tbuckley/cabot-search huggingface dataset:
CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin‐6/STAT‐3 Pathway
Authors: Kayaho Maeda, Tomoki Kosugi, Waichi Sato, Hiroshi Kojima, Yuka Sato, Daisuke Kamimura, Noritoshi Kato, Naotake Tsuboi, Yukio Yuzawa, Seiichi Matsuo, Masaaki Murakami, Shoichi Maruyama, Kenji Kadomatsu
Journal: Arthritis & Rheumatology (2015)

Interleukin-17 (IL-17)-producing T cells (Th17 cells) play critical roles in the pathogenesis of immune-related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN.Injections of pristane (2,6,10,14-tetramethylpentadecane [TMPD]) were administered to Bsg(-/-) or Bsg(+/+) mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens.Pristane induced LN more strikingly in Bsg(-/-) mice than in Bsg(+/+) mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg(-/-) mice. The expression of IL-17 was also increased in the kidneys of Bsg(-/-) mice, in proportion to LN disease activity. Furthermore, treatment with anti-IL-17 antibody reduced LN disease activity in Bsg(-/-) mice. Complementary to these phenotypes of Bsg(-/-) mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT-3 phosphorylation during this differentiation. Moreover, STAT-3 phosphorylation was suppressed by crosslinking of Bsg with its antibody.Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL-6/STAT-3 pathway.
Abstract P5-06-04: The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score
Authors: Yan Wang, Stefano Cairo, Olivier Deas, Anne-Renee Hartman, Joshua Jones, Alexander Gutin, Jerry Lanchbury, Zaina Sangale, Cara Solimeno, Jean-Gabriel Judde, Kirsten Timms, Keith Wilcoxen
Journal: Cancer Research (2015)

Abstract Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with that of BRCA1/2 mutation driven breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by dysfunction of genes other than BRCA1 or BRCA2. Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. Previously, we demonstrated that a subset of basal breast cancer (BBC) patient-derived xenograft (PDX) models responded robustly to single agent niraparib treatment. To understand the selectivity observed, the samples from a collection of 37 BBC PDX models have been subjected to homologous recombination deficiency (HRD) analysis. HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using three algorithms (LOH, TAI and LST scores), and the final HRD score is the sum of the LOH+TAI+LAST scores. Niraparib’s antitumor activity was investigated in patient derived BBC models with various HRD scores. The correlation between niraparib efficacy, HRD score and BRCA deficiency will be discussed. Citation Format: Yan Wang, Stefano Cairo, Olivier Deas, Anne-Renee Hartman, Joshua Jones, Alexander Gutin, Jerry Lanchbury, Zaina Sangale, Cara Solimeno, Jean-Gabriel Judde, Kirsten Timms, Keith Wilcoxen. The PARP inhibitor niraparib demonstrated activity in patient-derived triple-negative breast cancer xenograft models with high homologous recombination deficiency (HRD) score [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-04.
Abstract 5591: Simultaneous isolation and quantification of circulating exosomes for cancer biomarker discovery
Authors: Shailender S. Kanwar, Christopher J. Dunlay, Diane M. Simeone, Sunitha Nagrath
Journal: Cancer Research (2014)

