tbuckley/cabot-search huggingface dataset:
Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients
Authors: Thomas Condamine, George A. Dominguez, Je-In Youn, Andrew V. Kossenkov, Sridevi Mony, Kevin Alicea-Torres, Evgenii Tcyganov, Ayumi Hashimoto, Yulia Nefedova, Cindy Lin, Simona Partlova, Alfred Garfall, Dan T. Vogl, Xiaowei Xu, Stella C. Knight, George Malietzis, Gui Han Lee, Evgeniy Eruslanov, Steven M. Albelda, Xianwei Wang, Jawahar L. Mehta, Meenakshi Bewtra, Anil Rustgi, Neil Hockstein, Robert Witt, Gregory Masters, Brian Nam, Denis Smirnov, Manuel A. Sepulveda, Dmitry I. Gabrilovich
Journal: Science Immunology (2016)

PMN-MDSC in cancer patients can be distinguished from neutrophils by a genomic signature and by expression of the LOX-1 receptor.
FDA lifts hold on cancer immunotherapy trial placed after patients died
Authors: Owen Dyer
Journal: BMJ (2016)

The US Food and Drug Administration, which halted a trial of a promising but risky immunotherapy for acute lymphoblastic leukemia after hearing of the deaths of three young patients,1 has surprised observers by completing its review and lifting the clinical hold after just three days, in a process that usually takes months.

The FDA’s green light to Juno Therapeutics of Seattle to continue its trial of chimeric antigen receptor T cell (CAR-T) treatment is seen as a vote of confidence in the broader potential of cancer immunotherapy, a burgeoning field of research that was rocked earlier this week when Juno announced the three deaths from cerebral edema in the phase II “ROCKET” trial of its JCAR015 treatment.

CAR-T treatment involves removing T cells from the body, genetically engineering them …
Clofarabine Plus Low-Dose Cytarabine Induction Followed By Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine Consolidation In Acute Myeloid Leukemia Frontline Therapy For Older Patients
Authors: Aziz Nazha, Hagop M. Kantarjian, Farhad Ravandi, Xuelin Huang, Xuemei Wang, Elias Jabbour, Guillermo Garcia-Manero, Tapan M. Kadia, Alessandra Ferrajoli, Marina Konopleva, Gautam Borthakur, Jan A. Burger, Jennie Feliu, Stefan H. Faderl
Journal: Blood (2013)
Abstract 2481A: A novel chemically-modified curcumin (CMC 2.24) promotes chemosensitivity in neuroblastoma
Authors: David Tauber, Basia Galinski, Raquel Castellanos, Joseph Scaduto, Francis Johnson, Lorne Golub, Daniel A. Weiser
Journal: Cancer Research (2016)

Abstract Introduction The chemically modified curcumin, CMC 2.24 (TRB-N0224, Traverse Biosciences Inc.), was designed to overcome the poor solubility, bioavailability, and biological potency of naturally occurring curcumin in an effort to achieve superior safety and efficacy in chronic inflammatory conditions and cancer. It has been demonstrated that CMC 2.24 can sensitize cancer cells that are otherwise refractory to chemotherapy. Patients with neuroblastoma, a highly lethal childhood cancer of the peripheral sympathetic nervous system, often have de novo chemotherapy resistance and therefore succumb rapidly to their disease. We hypothesize that chemoresistance in primary refractory neuroblastoma is mediated by anti-apoptotic mechanisms that can be overcome when conventional therapy is combined with CMC 2.24. Experimental Procedures A heterogeneous panel of neuroblastoma cell lines was cultured under routine conditions and subjected to varying concentrations of CMC 2.24 to establish IC50s. Subsequent studies were focused on NB-EBc1, a MYCN non-amplified cell line, and IMR-5, a MYCN amplified cell line. IC50s were also generated for cisplatin as a single agent, and then when administered in combination with CMC 2.24. Whole protein cell lysates were extracted at 24, 48, and 72 hours after treatment and cell viability was measured by MTT proliferation assays. Results Proliferation defects were observed in all neuroblastoma cell lines treated with CMC 2.24 as compared to vehicle (DMSO) control. Relatively cisplatin-resistant cell lines had diminished cell viability when CMC 2.24 was added in combination with cisplatin, suggesting a synergistic effect. Alterations in response to CMC 2.24 treatment occur in anti-apoptotic proteins survivin and BARD1, found to be upregulated in chemoresistant cell lines. Additional mechanistic evaluation is ongoing. Conclusions There is no known curative therapy for patients with primary refractory neuroblastoma. CMC 2.24 enhances chemosensitivity in a panel of neuroblastoma cell lines and may provide a new therapeutic approach that can overcome de novo chemotherapy resistance. Further mechanistic and in vivo studies are needed to facilitate clinical development of a promising novel anti-cancer agent. Citation Format: David Tauber, Basia Galinski, Raquel Castellanos, Joseph Scaduto, Francis Johnson, Lorne Golub, Daniel A. Weiser. A novel chemically-modified curcumin (CMC 2.24) promotes chemosensitivity in neuroblastoma. [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 2481A.
Arthroscopic surgery for knee pain
Authors: Teppo L N Järvinen, Gordon H Guyatt
Journal: BMJ (2016)

