Documents published in Scipedia

• Chronic Kidney Disease, Time in Therapeutic Range and Adverse Clinical Outcomes in Anticoagulated Patients with Non-valvular Atrial Fibrillation: Observations from the SPORTIF Trials

  M. Proietti, D. Lane, G. Lip

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Chronic kidney disease (CKD) is highly prevalent in atrial fibrillation (AF) patients and associated with an increased risk of adverse outcomes. Our objectives were to study clinical features associated with CKD in AF patients and the impact of CKD on anticoagulation control, as reflected by time in therapeutic range (TTR). We also determined the impact of CKD and TTR in predicting adverse outcomes. We analysed pooled datasets from SPORTIF III and V trials, including 3646 patients assigned to warfarin with data on renal function. CKD (creatinine clearance < 60 ml/min) was present in 952 (26%) patients. TTR was higher in patients with normal renal function compared to those with CKD (p < 0.001). On logistic analysis, chronic AF and male sex were associated with TTR > 70%, whilst diabetes mellitus, aspirin use and CKD were inversely associated with TTR > 70%. On Cox regression analysis, CKD was an independent predictor for stroke (p = 0.006) and death (p < 0.001). TTR > 70% was independently associated with a lower risk of stroke (p = 0.024), death (p = 0.001) and major bleeding (p = 0.001). CKD is highly prevalent amongst AF patients and a risk factor for stroke and death. Adjusting for CKD, good quality anticoagulation control (TTR > 70%) was an independent predictor for lower risks of stroke, death and major bleeding.

  Abstract
  Chronic kidney disease (CKD) is highly prevalent in atrial fibrillation (AF) patients and associated with an increased risk of adverse outcomes. Our objectives were to study [...]

  • 0
  •  read

• Liver Flukes and the Microbiota in Cancer

  L. Osborne, L. WegenerParfrey

  Collection of EBioMedicine (2017).

  
  

  • 0
  •  read

• Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability

  J. Munkley, D. Vodak, K. Livermore, K. James, B. Wilson, B. Knight, P. Mccullagh, J. Mcgrath, M. Crundwell, L. Harries, H. Leung, C. Robson, I. Mills, P. Rajan, D. Elliott

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl LewisX (SLeX ), O -GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.

  Abstract
  Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control [...]

  • 0
  •  read

• Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival

  G. Metodieva, S. Adoki, B. Lausen, M. Metodiev

  Collection of EBioMedicine (2017).

  
  

  Abstract

  SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.

  Abstract
  SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of [...]

  • 0
  •  read

• Will LEDGIN molecules be able to play a role in a cure for HIV infection?

  T. Mesplède, M. Wainberg

  Collection of EBioMedicine (2017).

  
  

  • 0
  •  read

• Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

  M. Martínez-Hoyos, E. Perez-Herran, G. Gulten, L. Encinas, D. Álvarez-Gómez, E. Alvarez, S. Ferrer-Bazaga, A. García-Pérez, F. Ortega, I. Angulo-Barturen, J. Rullas-Trincado, D. Ruano, P. Torres, P. Castañeda, S. Huss, R. Menéndez, S. Valle, L. Ballell, D. Barros, S. Modha, N. Dhar, F. Signorino-Gelo, J. McKinney, J. García-Bustos, J. Lavandera, J. Sacchettini, M. Jimenez, N. Martín-Casabona, J. Castro-Pichel, A. Mendoza-Losana

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb ), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

  Abstract
  Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together [...]

  • 0
  •  read

• Alcohol and Steatosis: The Japanese Paradox

  A. Lonardo, S. Ballestri, D. Romagnoli, F. Nascimbeni

  Collection of EBioMedicine (2017).

  
  

  • 0
  •  read

• Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia

  Y. Liu, B. Wang, W. Zhang, J. Huang, B. Li, M. Zhang, L. Jiang, J. Li, M. Wang, Y. Dai, Z. Zhang, Q. Wang, J. Kong, B. Chen, Y. Zhu, X. Weng, Z. Shen, J. Li, J. Wang, X. Yan, Y. Li, Y. Liang, L. Liu, X. Chen, W. Zhang, J. Yan, J. Hu, S. Shen, J. Chen, L. Gu, D. Pei, Y. Li, G. Wu, X. Zhou, R. Ren, . Cheng, J. Yang, K. Wang, S. Wang, J. Zhang, J. Mi, C. Pui, J. Tang, Z. Chen, S. Chen

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4 -IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

  Abstract
  Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number [...]

  • 0
  •  read

• Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants

  N. Lin, O. Gonzalez, L. Registre, C. Becerril, B. Etemad, H. Lu, X. Wu, S. Lockman, M. Essex, S. Moyo, D. Kuritzkes, M. Sagar

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4 + T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4 + T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy.

  Abstract
  Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated [...]

  • 0
  •  read

• Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers

  A. Illendula, J. Gilmour, J. Grembecka, V. Tirumala, A. Boulton, A. Kuntimaddi, C. Schmidt, L. Wang, J. Pulikkan, H. Zong, M. Parlak, C. Kuscu, A. Pickin, Y. Zhou, Y. Gao, L. Mishra, M. Adli, L. Castilla, R. Rajewski, K. Janes, M. Guzman, C. Bonifer, J. Bushweller

  Collection of EBioMedicine (2017).

  
  

  Abstract

  Transcription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could more effectively address the stem cell like properties, such as self-renewal and chemo-resistance, that lead to the failure of traditional chemotherapy approaches. Core binding factor is a heterodimeric transcription factor comprised of one of 3 RUNX proteins (RUNX1-3) and a CBFβ binding partner. CBFβ enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFβ are frequently mutated in human leukemia. More recently, RUNX proteins have been shown to be key players in epithelial cancers, suggesting the targeting of this pathway could have broad utility. In order to test this, we developed small molecules which bind to CBFβ and inhibit its binding to RUNX. Treatment with these inhibitors reduces binding of RUNX1 to target genes, alters the expression of RUNX1 target genes, and impacts cell survival and differentiation. These inhibitors show efficacy against leukemia cells as well as basal-like (triple-negative) breast cancer cells. These inhibitors provide effective tools to probe the utility of targeting RUNX transcription factor function in other cancers.

  Abstract
  Transcription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could [...]

  • 0
  •  read