Abstract Membrane bound extracellular vesicles, including microvesicles and exosomes, are secreted by both normal and cancerous cells into the extracellular space and in blood circulation. These circulating extracellular vesicles (cirEVs) and exosomes in particular, are recognized as a potential source of disease biomarkers and also carry signature molecules for early stage cancer detection. However, to exploit the use of circulatory exosomes as a new diagnostic tool, a rapid, high-throughput and reproducible method is required for their isolation and to allow their molecular analysis. We have developed a simple and a low cost microfluidic-based platform to analyze cirEVs enriched in exosomes directly from blood serum in a single step allowing simultaneous capture and quantification of exosomes. To capture exosomes with specificity, we employed a microfluidic device “ExoChip” functionalized with antibodies against exosomes to capture cirEVs. Subsequent staining with a fluorescent dye that specifically labels the exosomes, we quantitated exosomes using a standard plate-reader. Ten independent ExoChip experiments performed using serum obtained from five pancreatic cancer patients and five healthy individuals revealed a statistically significant increase (2.34±0.31 fold, p &amp;lt;0.001) in exosomes captured in cancer patients when compared to healthy individuals. Exosomal origin of ExoChip immobilized vesicles were further confirmed using immuno-electron-microscopy and Western blotting. In addition, we demonstrate the ability of ExoChip to recover exosomes with intact RNA enabling profiling of exosomal-microRNAs through openarray analysis, which has potential applications in biomarker discovery. Based on our findings, ExoChip is a well suited platform to be used as an exosome-based diagnostic and research tool for molecular screening of human cancers. Citation Format: Shailender S. Kanwar, Christopher J. Dunlay, Diane M. Simeone, Sunitha Nagrath. Simultaneous isolation and quantification of circulating exosomes for cancer biomarker discovery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5591. doi:10.1158/1538-7445.AM2014-5591
Abstract 1363: Novel Role of Early Endosome Antigen 1 in Reactive Oxygen Species-dependent AT1 Receptor-mediated Signaling Linked to Hypertrophy in Vascular Smooth Muscle Cells
Authors: Rafal R Nazarewicz, Nikolay A Patrushev, Lu Hilenski, Masuko Ushio-Fukai, R. W Alexander
Journal: Circulation (2008)

Angiotensin II (Ang II) stimulates hypertrophy in vascular smooth muscle cells (VSMCs) primarily through the G protein-coupled receptor (GPCR) Ang II type 1 receptor (AT1R) at the cell membrane and after its internalization. Major outputs of AT1R leading to vascular hypertrophy are triggered by reactive oxygen species (ROS)-dependent transactivation of the EGF receptor (EGFR), followed by activation of p38MAPK, Akt, p70S6K, and ERK1/2. However, underlying regulatory mechanisms are largely unknown. The small GTPase Rab5 and its downstream effector early endosome antigen 1 (EEA1) regulate endosomal internalization of GPCR. We hypothesized that EEA1 could be a scaffold facilitating the multiple outputs of AT1R signaling including those involved in hypertrophy. We found that Ang II (0.1 μ M, 5 min) and H2O2 (100 μ M, 5 min) induce formation of a complex composed of EEA1, Rab5, AT1R and EGFR that is inhibited by PEG-catalase (100 U/ml) and PEG-superoxide dismutase (SOD, 200 U/ml), inferring the redox sensitivity of the process. To explore this possibility further, we showed that Ang II and H2O2 stimulate EEA1 threonine phosphorylation (3.0- and 2.0-fold, respectively) co-temporaneously with Ang II- and H2O2-induced complex formation. Inhibition of p38MAPK by inhibitors (SB202190, PD169316; 1 μ M) or treatment with PEG-catalase and PEG-SOD prevents EEA1 phosphorylation and its recruitment to the complex. To gain further insight, we used EEA1 siRNA to knock down EEA1 (80%). EEA1 siRNA significantly inhibits (79% control) Ang II-stimulated [3H]leucine incorporation in VSMC and is associated with decrease in Akt phosphorylation and its downstream p70S6K (80% and 50%, respectively) without affecting ROS-independent Erk1/2 phosphorylation. EEA1 siRNA does not affect Ang II-induced EGFR phosphorylation. Conclusion: ROS- and p38MAPK-dependent Ang II-induced EEA1 phosphorylation is involved in formation of a signaling complex (AT1R, EGFR, EEA1, Rab5) that is related to Ang II stimulated, AT1R- and EGFR-mediated vascular hypertrophy. Akt-dependent phosphorylation of the p70S6K kinase is also EEA1-dependent. These findings provide insight into a novel role for EEA1 in Ang II signaling in VSMC hypertrophy.
Risk factors associated with poor asthma control and quality of life in severe Spanish asthmatics
Authors: M.C. Vennera, C. Picado, L. Herraez, J. Galera, J. Casafont
Journal: European Respiratory Journal (2011)