A highly questionable practice without supporting evidence of even moderate quality

With 150 000 knee arthroscopies carried out in the United Kingdom each year, and about five times that number in the United States,1 2 arthroscopic partial meniscectomy—keyhole surgery for middle aged to older adults with knee pain to trim a torn meniscus—is one of the most common surgical procedures. Considering the enormous volume, it is natural to think that there is compelling evidence for the procedure being beneficial. Remarkably, this is not so.

It is barely a decade since the publication of the first controlled trial addressing knee arthroscopy using placebo surgery as a comparator.3 Since then a series of rigorous trials, summarised in two recent systematic reviews and meta-analyses, provide compelling evidence that arthroscopic knee surgery offers little benefit for most patients with knee pain.4 5 The latest …
A Myeloablative Conditioning Regimen With Fludarabine Demonstrates Good Results In UCBT With Hematologic Malignancies, Especially Acute Lymphoblastic Leukemia
Authors: Juan Tong, Sun Zimin, Liu Huilan, Geng Liangquan, Zheng Changcheng, Baolin Tang, Song Kaidi, Yao Wen, Liu Xin, Kaiyang Ding
Journal: Blood (2013)
Abstract 5292: An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets
Authors: Jasmine Dumas, Michael Gargano, Garrett M. Dancik
Journal: Cancer Research (2016)

Abstract The Gene Expression Omnibus (GEO) is a public repository of gene expression and sequence-based datasets, that currently includes &amp;gt;42,000 datasets with gene expression profiles obtained by microarray, and &amp;gt;12,000 datasets containing the keyword “cancer”. Although GEO has its own analysis tool (GEO2R) for identifying differentially expressed genes, evaluation of a single gene is not straightforward, and GEO2R was not designed to identify prognostic biomarkers based on survival analyses. In this work, we describe an online, easy-to-use tool for biomarker analysis in GEO datasets. shinyGEO is a web-based tool that allows a user to download the expression and sample data from a GEO dataset, select a gene of interest, and perform a survival or differential expression analysis in order to evaluate gene expression diagnostic or prognostic biomarkers. For both analyses, shinyGEO produces publication-ready graphics and generates R code ensuring that all analyses are reproducible. The tool is developed using shiny, a web application framework for R, a language for statistical computing and graphics. The web application and source code is available at the following link: http://bioinformatics.easternct.edu/shinyGEO/ Citation Format: Jasmine Dumas, Michael Gargano, Garrett M. Dancik. An online tool for biomarker analysis in Gene Expression Omnibus (GEO) datasets. [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 5292.
New Long-Acting Basal Insulins: Does Benefit Outweigh Cost?
Authors: Eberhard Standl, David R. Owen
Journal: Diabetes Care (2016)

