tbuckley/cabot-search huggingface dataset:
Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib.
Authors: A. Leary, L. M. Pickering, J. M. G. Larkin, M. O. Leach, M. E. Gore, A. Sohaib, D. J. Collins, D. Koh
Journal: Journal of Clinical Oncology (2011)

TPS154 Background: The anti-angiogenic tyrosine kinase inhibitor, sunitinib has been shown to significantly improve progression-free (PFS) and overall survival in RCC (Motzer 2009). However assessing response by conventional imaging is inadequate as sunitinib can alter perfusion and induce necrosis with no change in tumor size (Jaffe 2006). DW-MRI measures the motion of water molecules using the apparent diffusion coefficient (ADC) to quantify tissue diffusivity (D), an indirect measure of tissue density. ADC values are low in viable tumor and increase with treatment-induced apoptosis or necrosis (Theony 2010). In addition, DW-MRI obtained using low diffusion weightings can measure tissue perfusion (f) (Theony 2010; Koh 2006). Therefore DW-MRI may provide an early marker of response to sunitinib in RCC by detecting both changes in perfusion (anti-angiogenic effect) and changes in tissue diffusivity (necrosis). Methods: This is a single arm prospective study. Main inclusion criteria are metastatic clear cell RCC, eligible for first-line sunitinib and target lesion >2.5cm assessable by functional MRI. 30 patients will be enrolled and undergo DW-MRI at baseline and after 7 and 28 days of sunitinib. Two baseline DW-MRI are performed 1 day apart to assess reproducibility. Objective response will be assessed on CT after 12 weeks by RECIST and pts followed up for PFS. The primary endpoint is to determine whether DW-MRI can identify responders versus non-responders to sunitinib in RCC. Secondary endpoints include investigating whether quantitative measurement of diffusion and perfusion (ADC, D, f) by DW-MRI correlates with objective tumor response and PFS. For DW-MRI, targeted acquisition measurements will be made using up to 10b-values, ranging between 0 and 1000s/mm2. Unenhanced T1- and T2-, DCE-MR imaging sequences will also be performed. Paired baseline measurements will be used to compute measurement reproducibility. Absolute and % change in ADC, D and f at 7 and 28 days will be compared to baseline, and the limits of baseline reproducibility (Bland-Altman Statistics) used to define whether biomarker change is significant.
A Prospective Evaluation of Acute Traumatic Coagulopathy and Effects of Damage Control Resuscitation in Military Trauma Patients in Afghanistan
Authors: Zachary Edward Wright, Ian Stewart, Jonathan Sosnov, Heather F Pidcoke, Fedyk Chriselda, Hana Kwan, Kelly Heegard, Christopher White, Kevin Chung, Andrew P Cap
Journal: Blood (2014)
VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis
Authors: Sabrina Ceeraz, Petra A. Sergent, Sean F. Plummer, Alan R. Schned, Dov Pechenick, Christopher M. Burns, Randolph J. Noelle
Journal: Arthritis & Rheumatology (2016)

Objective The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V‐domain Ig–containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1α) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus‐prone mouse strain. Methods To evaluate whether genetic deficiency of VISTA affects the development of lupus, we interbred VISTA‐deficient mice with Sle1.Sle3 mice, a well‐characterized model of systemic lupus erythematosus (SLE). Results We demonstrated that the development of proteinuria and glomerulonephritis in these mice, designated Sle1.Sle3 VISTA −/− mice, was greatly accelerated and more severe compared to that in Sle1.Sle3 and C57BL/6 VISTA −/− mice. Analysis of cells from Sle1.Sle3 VISTA −/− mice showed enhanced activation of splenic CD4+ T cells and myeloid cell populations. No increase in titers of autoantibodies was seen in Sle1.Sle3 VISTA −/− mice. Most striking was a significant increase in proinflammatory cytokines, chemokines, and interferon (IFN)–regulated genes associated with SLE, such as IFNα, IFNγ, tumor necrosis factor, interleukin‐10, and CXCL10, in Sle1.Sle3 VISTA −/− mice. Conclusion This study demonstrates for the first time that loss of VISTA in murine SLE exacerbates disease due to enhanced myeloid and T cell activation and cytokine production, including a robust IFNα signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.
Quality of Life During Early Tyrosine Kinase Inhibitor Treatment As Self-Reported by Chronic Myeloid Leukemia Patients Participating in a Prospective Observational Study (SIMPLICITY)
Authors: Jorge E. Cortes, Michael J. Mauro, Stuart L. Goldberg, Ron Paquette, H. Jean Khoury, Ishan Hirji, Samuel Wagner, Sam Joo, Catherine Davis
Journal: Blood (2011)
Christmas crackers: highlights from past years of<i>The BMJ</i>’s seasonal issue
Authors: Navjoyt Ladher
Journal: BMJ (2016)