Background:  Several risk factors determined asthma control, which is a fundamental objective in patients9 management, however it is still insufficient.   Objective:  To assess how the lack of asthma control affects quality of life and which are the main factors associated.   Methods:  Observational, cross-sectional and multicenter study that included severe asthma patients. We assessed quality of life (QoL) using Mini-AQLQ questionnaire, anxiety and depression using Hospital Anxiety and Depression Scale, and hyperventilation by Nijmegen questionnaire.   Results:  343 patients participated in the study, 67.6% women. Mean age (SD) of asthma uncontrolled patients was slightly higher, especially when analyzed according to Spanish Guidelines for Asthma Management (GEMA) [48.5 (14.7) vs 44.1 (14.1) years, p=0.079]. A higher BMI was observed in uncontrolled patients [28.2 (5.8) kg/m 2  vs. 25.5 (4.9) kg/m 2 , p=0.006]. Smoking habit was not related to asthma control, while the uncontrolled group showed a significantly higher percentage of sedentary patients (49.7% vs 28.6%, p=0.016). Uncontrolled patients had worse QoL scores [4.4 (1.3) vs 6.1 (1.0), p   Conclusions:  Uncontrolled asthma patients had worse quality of life, showing higher levels of anxiety, depression and hyperventilation.
Development and characterization of prostate specific antigen inhibitors
Authors: Simon A. Williams, Meha H. Shah, Pratap Singh, Ciby J. Abraham, Aaron Lebeau, Thomas Lectka, Samuel R. Denmeade
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4381 

A characteristic of prostatic epithelia that is retained during the development and progression of prostate cancer is the secretion of prostate specific antigen (PSA). This property has been exploited for diagnostic purposes. The detection of PSA in serum is a valuable tool for disease diagnosis, the monitoring of progression, and response to therapy. PSA is a serine protease produced principally by men in the prostate and is under the transcriptional regulation of the androgen receptor. It is secreted by the luminal epithelia of the prostate gland and, when mixed with seminal fluid during ejaculation, cleaves structural proteins such as the seminogelins, leading to seminal liquefaction. While much is written about the utility of PSA as a disease marker, relatively little is reported on the role the protein plays in fertility or prostate cancer pathophysiology, where cancerous tissue continues to produce high levels of active enzyme. We sought generate inhibitors of PSA’s enzymatic activity for use in answering some of the fundamental questions regarding this protein. Here, we report on the design and generation of several PSA inhibitors including beta lactam serine protease inhibitors as the template for development and modeling of the enzyme’s active site. These inhibitors display varied activity profiles against PSA and other serine proteases, with functions that affect the viability of PSA-expressing cells. These activities are consistent with what was predicted by our modeling strategy. These initial compounds provide a promising starting point for the development PSA inhibitors with high potency and selectivity for its target. These may have utility in basic and preclinical studies, and eventually the clinic.
Continuous Subcutaneous Insulin Infusion
Authors: Ana Margarida Balsa, Celestino Neves, Marta Alves, Miguel Pereira, Davide Carvalho, J Luís Medina
Journal: Diabetes Care (1992)

Continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) represent two strategies of intensive insulin therapy, obtaining a strict metabolic control. The importance of such rigorous metabolic control in reducing the frequency and severity of diabetes long-term complications was highlighted by the Diabetes Control and Complication Trial (DCCT).To review the experience in the use of ISCI at Hospital São João, comparing it with the therapeutic modality of MID, regarding metabolic control, weight and body mass index (BMI), microalbuminuria, frequency of adverse events, lipid profile and quality of life.This retrospective, observational study included 25 type 1 diabetic patients followed-up on Endocrinology outpatient at Hospital São João, receiving CSII for more than 3 months after they were treated with MDI also for a period exceeding 3 months. For both periods of treatment, clinical data were obtained on the quality of glycaemic control (assessed by the levels of glycated hemoglobin--A1c), lipid profile, weight and body mass index (BMI) and microalbuminuria. To evaluate the impact on quality of life we used the ADDQoL questionnaire. A questionnaire was also used to determine the frequency of adverse events (severe hypoglycemia and ketoacidosis).The sample of 25 subjects with mean age of 33.35 ± 9.59 years, with a duration of disease, on average, of 17.1 ± 8.15 years and receiving ISCI for an average of 2.48 ± 1 08 years, obtained a decrease of 1.1% (p = 0.001) on the median value of A1c between 3 and 6 months of treatment when compared to MDI, reduction sustained throughout the analyzed period. The variation of the daily insulin requirements after pump placement was 12.75 units of insulin (p = 0.015), equivalent to a decrease of 0.20 units/kg (p = 0.023). The median of the distribution of BMI decreased 0.48 kg/m2 (p = 0.507) during CSII. The parameters of lipid profile and microalbuminuria showed no trend upward or downward after institution of CSII. The score obtained in the ADDQoL questionnaire was greater with CSII, the difference between the medians of the score distribution, before and after pump placement, was 0.056 (p = 0.92). There was a subjective perception of reduced frequency of adverse events with ISCI.The introduction of CSII allowed optimization of metabolic control, reduction of the daily insulin requirements and achievement of a higher level of satisfaction with no change in lipid profile, no weight gain and without increasing the frequency of adverse events.
Therapeutic targeting of MCT-1 in diffuse large B-cell lymphoma
Authors: Bojie Dai, Ronald Gartenhaus
Journal: Clinical Cancer Research (2008)