Although insulin introduced nearly a century ago has saved the lives of countless people with diabetes, improvements of this therapy continue as significant unmet needs remain (1–4). Even persons with type 2 diabetes who, compared with those with type 1 diabetes, exhibit a much more stable, yet disordered, metabolic milieu only achieve an intended HbA1c target of 7% or lower without hypoglycemic events in a minority of cases (1,3,4). Hypoglycemia and weight gain represent the most important obstacles to achieving the desired glycemic control with insulin therapy, despite major advances in education and empowerment of people with diabetes, the introduction of self-monitoring of blood glucose, improvement in the technical application of insulin, and the availability of a wide array of insulin preparations including insulin analogs (1–4). Intermediate and long-acting basal insulins represent the cornerstone of any insulin therapy regimen, and human NPH insulin, insulin glargine, and insulin detemir are currently the most widely used members of this class of insulin preparations. Discernable progress has been observed with improved day-to-day variability and a lowering in the risk of hypoglycemia with the introduction of the soluble long-acting preparations insulin glargine and insulin detemir compared with NPH insulin, which requires appropriate resuspension prior to administration to reduce variability (5). Against the background of the aforementioned unmet needs, however, a new generation of long-acting basal insulins has emerged aiming at new standards in terms of pharmacokinetics, efficacy, and safety (Fig. 1).



Figure 1 
Goals of analog design. hypos, hypoglycemia.



Modern drug development occurs in an era of increasingly strict regulations by global institutions such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that rightly demand enhanced safety checks of new chemical entities for clinical use such as the new long-acting insulin …
Abstract 2539: Cell cycle regulation influences the phenotype of breast and prostate cancer stem cells <i>in vitro</i>
Authors: Joseph Feduska, Carnellia Lee, Selvarangan Ponnazhagan
Journal: Cancer Research (2016)

Abstract The dissemination of metastases from the primary tumor accounts for over 90% of cancer-associated mortality. Despite advances on treatment modalities involving chemotherapeutic drugs, radiotherapy, and surgery, metastasis almost invariably arises by persistence of unresolved cancer cells following initial treatment. One intriguing explanation for this resiliency is the cancer stem-cell (CSC) hypothesis. According to the CSC model, phenotypic heterogeneity exists within the tumor, and a minority fraction of cells are able to reconstitute the tumor following ablation by current treatments. In like manner to their “normal” stem-cell counterparts, CSCs are capable of unlimited self-renewal, and the ability to “differentiate” to reconstitute the phenotypic heterogeneity of the initial tumor. Recent studies have sought to identify cancer stem cells in numerous types of solid tumors, including breast and prostate. Among the cell surface antigens utilized to identify the CSC subpopulations are CD24, CD44, CD133, and other factors associated with epithelial-to-mesenchymal transition (EMT). In this study, we sought to investigate the phenotypic changes associated with cell-cycle in breast (BCa-SC) and prostate (PCa-SC) cancer. We characterized in vitro the malignant and osteolytic human breast cancer cell line MDA-MB-231 and human prostate cancer cell line PC3, with the goal of identifying an optimal checkpoint where the CSC subpopulation would be most vulnerable to subsequent targeted chemotherapy. We found that common CSC markers are expressed in a time-dependent manner due to changes in the cell cycle. Our hypothesis is that temporal inhibition of the cell cycle when the CSC phenotype is least prominent will circumvent the chemo-resistance inherent to CSC. Citation Format: Joseph Feduska, Carnellia Lee, Selvarangan Ponnazhagan. Cell cycle regulation influences the phenotype of breast and prostate cancer stem cells in vitro. [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 2539.
Abstract LB-221: Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates (ADCs) demonstrate tumor specificity, unique sequence homology andin vitroandin vivoantitumor efficacy
Authors: David Eaverone, Jeff Behrens, Jillian Prendergast
Journal: Cancer Research (2016)

