tbuckley/cabot-search huggingface dataset:
Abstract 2659: A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer
Authors: Charly R. Good, Jozef Madzo, Shinji Maegawa, Nora Engel, Jaroslav Jelinek, Jean-Pierre Issa
Journal: Cancer Research (2016)

Abstract TET1 is a DNA demethylase that regulates DNA methylation, hydroxymethylation and gene expression patterns. It has a catalytic domain that oxidizes methylated cytosine into 5-hydroxymethylcytosine and can then be further oxidized or converted to un-methylated cytosine. TET1 has a CXXC domain that allows it to recognize and bind to long stretches of CpG dinucleotides, known as CpG islands (CGIs). Our previous work found TET1 to protect CGIs from aberrant methylation and that the CXXC domain limits its ability to regulate genes outside of CGIs. However, many of the methylation changes in cancer are outside CGIs. To determine if TET1 could possibly play a role in this hypomethylation, we searched for alternatively spliced forms of the protein. We identified a novel isoform of TET1 (TET1ALT) that lacks the CXXC domain but retains the demethylase domain. TET1ALT has a unique transcription start site from a strong alternate promoter upstream of exon 3, yielding a protein with a unique translation start site. We confirmed promoter activity using Luciferase constructs, and confirmed TET1ALT translation and function through overexpression experiments. Gene expression analyses by qPCR found that TET1ALT is silenced in mESCs but becomes activated in select embryonic and adult tissues while full length TET1 is favored in mESCs, but is repressed in adult tissues. Thus, there is an isoform switch during differentiation and TET1ALT is the major isoform expressed in adult cells. TET1ALT is over expressed in several cancer cell lines, including breast cancer. In conclusion, we have identified a novel isoform of TET1 that has the potential to regulate DNA methylation outside of CGIs and is the predominant isoform expressed in adult cells. We are investigating the hypothesis that TET1ALT may contribute to the methylation changes observed in cancer outside of CGIs, such as in gene bodies and in enhancers. Citation Format: Charly R. Good, Jozef Madzo, Shinji Maegawa, Nora Engel, Jaroslav Jelinek, Jean-Pierre Issa. A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2659.
Abstract 222: Inhibitors of mitochondrial transcription (IMT) specifically affect cancer cell proliferation
Authors: Tim Bergbrede, Axel Choidas, Raffaela Di Lucrezia, Sascha Menninger, Anke Unger, Koch Uwe, Peter Nussbaumer, Nina Bonekamp, Emily Hoberg, Victor Posse, Andrea Felser, Maria Falkenberg, Nils Göran Larsson, Claes M. Gustafsson, Bert M. Klebl
Journal: Cancer Research (2016)

Abstract Mitochondria contain a unique DNA genome (mtDNA) that encodes a number of key components of the respiratory chain. Levels of mtDNA gene expression correlate with the metabolic requirements of mammalian cells. Recently, the role of mitochondrial function for the development and progression of cancer has been highlighted. Oncogenes have been identified to redirect mitochondrial functions to increase cancer cell survival. Increased levels of oxidative phosphorylation have also been implicated in cancer cell resistance towards drugs. In agreement with this notion, compounds that inhibit respiration may specifically target such resistant cells. Finally, it was demonstrated that inhibition of mitochondrial gene expression leads to apoptosis in rapidly dividing cells. Based on these observations, we present a completely novel principle different from known electron transfer chain blockers to treat cancer by inhibiting mtDNA transcription. To this end a study to identify and characterize inhibitors of mitochondrial transcription (IMTs) with lead-like properties was initiated. A high throughput biochemical screening campaign was performed identifying small molecular weight inhibitors of PolRMT, the mitochondrial RNA polymerase, which controls mtDNA transcription. Upon hit optimization, potent compounds with biochemical and cellular IC50s in the low nanomolar range have been identified. IMTs displayed good physicochemical and pharmacological properties. They have been shown to be inactive on other RNA polymerases proving their excellent specificity. Testing IMTs in assays for cancer cell proliferation revealed potent inhibition of sensitive cell lines (double digit nanomolar range). Interestingly, none of the tested primary non-cancer cell lines was affected by the IMTs, indicating a good therapeutic window. Testing selected IMTs in pharmacokinetic studies in vivo revealed high exposures and no detectable adverse effects (single and repeated dosing). Medicinal chemistry optimization will help to identify candidate compounds for efficacy testing in xenograft models. Citation Format: Tim Bergbrede, Axel Choidas, Raffaela Di Lucrezia, Sascha Menninger, Anke Unger, Koch Uwe, Peter Nussbaumer, Nina Bonekamp, Emily Hoberg, Victor Posse, Andrea Felser, Maria Falkenberg, Nils Göran Larsson, Claes M. Gustafsson, Bert M. Klebl. Inhibitors of mitochondrial transcription (IMT) specifically affect cancer cell proliferation. [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 222.
Bilateral adrenal tuberculosis diagnosed by endoscopic ultrasound-guided fine-needle aspiration cytology
Authors: Malay Sharma, Amol Patil, Piyush Somani
Journal: Endoscopy (2016)

