Online first articles (not assigned to a volume)
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- R. Zhao, B. Choi, M. Lee, A. Bode, Z. DongCollection of EBioMedicine (2017).
Abstract
Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK) 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.Abstract
Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which [...]
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- J. Wu, M. Gao, S. Rice, C. Tsang, J. Beggs, D. Turner, G. Li, B. Yang, K. Xia, F. Gao, S. Qiu, Q. Liu, J. KerriganCollection of EBioMedicine (2017).
Abstract
Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patients HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients.Abstract
Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. [...]- 0
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- . Wei, H. Guo, M. Ma, R. Markham, X. YuCollection of EBioMedicine (2017).
Abstract
Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution.Abstract
Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome [...]- 0
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- V. Walker-Sperling, C. Pohlmeyer, P. Tarwater, J. BlanksonCollection of EBioMedicine (2017).
Abstract
Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4 + T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8 + T cells were not able to eliminate autologous resting CD4 + T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8 + T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8 + T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8 + T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.Abstract
Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the [...]- 0
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- L. Vranckx, J. Demeulemeester, S. Saleh, A. Boll, G. Vansant, R. Schrijvers, C. Weydert, E. Battivelli, E. Verdin, A. Cereseto, F. Christ, R. Gijsbers, Z. DebyserCollection of EBioMedicine (2017).
Abstract
Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.Abstract
Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency [...]- 0
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- H. Vanderven, F. Ana-Sosa-Batiz, S. Jegaskanda, S. Rockman, K. Laurie, I. Barr, W. Chen, B. Wines, P. Hogarth, T. Lambe, S. Gilbert, M. Parsons, S. KentCollection of EBioMedicine (2017).
Abstract
The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.Abstract
The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies [...]- 0
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- S. Ushiama, Y. Ishimaru, M. Narukawa, M. Yoshioka, C. Kozuka, N. Watanabe, M. Tsunoda, N. Osakabe, T. Asakura, H. Masuzaki, K. AbeCollection of EBioMedicine (2017).
Abstract
Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis. This system is referred to as the gut-brain axis. Here we show that both brush cells and type II taste cells are eliminated in the gastrointestinal tract of transcription factor Skn-1 knockout (KO) mice. Despite unaltered food intake, Skn-1 KO mice have reduced body weight with lower body fat due to increased energy expenditure. In this model, 24-h urinary excretion of catecholamines was significantly elevated, accompanied by increased fatty acid β-oxidation and fuel dissipation in skeletal muscle and impaired insulin secretion driven by glucose. These results suggest the existence of brain-mediated energy homeostatic pathways originating from brush cells and type II taste cells in the gastrointestinal tract and ending in peripheral tissues, including the adrenal glands. The discovery of food-derived factors that regulate these cells may open new avenues the treatment of obesity and diabetes. Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis along the gut-brain axis. We propose the concept that taste-receiving cells in the oral cavity and/or food-borne chemicals-receiving brush cells in the gut are involved in regulation of the body weight and adiposity via the brain. The discovery of food-derived factors that regulate these cells may open new avenues for the treatment of obesity and diabetes.Abstract
Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis. This system is referred [...]- 0
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- K. Tschapalda, Y. Zhang, L. Liu, K. Golovnina, T. Schlemper, T. Eichmann, M. Lal-Nag, U. Sreenivasan, J. McLenithan, S. Ziegler, C. Sztalryd, A. Lass, D. Auld, B. Oliver, H. Waldmann, Z. Li, M. Shen, M. Boxer, M. BellerCollection of EBioMedicine (2017).
Abstract
Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened > 320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.Abstract
Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications [...]- 0
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- T. Sinnberg, E. Makino, M. Krueger, A. Velic, B. Macek, U. Rothbauer, N. Groll, O. Pötz, S. Czemmel, H. Niessner, F. Meier, K. Ikenberg, C. Garbe, B. SchittekCollection of EBioMedicine (2017).
Abstract
Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that β-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that β-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo . Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance. We further demonstrate that β-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi.Abstract
Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas [...]- 0
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- Y. Shen, C. Pang, Y. Wu, D. Li, C. Wan, Z. Liao, T. Yang, L. Chen, F. WenCollection of EBioMedicine (2017).
