tbuckley/cabot-search huggingface dataset:
Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes
Authors: K. Martin Kortüm, Elias K. Mai, Nur H. Hanafiah, Chang-Xi Shi, Yuan-Xiao Zhu, Laura Bruins, Santiago Barrio, Patrick Jedlowski, Maximilian Merz, Jing Xu, Robert A. Stewart, Mindaugas Andrulis, Anna Jauch, Jens Hillengass, Hartmut Goldschmidt, P. Leif Bergsagel, Esteban Braggio, A. Keith Stewart, Marc S. Raab
Journal: Blood (2016)
Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition.
Authors: Cameron John Turtle, Carolina Berger, Daniel Sommermeyer, Tanya Budiarto, Laila-Aicha Hanafi, Katherine Melville, Barbara Pender, Natalia Steevens, Colette Chaney, Shelly Heimfeld, Sindhu Cherian, Brent L. Wood, Lori Soma, Xueyan Chen, Michael Jensen, Stan R. Riddell, David G. Maloney
Journal: Journal of Clinical Oncology (2015)

3006 Background: Genetically modified T cells derived from distinct T cell subsets differ in the capacity to persist after adoptive transfer. We are conducting the first phase I/II clinical trial in which patients (pts) with CD19+ B cell malignancies receive T cells comprised of a defined composition of CD8+ TCM and CD4+ T cells engineered to express a CD19 CAR. Methods: CD8+ TCM and CD4+ T cells were separately enriched from each patient, transduced with a CD19 CAR lentivirus and expanded in vitro. The cell product for infusion was formulated in a 1:1 ratio of CD8+:CD4+ CAR+ T cells and infused at one of three dose levels (2x105 – 2x107 CAR-T cells/kg) after lymphodepleting chemotherapy. Results: Thirty-seven pts with ALL (n = 20), NHL (n = 14) or CLL (n = 3) have been treated and 33/37 received a product that conformed to a prescribed CD8+:CD4+ composition. There was no serious acute infusional toxicity. Severe cytokine release syndrome (sCRS) consisting of fever, hypotension, coagulopathy and neurotoxicity associated with elevated serum IFN-γ and IL-6 was only observed in ALL pts with high tumor burden. One ALL patient treated at the highest cell dose died of complications associated with sCRS. No NHL or CLL pts had sCRS. Eighteen of 20 ALL pts were evaluated for response, with 15 (83%) achieving complete marrow remission by high resolution flow cytometry. Clinical responses in NHL included complete (n = 1) or partial (n = 6) remission in 7/13 pts. Two of 3 CLL pts achieved marrow remission by flow cytometry. The peak level and duration of persistence of both CD4+ and CD8+ CAR-T cells were associated with clinical response. We are investigating the impact of distinct lymphodepletion regimens on CAR-T cell proliferation and persistence in vivo. A T cell immune response to the murine CD19-specific scFv component of the CAR transgene was detected in a subset of pts with limited CAR-T cell persistence. Conclusions: Adoptive immunotherapy with CD19 CAR-T cells of defined subset composition is feasible and safe in a majority of heavily pretreated pts with refractory B cell malignancies and has potent anti-tumor activity at low cell doses. CAR-T cell doses for phase II studies in ALL and NHL cohorts have been determined. Clinical trial information: NCT01865617.
Long travel time to specialised stroke centre offsets potential benefits, study shows
Authors: Jacqui Wise
Journal: BMJ (2016)

Travelling 90 minutes or more to a specialist stroke centre offsets any survival benefits from the care provided, a retrospective US study has found.1

The retrospective cohort study compared outcomes in patients with acute stroke who received healthcare under Medicare and who were treated locally or referred to one of the 976 specialised primary stroke centres across the …
Abstract 2770: DERL3 hypermethylation alters rhabdomyosarcoma cell metabolism
Authors: Pere Llinas, Paula Lopez, Manel Esteller
Journal: Cancer Research (2016)