Abstract Siamab Therapeutics is developing monoclonal antibodies and antibody drug conjugates (ADCs) targeting tumor-associated carbohydrate antigens such as Sialyl-Tn (STn). These antibodies are selected using a proprietary glycan microarray that enriches for candidates whose binding is protein independent, highly specific and demonstrates exceptional target affinity. STn is a cancer specific antigen that is expressed on the surface of carcinomas including ovarian, colon, prostate, and pancreatic tumors but is rarely present in normal tissue. STn expression has been linked to innate immune suppression, a chemoresistant phenotype, metastasis, and poor prognosis. Previous attempts to target this antigen in the clinic with synthetic glycan vaccines proved safe but lacked efficacy. Siamab has developed over 20 murine mAbs that bind STn with high affinity and specificity. When formatted as ADCs, anti-STn mAb-ADCs target and selectively kill STn expressing cells and also demonstrate efficacy in multiple xenograft studies. Multiple murine mAbs perform well in IHC studies with multiple solid tumor samples and tissue microarrays and demonstrate high tumor specificity. Remarkable sequence homology across all murine mAbs was observed in both heavy and light chains, and hot spots for hypermutation were identified. Humanization was successfully completed using a selection of mAbs and multiple humanized mAbs maintain their target specific binding, affinity and cytotoxicity in vitro. Our data demonstrates that high-affinity, STn-specific mAbs show promise both as therapies for solid tumors and as a potential tool for the development of biomarkers and companion diagnostics enabling selection of patients most likely to respond to therapy. Citation Format: David Eaverone, Jeff Behrens, Jillian Prendergast. Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates (ADCs) demonstrate tumor specificity, unique sequence homology and in vitro and in vivo antitumor efficacy. [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 LB-221.
Abstract 602: BEZ235 efficacy in 3D-cancer cell line screening
Authors: Macarena Irigoyen, Gonzalo Castillo
Journal: Cancer Research (2016)

Abstract In vitro efficacy assessment of drugs in panels of tumor-derived cell lines has proven to be a powerful tool for predictive biomarker discovery. However, in the last few years it has become evident that particularly for tumor cell lines derived from solid tumors, the results do not always correlate with what is seen in xenografts as well as clinically. One of the reason is that traditionally these type of studies are done in monolayers (2D), which lack the complexity normally seen in vivo. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating 3-dimensional cellular interactions and physiological gradients, normally seen in a tumor microenvironment. In this study, we evaluated the efficacy of BEZ235, an imidazoquinoline, targeting the phosphatidylinositol 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR). BEZ235 was evaluated in a panel of 60 cell lines grown as spheroids, and this information was used to investigate genes associated with sensitivity. Cell lines grown as spheroids proved to be highly sensitive to the drug, where 45 of 60 cell lines showed an IC50 lower than 1 μM. Biomarker association analysis identified two mutated genes associated to BEZ235 sensitivity. The first biomarker was the phosphatase and tensin homolog (PTEN) a tumor suppressor gene, that when deregulated plays an important role in the development of several cancers. The second biomarker was AXIN1, a negative regulator of the WNT signaling pathway, and its deregulation has been associated with hepatocellular carcinoma. Since both PTEN and AXIN1 are thought to play a role in tissue invasion and metastasis, we studied the ability of BEZ235 to inhibit cellular invasion, and the results are discussed. Citation Format: Macarena Irigoyen, Gonzalo Castillo. BEZ235 efficacy in 3D-cancer cell line screening. [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 602.
Abstract 4690: Novel Ring1B-Bmi1 small molecule inhibitors target leukemia stem cells
Authors: Shirish Shukla, Felicia Gray, Weijang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Trupta Purohit, Jolanta Grembecka, Tomasz Cierpicki
Journal: Cancer Research (2016)