A 35-year-old patient presented with a 1-month history of fever, fatigue, and loss of weight and appetite. Clinical examination was unremarkable except for hypotension (90/60 mmHg). The cause of fever could not be ascertained from routine investigations. Biochemistry results were: serum albumin 2.8 gm/dL, international normalized ratio 1.4, serum cortisol 4 µg/dL, serum sodium 122 mEq/L, and serum potassium 5.8 mEq/L.
Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results
Authors: C. Loquai, A. Pavlick, D. Lawson, R. Gutzmer, J. Richards, M. E. Gore, C. J. de Boer, C. Uhlar, Z. Lang, S. O'Day
Journal: Journal of Clinical Oncology (2009)

9029 Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-α v integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m 2 ) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (&lt;20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC. Centocor, Centocor Research and Development, Inc. Centocor Research and Development, Inc. Johnson &amp; Johnson Centocor Research and Development, Inc. No significant financial relationships to disclose.
Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology
Authors: Lindsey Robert Baden, Sankar Swaminathan, Michael Angarone, Gayle Blouin, Bernard C. Camins, Corey Casper, Brenda Cooper, Erik R. Dubberke, Ashley Morris Engemann, Alison G. Freifeld, John N. Greene, James I. Ito, Daniel R. Kaul, Mark E. Lustberg, Jose G. Montoya, Ken Rolston, Gowri Satyanarayana, Brahm Segal, Susan K. Seo, Shmuel Shoham, Randy Taplitz, Jeffrey Topal, John W. Wilson, Karin G. Hoffmann, Courtney Smith
Journal: Journal of the National Comprehensive Cancer Network (2016)