Abstract Physiological cellular activity requires a precise control of the proteome. However, cancer cells have a distorted protein profile. It is likely that intrinsic defects in protein homeostasis participate in human tumorigenesis, such as alterations in de novo protein synthesis, or defects in protein degradation. In this last case, the ubiquitin (Ub) proteasome system (UPS) targets a variety of proteins, including functional proteins that are no longer needed. Without appropriate protein homeostasis maintained by the UPS, healthy cells can undergo malignant transformation, and this observation has been therapeutically exploited by the development of proteasome inhibitors as anticancer agents. Many of the cytoplasm UPS-degraded proteins are retrotranslocated from the endoplasmic reticulum (ER). In this regard, ER possesses a quality control mechanism, termed the ER-associated degradation mechanism (ERAD), that is induced in response to ER stress by a transcriptional program, known as the unfolded protein response (UPR), which leads to the accelerated degradation of unfolded proteins. Within the ERAD pathway, the Derlin proteins play a critical role. It has been proposed that Derlins form an export channel in the membrane of the ER through which the ERAD substrates pass to reach the proteasome. A previous study in our lab has shown that DERL3 silencing by DNA methylation deregulate SLC2A1 (GLUT1) degradation, promoting the Warburg effect. SLC2A1 is a key glucose receptor up-regulated in most solid tumors, allowing cancer cells to get the glucose they need for tumor progression. In this study we use an embryonic rhabdomyosarcoma cell line as a model to find out the role of DERL3 in these tumors, as the percentage of promoter hypermethylation is these tumors is approximately 60%. Rhabdomyosarcoma (RMS) is one of the leading causes of cancer related deaths among children, being the histological variant of embryonic rhabdomyosarcoma the most common soft tissue sarcoma of childhood and adolescence, with 350 cases per year in USA. The restoration of DERL3 expression in vitro promotes GLUT1 degradation and GLUT4 up-regulation, becoming cells sensitive to insulin. Moreover, it has been shown that DERL3 confers sensitivity against an ERAD related drug, Eeyarestatin I, opening a new approach for RMS treatment. All together, these initial findings highlight the role of DERL3 in RMS metabolism. Citation Format: Pere Llinas, Paula Lopez, Manel Esteller. DERL3 hypermethylation alters rhabdomyosarcoma cell metabolism. [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 2770.
Abstract 4804: Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment
Authors: Akshita P. Pillai, Subramanyam Dasari, Bhavani Patel, Souresh Banerjee, Alexander V. Kornienko, Gnanasekar Munirathinam
Journal: Cancer Research (2016)

Abstract Major cause for prostate cancer mortality is due to the development of castration-resistant prostate cancer (CRPC) which usually develops when prostate cancer patients undergo standard androgen deprivation therapy. Treatment options currently available for CRPC are not very efficient and have many side effects. Hence, there is an urgent need to identify effective treatment strategies for CRPC. Natural compounds have previously shown to be an effective alternative treatment strategy for cancer. Polygodial (PG) an active constituent of mountain pepper belonging to sesquiterpene dialdehyde family has shown to have several pharmacological benefits including anti-bacterial, anti-fungal, anti-inflammatory, and anti-cancer properties. The objective of this study is to determine the therapeutic effects of PG against CRPC in a pre-clinical study. Cell lines used in this study were androgen dependent LNCaP and CRPC C4-2, DU145, and PC-3 cells. MTT, soft agar, and wound healing assays were performed to evaluate the effects of PG respectively on cell survival, anchorage independent growth, and migration characteristics of prostate cancer cells. PC-3 cells were utilized to determine the anti-cancer mechanisms of PG. Cell viability assay results showed PG effectively inhibited cell proliferation of CRPC C4-2, DU145 and PC-3 cell lines as compared to androgen dependent LNCaP cells. PG treatment significantly reduced the colony growth of CRPC cells in soft agar plates as compared to controls which correlates with its inhibitory effect on anchorage independent growth of these cells. In addition, PG also reduced the migration potential of CRPC cells in a wound healing assay. Inhibition of anchorage independent growth and motility of PCa cells by PG suggests its tumor suppressive and anti-metastatic potential. Western blot analysis showed that PG treatment downregulated the expression of a key cell survival molecule, High mobility group box1 (HMGB1) while promoting PARP-1 cleavage in PC-3 cells. Interestingly, our results also showed that BiP/GRP78, a marker of endoplasmic reticulum (ER) stress was upregulated following PG treatment in PC-3 cells. These findings suggest that PG enforces its tumor suppressive action by inhibiting HMGB1 signaling axis with concurrent activation of ER stress pathway in CRPC cells. Taken together, our study shows that PG might be an effective chemotherapeutic natural compound especially for CRPC. Citation Format: Akshita P. Pillai, Subramanyam Dasari, Bhavani Patel, Souresh Banerjee, Alexander V. Kornienko, Gnanasekar Munirathinam. Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment. [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 4804.
Loss of nuclear pro–IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma
Authors: Clara Curiel-Lewandrowski, Hisato Yamasaki, Chuan Ping Si, Xiaoyi Jin, Yujun Zhang, Jillian Richmond, Marina Tuzova, Kevin Wilson, Beth Sullivan, David Jones, Nataliya Ryzhenko, Frederick Little, Thomas S. Kupper, David M. Center, William W. Cruikshank
Journal: Journal of Clinical Investigation (2014)

The article "Loss of nuclear pro-IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma" is being retracted, with the agreement of the corresponding author.Several duplicated bands were recently identified in the immunoblot images in Figures 1 and3, and the authors are unable to retrieve the original source files that were used to generate these data.
Oncolytic Viruses in Cancer Treatment
Authors: Sean E. Lawler, Maria-Carmela Speranza, Choi-Fong Cho, E. Antonio Chiocca
Journal: JAMA Oncology (2016)