Christmas crackers: highlights from past years of The BMJ's seasonal issueNavjoyt Ladher takes a trip through The BMJ's archive and revisits some memorable Christmas papers Navjoyt Ladher clinical editorThe BMJ Orthopaedic surgeons are smarter than anaesthetists. 1 Twenty seven is not a dangerous age for famous musicians. 2The oral health of British people is as good as, if not better than, that of Americans. 3Men are idiots.
Silent disease progression in clinically stable heart failure
Authors: Hani N. Sabbah
Journal: European Journal of Heart Failure (2016)

Abstract Heart failure with reduced ejection fraction ( HFrEF ) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death—even in patients who are ‘clinically stable’, or who are asymptomatic or only mildly symptomatic—because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF , including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed.
Abstract LB-010: Hijacking the E3 ubiquitin ligase cereblon to create efficient BRD4 degraders
Authors: Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, Jim Winkler, Andy Crew, Kevin Coleman, John Hines, Craig Crews
Journal: Cancer Research (2015)

Abstract BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as an attractive target in multiple pathological settings. For example, recent studies have demonstrated its importance in driving the proliferation of several cancers including NUT midline carcinoma, acute myelogenous leukemia (AML), multiple myeloma, Burkitt's Lymphoma (BL), and prostate cancer. Thus, BET bromodomain inhibitors have showed promising effects in certain preclinical settings, particularly in MYC-driven hematological malignancies, such as BL. Interestingly, we found that BRD4 inhibitors lead to a rapid and robust accumulation of BRD4 that, together with the reversible nature of binding to BRD4, may account for their moderate suppression of MYC expression and inhibition of cell proliferation. To circumvent these limitations, we designed a Proteolysis Targeting Chimera (PROTAC) compound, containing a BRD4 binding moiety and an E3 ubiquitin ligase cereblon ligand. By actively engaging the E3 ligase-proteasome degradation machinery, BRD4 PROTAC leads to fast and efficient degradation of BRD4. Consequently, it is more effective than small molecule BRD4 inhibitors in suppressing MYC levels and downstream signaling, which are associated with proliferation and survival of malignant cells. More importantly, we also demonstrated that BRD4 PROTAC is more effective in inhibiting BL cell proliferation and inducing apoptosis compared to BRD4 inhibitors. Our findings strongly demonstrate that a degrader of BRD4, in the form of a cereblon-based PROTAC, provides a better and more efficient strategy in targeting BRD4 than traditional small molecule inhibitors. Citation Format: Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, Jim Winkler, Andy Crew, Kevin Coleman, John Hines, Craig Crews. Hijacking the E3 ubiquitin ligase cereblon to create efficient BRD4 degraders. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-010. doi:10.1158/1538-7445.AM2015-LB-010
SWOG 0204; Phase 2 Trial of Thalidomide (T) + Dexamethasone (D) Induction Followed by Tandem Autotransplant (TAT) and Prednisone (P) + T Maintenance for Multiple Myeloma (MM).
Authors: Mohamad A. Hussein, Jason McCoy, Andrzej Jakubowiak, Brian G. Durie, John J. Crowley, Bart Barlogie
Journal: Blood (2005)
Differences In Clinical Characteristics and Prognostic Features Between Patients with Myelodysplastic Syndromes (MDS) From Korea, Japan, and Germany
Authors: Andrea Kuendgen, Je-Hwan Lee, Akira Matsuda, Kyoo Hyung Lee, Jung-Hee Lee, Norbert Gattermann, Rainer Haas, Ulrich Germing
Journal: Blood (2010)
585. Long Non-Coding RNA NEAT1 Functions as a ceRNA to Regulate E2F3 Expression by Sponging miR-377-3p in Non-Small Cell Lung Cancer
Authors: Chengcao Sun
Journal: Molecular Therapy (2016)

