructed to predict hazard of mortality. Stratified models predicted hazard of mortality both for patients who were both node negative and node positive. Results There were 45,113 patients with ≥ 18 LNs and 18,865 patients with &lt; 18 LNs examined. The &lt; 18 LN group, compared with the ≥ 18 LN group, had more favorable tumor characteristics, with a lower proportion of T3 and T4 lesions (27.9% v 39.8%), fewer patients with positive nodes (46.6% v 60.5%), and lower rates of extracapsular extension (9.3% v 15.1%). Risk-adjusted Cox models predicting hazard of mortality by LN count showed an 18% increased hazard of death for patients with &lt; 18 nodes examined (hazard ratio [HR] 1.18; 95% CI, 1.13 to 1.22). When stratified by clinical nodal stage, there was an increased hazard of death in both groups (node negative: HR, 1.24; 95% CI, 1.17 to 1.32; node positive: HR, 1.12; 95% CI, 1.05 to 1.19). Conclusion The results of our study demonstrate a significant overall survival advantage in both patients who are clinically node negative and node positive when ≥ 18 LNs are examined after neck dissection, which suggests that LN count is a potential quality metric for neck dissection.
Visual Impairment in Old and Very Old Community-dwelling Asian Adults
Authors: Charumathi Sabanayagam, Eva Fenwick, Peng Guan Ong, Min Li Tey, Robyn Tapp, Ching-Yu Cheng, Gemmy Chui Ming Cheung, Tin Aung, Tien Y. Wong, Ecosse Lamoureux
Journal: Ophthalmology (2016)
Circulating Epstein-Barr Virus DNA in Serum of Patients with Lymphoepithelioma-like Carcinoma of the Lung
Authors: Roger K. C. Ngan, Timothy T. C. Yip, Wai-Wai Cheng, John K. C. Chan, William C. S. Cho, Victor W. S. Ma, Kwong-Kee Wan, Siu-Kie Au, Chun-Key Law, Wai-Hon Lau
Journal: Clinical Cancer Research (2002)

Purpose: The purpose of this work was to study the sera of patients with lymphoepithelioma-like carcinoma (LELC) of the lung for circulating EBV DNA.

Experimental Design: Prospectively collected serum samples from five female patients with advanced, inoperable LELC of the lung were measured for free circulating EBV DNA using a quantitative PCR technique. EBV-encoded small RNA (EBER)-1 was assayed in serial serum samples of three of the five patients, either from the start or during the initial phase of chemotherapy/radiotherapy until their terminal event or last follow-up. There was only a single-point sample for analysis in the fourth and fifth patients. Six other patients with LELC of the lung were also retrospectively identified, and their sera were tested for EBER-1 at either the first visit plus the last follow-up visit ( n = 2), the first visit only ( n = 2), or the last follow-up visit only ( n = 2).

Results: Prospectively collected serum samples from five patients and retrospectively collected serum samples from two patients who had clinical disease at initial serum measurement showed detectable levels of EBER-1. Retrospectively collected serum samples from four patients with no clinical disease had negative sera. There is consistent correlation between the clinical response to treatment and subsequent clinical course of LELC and serum EBER-1 levels in the three prospective patients with longitudinal serum monitoring.

Conclusions: This study shows for the first time that free EBV DNA can be detected in the serum of patients with LELC of the lung and further suggests the feasibility of its use for monitoring response to therapy in advanced cases.
Prognostic Impact of Peripheral Blood Count Recovery and Cytogenetic Remission Prior to Reduced Intensity Allogeneic Transplantation in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndromes
Authors: Moussab Damlaj, Hassan B Alkhateeb, Mehrdad Hefazi, Daniel K. Partain, Aref Al-Kali, Shahrukh K. Hashmi, Naseema Gangat, Mark R Litzow, William J Hogan, Mrinal M Patnaik
Journal: Blood (2015)