Oncolytic viruses (OVs) are emerging as important agents in cancer treatment. Oncolytic viruses offer the attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, therefore acting as potential in situ tumor vaccines. Moreover, OVs can be engineered for optimization of tumor selectivity and enhanced immune stimulation and can be readily combined with other agents. The effectiveness of OVs has been demonstrated in many preclinical studies and recently in humans, with US Food and Drug Administration approval of the oncolytic herpesvirus talimogene laherparepvec in advanced melanoma, a major breakthrough for the field. Thus, the OV approach to cancer therapy is becoming more interesting for scientists, clinicians, and the public. The main purpose of this review is to give a basic overview of OVs in clinical development and provide a description of the current status of clinical trials.In 2016 approximately 40 clinical trials are recruiting patients, using a range of OVs in multiple cancer types. There are also many more trials in the planning stages. Therefore, we are now in the most active period of clinical OV studies in the history of the field. There are several OVs currently being tested with many additional engineered derivatives. In OV clinical trials, there are a number of specific areas that should be considered, including viral pharmacokinetics and pharmacodynamics, potential toxic effects, and monitoring of the patients' immune status. Clinical development of OVs is increasingly focused on their immune stimulatory properties, which may work synergistically with immune checkpoint inhibitors and other strategies in the treatment of human cancer.Oncolytic viruses are an active area of clinical research. The ability of these agents to harness antitumor immunity appears to be key for their success. Combinatorial studies with immune checkpoint blockade have started and the results are awaited with great interest.
Specific Inhibition Of Ectodomain Shedding Of GPIba By Targeting Its Shedding Cleavage Site
Authors: Xin Liang, Susan R. Russell, Sandra Estelle, Limei H. Jones, Sungyun Cho, Mark L. Kahn, Michael C. Berndt, Silvia T. Bunting, Jerry Ware, Renhao Li
Journal: Blood (2013)
Abstract 4202: Peptide probes binding to radiation-inducible cell surface GRP78 as a novel targeting strategy for various tumors
Authors: Vaishali Kapoor, David Dadey, Kim Nguyen, Hua Li, Buck Rogers, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2016)

Abstract Traditional radiation therapy is often associated with significant toxicity to normal cells that could limit the success of cancer therapy. The greater understanding in the molecular differences between cancer cells and normal cells has lead to targeted therapies in cancer treatment. We have discovered novel radiation-inducible antigens in cancer using phage-display peptide libraries. One such inducible-antigen is Glucose regulated protein 78kDa (GRP78) that was shown to bind the hexapeptide GIRLRG. GRP78 is known to regulate cellular stresses, including hypoglycemia, hypoxia and the ER stress response. It is over-expressed in different cancer subtypes and has been correlated to their poor prognosis. In this study, we evaluated the cell surface induction of GRP78 post irradiation (IR) on lung cancer (A549 and LLC), glioma (D54 and GL261) and endothelial (HUVEC and 3B11) cell lines using flow cytometry. Significantly higher surface expression of GRP78 was observed in all cell lines. We determined the specificity of GIRLRG to bind tumors in vivo using nano SPECT technology. GIRLRG was conjugated to a 40KDa PEG (for longer circulation time) and radiolabelled with 111Indium (111In) using diethylene triamine pentaacetic acid (DTPA) as the chelator. The A549 tumor bearing nude mice were irradiated (3Gy x 3 times) or sham irradiated prior to tail vein injections of 111In labeled GIRLRG. The mice were imaged 48h and 96h post injection using nano CT-SPECT imager. The SPECT images revealed that GIRLRG specifically bound to the irradiated A549 tumors while little or no binding was seen in the sham irradiated tumors. The post-SPECT imaging bio-distrubution also revealed maximum uptake in irradiated tumors. We further evaluated tumor binding of GIRLRG in Glioma (D54), esophageal cancer (OE33), cervical cancer (HT3), and pancreatic cancer (BxPC3). The nano-SPECT imaging showed that GIRLRG specifically bound to all the irradiated tumors tested. Phosphor images of the tumor sections showed that GIRLRG specifically bound to the tumors and not to normal tissues. In conclusion, GIRLRG peptide has high affinity to GRP78 in vitro and in vivo. Radiolabeled GIRLRG is a novel tool for imaging tumors and may be developed further as a therapeutic agent to deliver cancer specific drugs or therapeutic radioisotopes. Citation Format: Vaishali Kapoor, David Dadey, Kim Nguyen, Hua Li, Buck Rogers, Dinesh Thotala, Dennis Hallahan. Peptide probes binding to radiation-inducible cell surface GRP78 as a novel targeting strategy for various 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 4202.
Impact Of Major Molecular Response On Overall Survival and Its Time Of Achievement On Complete Molecular Response Incidence In Chronic Myeloid Leukemia Patients Treated By Tyrosine Kinase Inhibitors In First Chronic Phase
Authors: Mauricette Michallet, Mohamad Sobh, Helene Labussiere, Lila Gilis, Fiorenza Barraco, Madeleine Etienne, Oriane Le Borgne, Isabelle Tigaud, Sandrine Hayette, Sophie Ducastelle, Xavier Thomas
Journal: Blood (2013)
P0546 : In vivo impact of precore mutations of HBV on viral replicative capacity, viral protein processing, and virion assembly. molecular correlates of histologic and immunohistochemical aspects in liver tissue from patients with chronic hepatitis B
Authors: C. Minosse, A. Baiocchini, S. Coen, P. Zaccaro, U. Visco Comandini, R. Lionetti, M. Montalbano, F. Del Nonno, M. Vivarelli, G. D’Offizi, M.R. Capobianchi, S. Menzo
Journal: Journal of Hepatology (2015)
Abstract 3380: Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells
Authors: Monica Burgett, Justin Lathia, Patrick Roth, Amy Nowacki, Elena Pugacheva, Ping Huang, Amit Vasanji, Li Meizhang, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy Rich, Michael Weller, Candece Gladson
Journal: Cancer Research (2016)