B50  The MCT-1 (Multiple Copies in T-cell lymphoma-1) oncogene was originally identified in a T-cell lymphoma cell line and there is growing evidence of its involvement in human lymphomagenesis. The exact molecular mechanism(s) by which MCT-1 transforms cells is still emergent; however there is data implicating it in modulating the translation of cancer-related genes. The stability of MCT-1 protein was recently shown to be regulated by MEK/ERK signaling. Here, we report that MCT-1 is highly expressed in 85% of human diffuse large B cell lymphomas (DLBCL), suggesting the feasibility of therapeutic targeting of MCT-1 for DLBCL. MCT-1 physically associates with ERK and we have documented the co-localization of MCT-1 with ERK in primary DLBCL samples. Employing a small inhibitory molecule interfering with ERK function we were able to interrupt the association between MCT-1 and ERK, as well as decrease levels of MCT-1 protein and phosphorylation. Furthermore, knocking down ERK expression using a specific small interfering RNA (siRNA) decreased MCT-1 protein levels, whereas overexpression of ERK increased MCT-1. We were able to demonstrate, using the ERK inhibitor, dramatically reduced clonogenic capacity of lymphoma cell lines. Significantly, treatment with the ERK inhibitor had marked anti-tumor activity in a human lymphoma xenograft model established from DLBCL cell lines. This provided in vivo proof of principle for the therapeutic potential of ERK inhibitors in MCT-1 overexpressing lymphomas. Finally, these data support the development of novel small inhibitory molecules directed towards MCT-1 and its upstream kinases as a promising approach in DLBCL.
Abstract 18521: Sensory Neuropathy Jeopardizes Nociceptive-mediated Liberation and Homing of Stem Cells in Mice and Patients With Diabetes
Authors: Zexu Dang, Davide Maselli, Gaia Spinetti, Maria Sambataro, Elena Seganfreddo, Federico Quaini, Jonathan Rowlinson, Bruno Lorusso, Carlotta Reni, Gian P Fadini, Paolo Madeddu
Journal: Circulation (2014)

Introduction: Diabetic sensory neuropathy (SN) causes either unbearable pain or lack of ischemic pain perception. It remains unknown if SN affects bone marrow (BM) with consequence for stem cell (SCs) liberation upon tissue injury. We reported that ischemia induces the liberation of Lineage - Sca-1 + c-kit + (LSK)SCs co-expressing the SP receptor NK1 (LSK-NK1) via a neuronal circuitry projecting to the BM and a humoral mechanism consisting of the generation of a chemoattractant gradient of Substance P (SP) between the circulation and BM. We hypothesize that SN might contribute to faulty SC liberation in diabetes. Results: Nociceptive fibers coexpressing SP and NGF are reduced in BM of type 1 (T1D, streptozotocin-induced) and type 2 diabetic (T2D, Leptin-receptor knockout) mice compared with controls. BM SN was prevented by systemic AAV-mediated NGF gene therapy. Upon induction of limb ischemia, a gradient of SP is created between skeletal muscle&gt;circulation&gt;BM in non-diabetic mice, which associates with LSK-NK1 cell liberation and homing to the ischemic limb. These phenomena are abrogated in T1D mice. Furthermore, in vitro SP-induced migration of BM LSK-NK1 cells is reduced in T1D mice ( P &lt;0.05 vs. ND mice). For clinical translation, we studied the association of SN and SC liberation in T2D with or without vascular complications. Sensory fibers were found reduced in BM of T2D patients. In addition, critical limb ischemia fails to create an SP gradient and induce CD34+NK1+ SC release. Pain is an acknowledged side effect of BM stimulation by granulokines. We found that BM stimulation with G-CSF fails to induce CD34+NK1+ SC liberation in T2D patients, with this phenomenon being directly correlated to pain score and increase in SP levels. Conclusions: We are the first to show that diabetes is associated with NGF-sensitive BM SN in animal models and humans. Two nociceptive mechanisms fail following ischemia or granulokine stimulation: the ability of nerve terminals to coordinate SP release between periphery and BM and responsiveness of NK1 SCs to SP-induced chemoattraction. These findings open new avenues to rescue diabetic SC mobilopathy and thereby encourage vascular repair.
Abstract 16397: Correlates of Successfully Achieving Statin Therapy Targets in Pediatric Patients
Authors: Michael Mendelson, Todd Regh, Heather Harker, Nicole Palumbo, James Nevin, Phillip K Johnson, Suzanne Griggs, Meera Boghani, Nirav Desai, Elizabeth Yellen, Lucy Buckley, Annette Baker, Mathew Gillman, Justin Zachariah, Dionne Graham, Sarah D de Ferranti
Journal: Circulation (2014)