Abstract
The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deekss funnel plot was used to detect publication bias. Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64–0.75), specificity, 0.83 (95%CI 0.78–0.86), PLR, 4.04 (95%CI 3.13–5.20), NLR, 0.36 (95%CI 0.30–0.44), and DOR, 11.17 (95%CI 7.31–17.07). The area under the SROC curve was 0.84 (95%CI 0.81–0.87). There was no evidence of publication bias. Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors.Abstract
The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed [...]- 0
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- S. Serrano-Villar, D. Rojo, M. Martínez-Martínez, S. Deusch, J. Vázquez-Castellanos, R. Bargiela, T. Sainz, M. Vera, S. Moreno, V. Estrada, M. Gosalbes, A. Latorre, J. Seifert, C. Barbas, A. Moya, M. FerrerCollection of EBioMedicine (2017).
Abstract
While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms underlying the contributions of gut bacteria and their molecular agents (metabolites and proteins) to immune recovery remain unexplored. To study this, we examined the active fraction of the gut microbiome, through examining protein synthesis and accumulation of metabolites inside gut bacteria and in the bloodstream, in 8 healthy controls and 29 HIV-infected individuals (6 being longitudinally studied). We found that HIV infection is associated to dramatic changes in the active set of gut bacteria simultaneously altering the metabolic outcomes. Effects were accentuated among immunological ART responders, regardless diet, subject characteristics, clinical variables other than immune recovery, the duration and type of ART and sexual preferences. The effect was found at quantitative levels of several molecular agents and active bacteria which were herein identified and whose abundance correlated with HIV immune pathogenesis markers. Although, we cannot rule out the possibility that some changes are partially a random consequence of the disease status, our data suggest that most likely reduced inflammation and immune recovery is a joint solution orchestrated by both the active fraction of the gut microbiota and the host.Abstract
While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms [...]- 0
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- M. Roerecke, R. Nanau, J. Rehm, M. NeumanCollection of EBioMedicine (2017).
Abstract
Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis has not been systematically examined. We searched Medline, Embase, and ProQuest Dissertations & Theses Global for original data on the relationship between alcohol consumption and hepatic steatosis measured by non-invasive imagery, excluding studies conducted in participants < 18 years, or subgroups related to viral and drug-induced liver disease. We identified 18 articles reporting adjusted data (Japan = 11, other high-income countries = 7). Random-effect categorical meta-analyses (< 20 g/day pure alcohol consumption vs non-drinkers) and dose-response meta-analyses for the whole range of alcohol consumption were conducted. In total, 99, 370 participants and 25, 662 cases of hepatic steatosis were included. In Japan, low alcohol consumption was consistently associated with substantially reduced incidence and prevalence of hepatic steatosis compared to non-drinkers (RR for < 20 g pure alcohol/day = 0.75, 95% CI: 0.71–0.79, I2 = 0%). No overall association was found in other countries (RR = 1.05, 95% CI: 0.86–1.30, I2 = 84%). Dose-response analyses in Japan (up to 80 g/day) showed an inverse relationship in men and a J-shape in women. Alcohol consumption showed a complex association with hepatic steatosis with substantial differences by ethnicity and sex. Low alcohol consumption was beneficial in Japan with good epidemiological evidence, whereas there was no association in other countries. However, heterogeneity was large in countries other than Japan. More and higher quality research in diverse ethnic populations is needed to further clarify this relationship.Abstract
Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis [...]- 0
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- C. Psomas, M. Younas, C. Reynes, R. Cezar, P. Portalès, E. Tuaillon, A. Guigues, C. Merle, N. Atoui, C. Fernandez, V. Moing, C. Barbuat, G. Marin, N. Nagot, A. Sotto, J. Eliaou, R. Sabatier, J. Reynes, P. CorbeauCollection of EBioMedicine (2017).
Abstract
Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79–82.86], p = 0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.Abstract
Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, [...]- 0
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- M. Proietti, D. Lane, G. LipCollection 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
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- 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. ElliottCollection 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
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- G. Metodieva, S. Adoki, B. Lausen, M. MetodievCollection 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
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- 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-LosanaCollection 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
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- 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. ChenCollection 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
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- N. Lin, O. Gonzalez, L. Registre, C. Becerril, B. Etemad, H. Lu, X. Wu, S. Lockman, M. Essex, S. Moyo, D. Kuritzkes, M. SagarCollection 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
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- 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. BushwellerCollection 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
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- T. Friedrich, M. Söhn, T. Gutting, K. Janssen, H. Behrens, C. Röcken, M. Ebert, E. BurgermeisterCollection of EBioMedicine (2017).