Infectious diseases are important causes of morbidity and mortality in patients with cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This portion of the guidelines highlights the sections on antifungal and antiviral prophylaxis. Antifungal and antiviral prophylaxis recommendations have expanded over the past few years. New agents for the treatment of fungal infections and incorporation of therapeutic drug monitoring are presented. Antiviral prophylaxis for hepatitis B and management considerations for hepatitis C and HIV have been further developed.
Abstract 2532: Alginate-based 3D system for the enrichment and culture of cancer stem cells
Authors: Karen A. Simon, Sylaja Murikipudi, Harry A. Rogoff, Chiang J. Li
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSCs)—cancer cells which have the ability to undergo “self-renewal” are considered to be responsible for the recurrence and metastasis of tumors. The development of a culture system which can mimic aspects of the tumor microenvironment within the cancer stem cell niche is important to elucidate the mechanisms that underlie the growth and survival of CSCs and to identify compounds that can target and eliminate this highly malignant cell population. Here we demonstrate the use of an alginate-based 3D cell culture as an in vitro system for enriching and maintaining the stemness properties of cancer cell lines. In this work, we used alginate gels as a three-dimensional (3D) matrix to culture cancer cell lines. Alginate is an ideal system for CSC because of its inertness and ability to provide a hypoxic environment essential for maintaining the stem-like properties of these cells. We found that cells cultured in the alginate 3D matrix have increased CSC-related gene expression and alterations in metabolic-related gene expression that are consistent with changes reported to occur in CSC that help them to maintain their drug resistant and invasive properties. In order to be useful as a drug screening platform to identify CSC targeting agents, we verified that the high stemness characteristics of the cells cultured in the alginate 3D matrix can be maintained over multiple passages and many months of continuous culture. The CSC cultures in the alginate 3D matrix were found to be resistant to both conventional chemotherapy and targeted therapeutics, while remaining sensitive to CSC targeting agents BB608 and BB503. These results support the potential of the alginate 3D culture system in the enrichment and expansion of CSCs, and provide a reliable in vitro system for the development and evaluation of CSC-targeting agents. Citation Format: Karen A. Simon, Sylaja Murikipudi, Harry A. Rogoff, Chiang J. Li. Alginate-based 3D system for the enrichment and culture of cancer stem cells. [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 2532.
Cost-effectiveness of community-based screening and treatment for chronic hepatitis B in The Gambia: an economic modelling analysis
Authors: Shevanthi Nayagam, Lesong Conteh, Elisa Sicuri, Yusuke Shimakawa, Penda Suso, Saydiba Tamba, Ramou Njie, Harr Njai, Maud Lemoine, Timothy B Hallett, Mark Thursz
Journal: The Lancet Global Health (2016)

BackgroundDespite the high burden of hepatitis B virus (HBV) infection in sub-Saharan Africa, absence of widespread screening and poor access to treatment leads to most people remaining undiagnosed until later stages of disease when prognosis is poor and treatment options are limited. We examined the cost-effectiveness of community-based screening and early treatment with antiviral therapy for HBV in The Gambia.MethodsIn this economic evaluation, we combined a decision tree with a Markov state transition model to compare a screen and treat intervention consisting of adult community-based screening using a hepatitis B surface antigen (HBsAg) rapid test and subsequent HBV antiviral therapy versus current practice, in which there is an absence of publicly provided screening or treatment for HBV. We used data from the PROLIFICA study to parameterise epidemiological, primary screening, and cost information, and other model parameter inputs were obtained from a literature search. Outcome measures were cost per disability-adjusted life-year (DALY) averted; cost per life-year saved; and cost per quality-adjusted life-year (QALY) gained. We calculated the incremental cost-effectiveness ratios (ICERs) between current practice and the screen and treat intervention. Costs were assessed from a health provider perspective. Costs (expressed in 2013 US$) and health outcomes were discounted at 3% per year.FindingsIn The Gambia, where the prevalence of HBsAg is 8·8% in people older than 30 years, adult screening and treatment for HBV has an incremental cost-effectiveness ratio (ICER) of $540 per DALY averted, $645 per life-year saved, and $511 per QALY gained, compared with current practice. These ICERs are in line with willingness-to-pay levels of one times the country's gross domestic product per capita ($487) per DALY averted, and remain robust over a wide range of epidemiological and cost parameter inputs.InterpretationAdult community-based screening and treatment for HBV in The Gambia is likely to be a cost-effective intervention. Higher cost-effectiveness might be achievable with targeted facility-based screening, price reductions of drugs and diagnostics, and integration of HBV screening with other public health interventions.FundingEuropean Commission.
ECOG 8141: A prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high grade upper tract urothelial carcinoma.
Authors: Jean H. Hoffman-Censits, Vitaly Margulis, Noah M. Hahn, Edouard John Trabulsi, Allison Beaver, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2016)