Recently, the long non-coding RNA (lncRNA) NEAT1 has been identified as an oncogenic gene in multiple cancer types and elevated expression of NEAT1 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in progression of non-small cell lung cancer (NSCLC). In our studies, we identified NEAT1 was highly expressed in NSCLC patients and was a novel regulator of NSCLC progression. Patients whose tumors had high NEAT1 expression had a shorter overall survival than patients whose tumors had low NEAT1 expression. Further, NEAT1 significantly accelerates NSCLC cell growth and metastasis in vitro and tumor growth in vivo. Additionally, by using bioinformatics study and RNA pull down combined with luciferase reporter assays, we demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for has-miR-377-3p, antagonized its functions and led to the de-repression of its endogenous targets E2F3, which was a core oncogene in promoting NSCLC progression. Taken together, these observations imply that the NEAT1 modulated the expression of E2F3 gene by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and NSCLC progression.
349. AAV-Mediated In Utero Gene Therapy To Treat Genetic Hearing Loss
Authors: Min-A. Kim, Seung-Hyun Bae, Ye-Ri Kim, Byeonghyeon Lee, Se-Kyung Oh, Un-Kyung Kim, Kyu-Yup Lee
Journal: Molecular Therapy (2015)

Gene therapy for treating genetic hearing loss has made astonishing progress with biotechnical advance, but it still remains the difficulty to treat the disorder ultimately. A diversity of viral vectors are used in gene therapy as vehicle for delivery of therapeutic gene. Moreover, the successful outcome of the gene therapy depends on timing and delivery route as well as titer of virus. Here, we demonstrate that gene therapy by in utero is a promising tool for treating genetic hearing loss. We used adeno-associated virus serotype 1 (AAV1) to express therapeutic gene in mice. To evaluate the safety and efficiency of virus, we transferred an AAV1-GFP into the otocyst at embryonic day 12.5, and the contralateral ear was used as a control. After the gene transfer, a strong expression of transgene was observed without ototoxicity within cochlea and the hearing ability was unaffected by AAV. These results were identified by several histological interpretations and auditory brainstem responses, respectively. We also examined a successful expression of an AAV1-MsrB3-GFP within hair cells in the same way. Together, these results indicate that gene therapy by in utero is potential strategy to treat genetic hearing loss by monogenic mutations. It may apply to treat the deficiency of the MsrB3 gene which results in autosomal recessive non-syndromic hearing loss, DFNB74, in humans.
655. Comparative Viability, Potency and In Vivo Efficacy of a Fresh or Cryopreserved Cell Therapy for the Treatment of Degenerative Disc Disease
Authors: Lara I. Silverman, Galina Dulatova, Kavita Gupta, Terry Tandeski, Chinne Chintalacharuvu, Antwain Howard, Kevin Foley
Journal: Molecular Therapy (2015)