Abstract Leukemia is a clonal neoplastic disorder which possesses a rare population of cells, termed leukemia stem cells (LSCs), capable of limitless self-renewal and are necessary to initiate, sustain or regenerate the disease. Targeting LSCs self-renewal not only would offer substantial therapeutic benefit but also likely to be essential and sufficient for selective eradication of LSCs. BMI1, polycomb group protein, has been identified and shown to be required for self-renewal of LSCs. Bmi1 alongwith Ring1B constitute enzymatic active unit of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (H2AK119ub). Considering Bmi1 as a key regulator of self-renewal, targeting Bmi1 activity could impair LSCs self-renewal ability and may represent a new therapeutic approach for leukemia. Thus, in this study we aimed to develop and characterize novel small molecule inhibitors for Ring1B - Bmi1. Using NMR fragment-based screening and extensive medicinal chemistry optimization we developed WY332 that binds to Ring1B-Bmi1 with low micromolar affinity. Further characterization of the WY332 demonstrated selective reduction in Ring1B-Bmi1 mediated H2AK119ub levels in in vitro and in leukemic cells. Contrary, structurally similar and less potent compound displayed similar effect at much higher concentrations establishes that higher binding affinity of potent inhibitor is associated with blocking Ring1B-Bmi1 E3 ligase activity. Further evaluation of lead inhibitor, WY332, in colony formation assay using leukemic cells demonstrated significant decrease in the number and size of the colonies indicated that interference with Ring1B- Bmi1 activity alter the frequency of LSCs colony forming potential. Moreover, expression analysis of CD11b and CD34, cell surface markers associated with myeloid differentiation and AML LSCs phenotype, in WY332 treated TEX cells revealed marked increase in CD11b expression and significantly decreased CD34 expression establishes the specific effect of our Ring1B-Bmi1 small molecule inhibitors on induction of differentiation in leukemic cells. Interestingly, gene expression analysis of TEX cells treated with WY332 revealed significant increase in expression of genes suppressed in LSCs. Overall, these compounds represent the novel small molecule inhibitors of Ring1B-Bmi1 which inhibit E3 ubiquitin ligase activity and impair leukemic stem cell self-renewal capacity. Citation Format: Shirish Shukla, Felicia Gray, Weijang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Trupta Purohit, Jolanta Grembecka, Tomasz Cierpicki. Novel Ring1B-Bmi1 small molecule inhibitors target leukemia 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 4690.
Abstract 3811: The mechanobiome of pancreatic ductal adenocarcinoma: a new, targetable drug space
Authors: Alexandra Surcel, Qingfeng Zhu, Eric Schiffhauer, Robert A. Anders, Douglas N. Robinson
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality, with 37,000 people dying annually in the US. Existing strategies for treating cancer primarily mainly focus on inhibiting cell growth through specific genetic pathways, which typically either fail to completely abolish the disease or which lead to compensatory regulatory changes, and hence, drug resistance. Targeting cell mechanics remains an under-used approach for drug development. The direct driver of cell shape change events intrinsic to cellular functions, such migration and invasion, is the mechanobiome - a collection of cytoskeletal proteins which are the final determinants of a cell's mechanical attributes and which lie downstream of KRAS and other regulatory molecules. Targeting, and ultimately, inhibiting these processes is less likely to be subject to compensatory regulation by cancer cells. We determined via western blot analysis and immunohistochemistry of patient-derived samples that key players involved in mechanosensation-myosin IIA, IIC, α-actin-4, and filamin B -show increased expression in cancerous ductal epithelial over normal tissue, while non-mechanosensory, or variable mechanosensory, paralogs (myosin IIB, α-actin-1, and filamin A) show decreased expression. This upregulation of highly mechanosensory proteins has initiated an investigation into the necessity and sufficiency of the myosin II paralogs in PDAC metastasis through overexpression and knockdown of expression, coupled with mechanical assays. In addition to resolving the mechanobiome of PDAC, we have previously shown that targeting of myosin IIC by 4-hydroxyacetophenone affects PDAC mechanics. We are testing the in vivo efficacy of 4-HAP by conducting a murine multi-arm study of metastatically human derived pancreatic cancer cells. Preliminary results suggest a protective effect against the metastasis of human pancreatic cancer cells among mice treated with 4-HAP every other day. Citation Format: Alexandra Surcel, Qingfeng Zhu, Eric Schiffhauer, Robert A. Anders, Douglas N. Robinson. The mechanobiome of pancreatic ductal adenocarcinoma: a new, targetable drug space. [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 3811.
Case 17-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Jeffrey D. Bernhard, Eugene J. Mark
Journal: New England Journal of Medicine (1986)

Presentation of CaseAn 18-year-old man was admitted to the hospital because of bilateral apical infiltrates and skin lesions.He was in excellent health until three years earlier, when cystic acne appeared on the neck and back. Three months before admission multiple new lesions developed. A dermatologist noted inflamed cystic and nodular lesions, 0.3 to 1.5 cm, on the face, chest, and back. Ten were ulcerated to a depth of 0.5 to 1.0 cm and drained purulent material. Cultures of the lesions yielded no growth of pathogens on two occasions and yielded Staphylococcus aureus once. Tetracycline was administered, followed by . . .