This innovative ethnographic study animates the racial politics that underlie genomic research into type 2 diabetes, one of the most widespread chronic diseases and one that affects ethnic groups ...disproportionately. Michael J. Montoya follows blood donations from "Mexican-American" donors to laboratories that are searching out genetic contributions to diabetes. His analysis lays bare the politics and ethics of the research process, addressing the implicit contradiction of undertaking genetic research that reinscribes race's importance even as it is being demonstrated to have little scientific validity. In placing DNA sampling, processing, data set sharing, and carefully crafted science into a broader social context, Making the Mexican Diabetic underscores the implications of geneticizing disease while illuminating the significance of type 2 diabetes research in American life.
Resistance to cancer therapy is a challenge because of innate tumor heterogeneity and constant tumor evolution. Since the pathway of resistance cannot be predicted, combination therapies may address ...this progression. We discovered that in addition to IGF1 and IGF2, IGFBP-3 binds bFGF, HGF, neuregulin, and PDGF AB with nanomolar affinity. Because growth factors drive resistance, simultaneous inhibition of multiple growth factor pathways may improve the efficacy of precision therapy. Growth factor sequestration by IGFBP-3-Fc enhances the activity of EGFR inhibitors by decreasing cell survival and inhibiting bFGF, HGF, and IGF1 growth factor rescue and also potentiates the activity of other cancer drugs. Inhibition of tumor growth in vivo with adjuvant IGFBP-3-Fc with erlotinib versus erlotinib after treatment cessation supports that the combination reduces cell survival. Inhibition of multiple growth factor pathways may postpone resistance and extend progression-free survival in many cancer indications.
Accumulating lines of experimental evidence have revealed that hypoxia‐inducible factors, HIF‐1α and HIF‐2α, are key regulators of the adaptation of cancer‐ and metastasis‐initiating cells and their ...differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin‐like growth factor‐1 receptor (IGF‐1R), stem cell factor (SCF) receptor KIT, transforming growth factor‐β receptors (TGF‐βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3′‐kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up‐regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency‐associated transcription factors (Oct‐3/4, Nanog and Sox‐2), glycolysis‐ and epithelial‐mesenchymal transition (EMT) programme‐associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self‐renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.
Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration ...of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. GDNF administration has recently been shown to be an effective treatment for Parkinson's disease, with clinical trials currently in progress. Trials with NGF for Alzheimer's disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain-barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process.
Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory ...Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.
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•Sequence variation in IRF4 is associated with pigmentation features including freckles•This sequence is located in an enhancer element that affects expression of IRF4•The transcription factors MITF and TFAP2A regulate expression from this element•Together, MITF and IRF4 affect regulation of the pigmentation enzyme TYR
A polymorphism in a noncoding region of IRF4, a transcription factor involved in immune signaling, is found to affect human pigmentation. This polymorphism affects the ability of the transcription factors TFAP2A and MITF to regulate IRF4 levels, which in turn results in reduced levels of the pigmentation enzyme Tyrosinase.
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after ...injury
, but efficient reversal of this regrowth failure remains elusive
. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity
, (ii) growth-supportive substrate
and (iii) chemoattraction
-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI
; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor
delivered via spatially and temporally controlled release from biomaterial depots
, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to ...determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.
Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and ...TLR2 specifically activated the endoplasmic reticulum (ER) stress sensor kinase IRE1alpha and its downstream target, the transcription factor XBP1. Previously described ER-stress target genes of XBP1 were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with that finding, activation of IRE1alpha by ER stress acted in synergy with TLR activation for cytokine production. Moreover, XBP1 deficiency resulted in a much greater bacterial burden in mice infected with the TLR2-activating human intracellular pathogen Francisella tularensis. Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses.
Tissue engineering is a rapidly developing field with many potential clinical applications in tissue and organ regeneration. The development of a mature and stable vasculature within these engineered ...tissues (ET) remains a significant obstacle. Currently, several growth factors (GFs) have been identified to play key roles within in vivo angiogenesis, including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), FGF and angiopoietins. In this article we attempt to build on in vivo principles to review the single, dual and multiple GF release systems and their effects on promoting angiogenesis. We conclude that multiple GF release systems offer superior results compared to single and dual systems with more stable, mature and larger vessels produced. However, with more complex release systems this raises other problems such as increased cost and significant GF–GF interactions. Upstream regulators and pericyte-coated scaffolds could provide viable alternative to circumnavigate these issues.
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