Abstract The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM), which requires endothelial cell (EC) migration. Here, we show that angiogenesis can also be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and ECs. The direct interaction between CSCs and ECs was mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs. Using in vitro assays, we found that this interaction increased network formation and migration-associated signaling events in ECs, including activation of integrin αvβ3, FAK, bone marrow tyrosine kinase on chromosome X (BMX), p130CAS, ERK and JNK. Comparison of the effects of co-culturing CSCs with ECs versus the effects of conditioned media from CSCs co-cultured with ECs indicated that upstream and downstream effector activation was not attributed to a secreted factor(s). Activation of αvβ3 and BMX was required for migration stimulated by direct binding but not for migration stimulated by soluble factors. RGD-peptide treatment of mice with established intracerebral GBM xenografts significantly reduced the percentage of Sox2-positive tumor cells (consistent with CSCs) in close proximity to ECs, decreased integrin αvβ3 and BMX activation and p130CAS phosphorylation in the ECs, and reduced the vessel surface area. These results show that direct interactions between CSCs and ECs have potent effects on EC migration and reveal a previously unrecognized aspect of the regulation of angiogenesis in GBM that can impact therapeutic anti-angiogenic targeting. Citation Format: Monica Burgett, Justin Lathia, Patrick Roth, Amy Nowacki, Elena Pugacheva, Ping Huang, Amit Vasanji, Li Meizhang, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy Rich, Michael Weller, Candece Gladson. Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial 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 3380.
Impaired <i>Porphyromonas gingivalis</i>–Induced Tumor Necrosis Factor Production by Dendritic Cells Typifies Patients With Rheumatoid Arthritis
Authors: Kim C. M. Santegoets, Mark H. Wenink, Felipe A. Vieira Braga, Marta Cossu, Femke B. G. Lamers‐Karnebeek, Piet L. C. M. van Riel, Patrick D. J. Sturm, Wim B. van den Berg, Timothy R. D. J. Radstake
Journal: Arthritis & Rheumatology (2015)

Objective The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA), and the severity of periodontitis can affect the level of arthritis. Porphyromonas gingivalis is one of the main bacteria involved in periodontitis. Our aim was to determine if there are differences in the innate immune response against P gingivalis between healthy controls and RA patients. Methods Monocyte‐derived dendritic cells (DCs) from healthy controls, RA patients, and patients with psoriatic arthritis (PsA) were stimulated with P gingivalis , a range of other bacteria, and Toll‐like receptor agonists. Cytokine production was determined, and blocking studies were performed to determine which receptors were involved in differential recognition of P gingivalis . Effects on T cell cytokines were also determined in cultures of peripheral blood mononuclear cells (PBMCs). Results Upon stimulation with P gingivalis , RA patient DCs produced less tumor necrosis factor as compared to healthy control DCs, which was not observed in PsA patients or upon stimulation with other bacteria. In addition, P gingivalis –mediated activation of RA patient PBMCs showed a clear reduction of interferon‐γ production. Among the various possible underlying mechanisms investigated, only blockade of CR3 abolished the difference between RA patients and healthy controls, suggesting the involvement of CR3 in this process. Conclusion Immune cells from RA patients display a reduced response to P gingivalis , which has functional consequences for the immune response. This may result in prolonged survival of P gingivalis , possibly driving autoantibody formation and a self‐perpetuating loop of chronic inflammation. The possible role of CR3 in this process warrants further investigation.