Introduction Cryopreserving cells provides many benefits for clinical use and commercialization. Cryopreservation allows for long-term (>2 year) shelf life, off-the-shelf usability, and completion of safety/functional testing prior to dosing. Our lab has identified a method to isolate progenitor cells directly from human disc tissue and create a therapeutic cells known as discogenic cells to treat degenerative disc disease. At the 2013 ASGCT meeting, we presented an in vitro potency assay for discogenic cells based on accumulation of proteoglycan. Now, we compared the potency and viability of fresh (F) and cryopreserved (C) discogenic cells in vitro and in vivo. We hypothesized that in all studies, the F and C cells would perform comparably. Methods Discogenic cells were combined with Profreeze and 7.5% DMSO. Vials were either tested immediately, or after controlled rate freezing and storage below -135 °C. The metabolic activity of cells after 24 hours culture was assayed using Alamar Blue (n=6). Also, the cells were stained with live/dead fluorescent dye. Finally, matrix formation (potency) was assessed by incubating cells in DMEM/F12 with 5% FBS, 10 ng/ml TGFb and 100 nM dex (n=6) for 10 days. The samples were digested with papain and the amount of GAG was quantified via DMMB assay. For the in vivo study, using a previously validated model, three lumbar discs of 4 Gottingen minipigs were injured (note: all animal work approved by private IACUC). After four weeks, each animal received either no treatment (sham), gel control (1% w/v of high MW hyaluronic acid), 100,000 F cells with gel, or 100,000 C cells with gel (n=3/condition). Cryoprotectant was not removed prior to dosing. Four weeks after injection, the discs were processed for paraffin histology and stained with H&E, Saf O and Masson's trichrome. Also, x-rays were performed every 4 weeks and disc height calculated using 18 boney landmarks. Results Viability remained high after cryopreservation, as seen via live/dead staining and quantitatively using Alamar Blue (Figure 1, A-B). The in vitro potency assay demonstrated similar accumulation of GAG after 10 days (Figure 1, C). In vivo, the control discs continued to decrease in height after treatment but both cell-treated discs improved similarly. Histology showed variable morphology across discs, with no unique differences between fresh and frozen treatments. Discussion Maintaining viability and potency after cryopreservation is a crucial step towards commercializing a cell therapy product. These studies validate the cryopreservation protocols and support the advancement of cryopreserved discogenic cells into clinical trials as a treatment for degenerative disc disease.
Abstract 4265: Identification of new NTRK1 gene fusion as oncogene target in colon cancer
Authors: Laurent Creancier, Caroline Dejean, Isabelle Vandenberghe, Jean-Christophe Blanchet, Yannick Aussagues, Jean Philippe Annereau, Janick Selves, Anna Kruczynski
Journal: Cancer Research (2015)

Abstract In an effort to better characterize the activity of a multi-kinase inhibitors, antiproliferative activity was evaluated against a panel of human tumor cell lines. Among the different cell lines tested we have been able to highlight that the KM12 human colorectal carcinoma present hypersensitivity to inhibition. By intersecting the results of activity of the compound and the bibliographic data, we could confirm that the activity of the compound was mediated by the inhibition of phosphorylation of the receptor NTRK1. The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the hight-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a human colon carcinoma as a transforming oncogene activated by a somatic rearrangement that fused TPM3 (non-muscle tropomyosin) gene to kinase domain of a novel tyrosine-kinase receptor. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. Using differential quantitative reverse transcriptase PCR and optimised immunohistochemistry we could confirm the existence of low frequency (0.5%) NTRK1 re-arranged / activated forms in colorectal carcinoma. A same colorectal tumor sample could contain different fusion transcripts, highlighting the molecular heterogeneity of this type of tumor Furthermore we detect a novel NTRK1 fusion in colorectal carcinoma clinical samples corresponding to oncogenic rearrangement TRK-T2 identified in papillary thyroid carcinoma. These results confirm the potential interest of the target NTRK1 in the panel of targeted therapies against colorectal cancer. Citation Format: Laurent Creancier, Caroline Dejean, Isabelle Vandenberghe, Jean-Christophe Blanchet, Yannick Aussagues, Jean Philippe Annereau, Janick Selves, Anna Kruczynski. Identification of new NTRK1 gene fusion as oncogene target in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2015-4265
Abstract 3261: Cytochrome p450 3a5 manipulates the progression of hepatocellular carcinoma via selectively targeting ros/mtorc2/p-akt (s473) signaling
Authors: lei chen, hongyang Wang
Journal: Cancer Research (2015)