TPS4585 Background: Upper tract urothelial cancer (UTUC) accounts for approximately 5% of all urothelial cancers. At presentation, 30% of patients demonstrate invasive and/or locally advanced disease, 30-40% have regional lymph node involvement, and 20% harbor metastatic disease. Five-year cancer specific survival (CSS) rates for pT2 and pT3 tumors are 73% and 40%, respectively. For the more common urothelial bladder cancer, cisplatin based neoadjuvant chemotherapy (NAC) is supported by Level 1 evidence with a 5% absolute improvement in overall survival compared to cystectomy alone, and a pathologic complete response rate (pCR) of 38%. There are no large scale prospective data on the use of NAC in UTUC. NCCN guidelines for UTUC recommend consideration of adjuvant chemotherapy in selected patients. Poor renal function after radical nephroureterectomy (RNU) limits cisplatin candidacy, highlighting the potential greater urgency for NAC in this population compared to bladder cancer. A large retrospective study of NAC prior to RNU for UTUC demonstrated a 14% pCR rate. Favorable oncologic outcomes with NAC for UTUC have been reported compared to historic controls. Methods: Sixty patients with high grade UTUC without metastases who are planned for RNU will be enrolled. The presence of high grade disease on biopsy histology or a positive urine cytology with a radiographically visible upper tract tumor is required. Patients with CrCl > 50 will receive accelerated MVAC and those with CrCl > 30 and < 50 will receive carboplatin and gemcitabine, both for 4 cycles. We hypothesize that NAC for high-grade UTUC prior to RNU will be well tolerated, and result in an 18% pCR rate. Distant recurrence-free survival, event-free survival, bladder cancer-free survival, cancer specific survival, and renal functional outcomes will be measured. Blood and pathologic samples will be collected for evaluation of markers of chemotherapy response/resistance. Clinical trial information: NCT02412670.
Abstract 5001: Quantitative systems pharmacology modeling and analysis provides biological insights into anti-PD-1 dosing and predicts optimal PD-1 x TIM-3 therapeutic properties for bispecifics and fixed dose combinations in immuno-oncology
Authors: Joshua Apgar, Jamie Wong, Ryan Phennicie, Robert Mabry, Tatiana Novobrantseva, Michael Briskin, John M. Burke
Journal: Cancer Research (2016)

Abstract The goal of this collaboration was to enable early quantitative thought experiments and risk assessments by developing and interrogating a quantitative systems pharmacology (QSP) model of the co-modulation inhibitory receptors PD-1 and TIM-3 in immuno-oncology. The QSP model was to: (1) provide predictions of best-in-class profiles for a PD-1 and TIM-3 fixed dose combination (FDC) and dual antagonist platforms, and (2) provide biological insights. The QSP model was based on first principles as a system of elementary mass-action, mechanistic PKPD, ordinary differential equations. The model parameters and reactions were based on biophysics, and are interpretable. The model reactions include protein synthesis and elimination, ligand-receptor and drug-target formation and turnover, and drug administration and first order clearance. There were four versions of the model: PD-1 monospecific, TIM-3 monospecific, PD-1 x TIM-3 bispecific and fixed dose combination (FDC) targeting PD-1 and TIM-3. The monospecific models were then benchmarked against published data such that model parameter values were set to known values and unknown parameters were estimated. Once benchmarked, the FDC and bispecific models were analyzed by systematically investigating how tuning the model parameters (e.g., affinity, avidity, dose, half-life, target expression, etc.) impacted target inhibition, and to simulate patient variability. The model predictions were in good agreement with published clinical data from Nivolumab and Pembrolizumab, providing a hypothesis for the apparent inconsistencies in similar clinical doses for therapeutics with affinities differing by several orders of magnitude, and data from RMT3-23 in the TIM-3 driven mouse model. QSP model analysis predicted: (1) there would be diminishing returns on very tight binding biologics due to Target Mediated Drug Disposition (TMDD) that offsets potency, and (2) there is no advantage between FDC, 2-2 bispecific, and 2-1 bispecific formats, which are predicted to be roughly equivalent. Citation Format: Joshua Apgar, Jamie Wong, Ryan Phennicie, Robert Mabry, Tatiana Novobrantseva, Michael Briskin, John M. Burke. Quantitative systems pharmacology modeling and analysis provides biological insights into anti-PD-1 dosing and predicts optimal PD-1 x TIM-3 therapeutic properties for bispecifics and fixed dose combinations in immuno-oncology. [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 5001.
Hemophagocytic Lymphohistiocytosis in a Patient with Relapsed Chronic Lymphocytic Leukemia Treated with Ibrutinib
Authors: Maria Ciccone, Maurizio Cavallari, Simonetta Falzoni, Francesco Cavazzini, Olga Sofritti, Luca Formigaro, Francesco Di Virgilio, Gian Matteo Rigolin, Antonio Cuneo
Journal: Blood (2015)
Abstract 2816: Evaluation of Cdk5 inhibitors in neural crest tumors
Authors: Robin E. Norris, John J. Pink, Tej Pareek, John L. Letterio
Journal: Cancer Research (2016)