Abstract
Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001, n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.Abstract
Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human [...]- 0
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- K. Chng, S. Chan, A. Ng, C. Li, A. Jusakul, D. Bertrand, A. Wilm, S. Choo, D. Tan, K. Lim, R. Soetinko, C. Ong, D. Duda, S. Dima, I. Popescu, C. Wongkham, Z. Feng, K. Yeoh, B. Teh, P. Yongvanit, S. Wongkham, V. Bhudhisawasdi, N. Khuntikeo, P. Tan, C. Pairojkul, J. Ngeow, N. NagarajanCollection of EBioMedicine (2017).
Abstract
Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty primary CCA tumors and matched normals, from both liver fluke (Opisthorchis viverrini ) associated (OVa, n = 28) and non-O. viverrini associated (non-OVa, n = 32) cancers, were profiled using high-throughput 16S rRNA sequencing. A distinct, tissue-specific microbiome dominated by the bacterial families Dietziaceae, Pseudomonadaceae and Oxalobacteraceae was observed in bile duct tissues. Systemic perturbation of the microbiome was noted in tumor and paired normal samples (vs non-cancer normals) for several bacterial families with a significant increase in Stenotrophomonas species distinguishing tumors vs paired normals. Comparison of parasite associated (OVa) vs non-associated (non-OVa) groups identified enrichment for specific enteric bacteria (Bifidobacteriaceae, Enterobacteriaceae and Enterococcaceae ). One of the enriched families, Bifidobacteriaceae, was found to be dominant in the O. viverrini microbiome, providing a mechanistic link to the parasite. Functional analysis and comparison of CCA microbiomes revealed higher potential for producing bile acids and ammonia in OVa tissues, linking the altered microbiota to carcinogenesis. These results define how the unique microbial communities resident in the bile duct, parasitic infections and the tissue microenvironment can influence each other, and contribute to cancer.Abstract
Cholangiocarcinoma (CCA) is the primary cancer of the bile duct system. The role of bile duct tissue microbiomes in CCA tumorigenesis is unestablished. To address this, sixty [...]- 0
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- C. Brégnard, J. Guerra, S. Déjardin, F. Passalacqua, M. Benkirane, N. LaguetteCollection of EBioMedicine (2017).
Abstract
Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4FANCP deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis.Abstract
Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4FANCP deficiency as a working [...]- 0
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- F. Bolduc, A. Lau, C. Rosenfelt, S. Langer, N. Wang, L. Smithson, D. Lefebvre, R. Alexander, C. Dickson, A. Li, A. Becker, P. Subbarao, S. Turvey, J. Pei, M. Sears, P. MandhaneCollection of EBioMedicine (2017).
Abstract
In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37, p < 0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7, SE 1.8, p < 0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca2 + -Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila . Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.Abstract
In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton [...]- 0
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- M. Berendsen, J. Smits, M. Netea, A. VenCollection of EBioMedicine (2017).
Abstract
Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called “non-specific effects”. We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under five. We use a Big Data design, including cross-sectional data for 368, 450 children from 33 SSA countries. Logistic regression analysis is used with control factors at child, mother, household and context level. Overall, BCG vaccination did not affect stunting in SSA children (OR 1.00 [0.98–1.03]). Timing of BCG vaccination was of importance (βtime = 0.067 [0.061–0.073]): compared to unvaccinated children, BCG was associated with lower odds on stunting for children vaccinated early in life (OR 0.92 [0.89–0.94]) and higher odds for children vaccinated later in infancy (OR 1.64 [1.53–1.76]). Similar findings were done for diphtheria-tetanus-pertussis (DTP)1 and measles vaccination, and when hemoglobin concentration was used as outcome variable. We found a general time-dependent pattern of non-specific effects of vaccination, with positive associations for vaccinations given early in life and negative associations for vaccinations given later in infancy. If confirmed in further research, our findings may provide a new perspective on the non-specific effects of vaccination.Abstract
Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called “non-specific effects”. We evaluate these effects, as [...]- 0
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- I. Audenhove, J. GettemansCollection of EBioMedicine (2017).
Abstract
Since their discovery, nanobodies have been used extensively in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from Camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes outperforming monoclonal antibodies. In this review, we evaluate the current status of nanobodies to study, diagnose, visualize or inhibit cancer-specific proteins and processes. Nanobodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. More in vivo and clinical studies are however eagerly awaited to unleash their full potential.Abstract
Since their discovery, nanobodies have been used extensively in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from Camelid [...]- 0
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- W. Altarche-Xifro, U. Vicino, M. Muñoz-Martin, A. Bortolozzi, J. Bové, M. Vila, M. CosmaCollection of EBioMedicine (2017).
Abstract
Parkinsons disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinsons disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinsons disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4 weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinsons disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach.Abstract
Parkinsons disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive [...]- 0
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