Abstract CYP3A5, one of the cytochrome P450 superfamily members, is involved in the metabolism of drugs, carcinogens, and endogenous molecules. Previous studies mainly focused on the role of CYP3A5 polymorphism or altered enzyme activity during carcinogenesis. However, the potential physiological function of CYP3A5 in tumor progression remains largely unknown. In our present study, the expression of CYP3A5 was firstly reported frequently down-regulated in not only 159 clinical HCC samples but also 4 external HCC cohort(n = 695). Tumors with reduced level of CYP3A5 were more likely to have aggressive characteristics (vascular invasion and poor differentiation), together with the worse overall survival time and time to disease recurrence. The exogenous expression of CYP3A5 was associated with the induction of TIMP1/2 and dysfunction of MMP2/9, which suppressed HCC migration and invasion in vitro and in vivo mechanically through inhibiting AKT signaling. Strikingly, the selective inhibition of AKT phosphorylation at Ser473(instead of Thr308) residue was found in CYP3A5-stable cells with an mTORC2-dependent manner. Co-immunoprecipitation and kinase assay further confirmed that mTORC2 kinase activity rather than Rictor/mTOR complex integrity was necessary for the inhibition of p-AKT(S473). Importantly, CYP3A5-induced ROS accumulation was identified as the key factor for the regulation of mTORC2 activity, in line with the decreased GSH/GSSG contents in most clinical HCC samples with relatively lower metastatic capacity. Together, these findings highlighted the novel function of CYP3A5 in the regulation of tumor metastasis via enhancing ROS level and in turn arresting mTORC2/p-AKT(S473) signaling, which may serve as a potential prognostic biomarker and therapeutic target for HCC. Citation Format: lei chen, hongyang Wang. Cytochrome p450 3a5 manipulates the progression of hepatocellular carcinoma via selectively targeting ros/mtorc2/p-akt (s473) signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3261. doi:10.1158/1538-7445.AM2015-3261
Pemetrexed (P) and Cisplatin (C) as either Induction (IC) or Adjuvant (AC) Chemotherapy in stage IB-II Non-Small Cell Lung Cancer (NSCLC): A randomized phase 2 study (EORTC 08051)
Authors: Jan Van Meerbeeck, P Germonpre, Frank Vermassen, J Welch, PE Van Schil
Journal: Journal of Thoracic Oncology (2009)
Identification of prognostic tumor markers in HIV+ diffuse large B-cell lymphoma (DLBCL).
Authors: C. Chao, M. Silverberg, D. I. Abrams, R. Haque, H. D. Zha, O. Martinez-Maza, M. McGuire, M. D. Chi, B. Castor, L. Xu, J. Said
Journal: Journal of Clinical Oncology (2011)

8055 Background: About half of HIV+ DLBCL patients die within 2 yrs of diagnosis. Identification of prognostic tumor markers may assist clinical risk stratification and inform therapeutic developments. We examined if certain tumor markers in HIV+ DLBCL are associated with mortality. Methods: H&E slides from HIV+ DLBCL cases diagnosed 1996-2007 in the Kaiser Permanente California Health Plan were reviewed to identify representative tumor blocks for tissue microarray (TMA) construction. Immunohistochemistry staining of TMA cores was used to analyze the expression of selected markers. Percent of DLBCL cells with visible marker staining was scored on a scale from 0-4 (0-9%, 10-24%, 25-49%, 50-74% and ≥75%). Epstein-Barr Virus (EBV) infection was determined by in situ hybridization of EBV RNA. Positivity for each marker was determined based on previously established cut-off values. Each marker’s prognostic significance on 2-yr mortality was first evaluated in a univariate Cox model. Markers showing a mortality association at p<0.10 level were examined in a multivariable Cox model, adjusting for stage, presence of B symptom, Germinal Center phenotype, prior AIDS and CD4+ count. Results: Of 194 HIV+ DLBCL cases identified; 80 had sufficient tissue for study inclusion. In the adjusted analysis, cMYC positivity was significantly associated with a 3-fold increase in 2-yr mortality (Table). Other markers were not significantly associated with mortality. Conclusions: cMYC expression may be associated with increased mortality in HIV+ DLBCL patients. Our initial findings should be confirmed in larger studies. Tumor marker expression and hazard ratio (HR) of marker positivity on 2-yr mortality. Marker category EBV Cell cycle promoter B-cell activator Apoptosis regulator Marker EBER Cyclin E SKP2 cMYC FOXP1 PKC-β2 P27 Ki-67 GAL3 P53 BCL2 Survivin BLIMP1 Cutoff score for marker positivity 3+ 3+ 3+ 1+ 2+ 3+ 1+ 3+ 3+ 2+ 2+ 2+ 2+ % of cases positive for marker 31% 23% 8% 64% 36% 61% 39% 35% 26% 16% 51% 77% 10% Univariate HR 2.86 1.17 0.28 2.08 0.77 0.97 1.43 0.73 0.72 0.58 1.17 1.23 2.57 Univariate p value <0.01 0.69 0.21 0.07 0.49 0.93 0.29 0.42 0.45 0.31 0.64 0.62 0.05 Adjusted HR 2.16 - - 3.18 - - - - - - - - 1.09 Adjusted p value 0.09 - - 0.03 - - - - - - - - 0.90