Introduction: Targeting LDL-C goals for statin therapy is currently recommended for children and adolescents in NHLBI pediatric guidelines; however, there is limited information about clinical factors, especially modifiable ones, that impact successful achievement of LDL-C goals. Methods: We analyzed data prospectively collected as part of a quality improvement initiative, SCAMP® (Standardized Clinical Assessment and Management Program), in the Preventive Cardiology Clinic at Boston Children’s Hospital, Boston, MA. We included patients initiated on statin therapy from September 2010 to March 2014. Achieving LDL target was defined as an LDL-C &lt; 130 mg/dL or an LDL-C &lt; 100mg/dL with a high level risk factor (i.e. diabetes, etc.). The impact of baseline CVD risk factors were assessed in Cox proportional hazards models. Results: Among the 1521 pediatric patients and 3813 clinical encounters that occurred over the 3.5 year period, 116 patients were defined as initiating statin therapy. Complete data was available on 79 patients (mean [SD] age 14 [4] years; 47% female; median [IQR] LDL-C 215 [79] mg/dL). The probability of achieving LDL-C goal within 365 and 500 days of starting a statin was 0.55 (95% CI 0.44-0.68) and 0.67 (0.55-0.79), respectively; Figure 1. In univariate analyses, female sex (p=0.01) and lower baseline LDL-C (p=0.04) was associated with more rapid achievement of LDL-C goals, but not age (p=0.8), BMI (p=0.2), exercise (p=0.6), nutritional factors (p=0.3), screen time (p=0.3), cigarette smoking (p=0.9), or family history of early CVD (p=0.3). Conclusions: The majority of children reached LDL-C treatment goals with statin therapy. Baseline modifiable lifestyle CVD risk factors such as diet and exercise were not associated with achieving LDL-C goal on statin therapy in children and adolescents. Increased support and monitoring may be needed, particularly for males, in order to achieve therapy goals.
Abstract 1806: Notifiable Genetic Variants on Commercially Available SNP Arrays: Implications for Research Participants in Genome-wide Association Studies for Cardiovascular Disease
Authors: Andrew D Johnson, Anupama Bhimavarapu, Emelia J Benjamin, Caroline Fox, Daniel Levy, Gail P Jarvik, Christopher J O'Donnell
Journal: Circulation (2009)

In recent years, genome-wide association studies (GWAS) for cardiovascular disease (CVD) have been conducted with increasing sample sizes using dense arrays of single nucleotide polymorphisms (SNPs). While criteria exist for determining if incidental genetic findings should be reported back to research participants, a comprehensive survey of the extent of potentially notifiable variants on genotyping arrays now widely applied in GWAS and in direct to consumer genetic tests has not been reported. We hypothesized that while genotyping arrays are generally designed to measure common variants with modest clinical impact a comprehensive survey might reveal some lower frequency genetic variants with more substantial clinical impact that could warrant participant notification regarding genotype status. Using bioinformatics techniques and multiple public genome databases, we surveyed 18 commercial SNP arrays and HapMap, searching for variants tested for genetic disorders in ≥ 2 CLIA-approved US labs within the Ge...