Abstract Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed proline-directed serine threonine kinase active mainly in post-mitotic neurons due to abundant expression of its obligate activating partners p35 and/or p39. Cdk5 has been viewed narrowly as a neuron-specific kinase and as an essential regulator of neuronal function and migration. Recently, Cdk5 activity has been implicated in mediating tumor invasion, progression, and metastasis. We have found invariably high expression and activity of Cdk5/p35 in a series of pediatric tumor cell lines including neuroblastoma. To evaluate the potential role of Cdk5 inhibitors in the treatment of neural crest tumors, we evaluated the in vitro kinase activity and growth inhibition of 4 Cdk5 inhibitors (AT7519, dinaciclib, flavopiridol, and seliciclib). We compared the in vitro activity against Cdk2/cyclin E, Cdk5/p25, Cdk5/p35, Cdk7/cyclin H, and Cdk9/cyclin K. Using a DNA-based proliferation assay, we assessed the in vitro growth inhibition in a panel of 10 neural crest-derived tumors (melanoma, neuroblastoma, Ewing sarcoma). All Cdk5 inhibitors demonstrated enzyme and growth inhibition at clinically achievable concentrations. Dinaciclib was the most potent inhibitor of Cdk5/p35 with an enzyme IC50 of 0.0002 μM, compared to 0.003 μM for AT7519, 0.021 μM for flavopiridol, and 0.097 μM for seliciclib. Dinaciclib was also the most potent inhibitor of Cdk2. However, flavopiridol and AT7519 were the most potent inhibitors of Cdk7 and Cdk9, respectively. Across all cell lines, dinaciclib was the most potent inhibitor of growth. The median (range) growth inhibition IC50 for dinaciclib was 0.006 μM (0.004 - 0.14), compared to 0.079 μM (0.045-0.16) for flavopiridol, 0.52 μM (0.14 - &amp;gt;15) for AT7519, and 13.2 μM (7.8 - 22.1) for seliciclib. Interestingly, within the Ewing sarcoma cell lines, there was disparate sensitivity to the 2 most potent Cdk5 inhibitors, dinaciclib and AT7519. Based on the activity of these Cdk inhibitors in neural-crest tumors, we expanded our evaluation of AT7519 in 6 pediatric tumor cell lines (medulloblastoma, rhabdomyosarcoma, osteosarcoma) and found similar in vitro potency with a median (range) IC50 of 0.43 μM (0.20 - 1.26). AT7519, dinaciclib, flavopiridol, and seliciclib demonstrated in vitro growth inhibition in a panel of neural crest and pediatric solid tumor cell lines at clinically achievable concentrations. Further in vivo evaluations and in vitro combination studies including this novel class of agents in models of neural crest and select pediatric cancers are warranted. Citation Format: Robin E. Norris, John J. Pink, Tej Pareek, John L. Letterio. Evaluation of Cdk5 inhibitors in neural crest tumors. [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 2816.