Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-16 Marta A. Toscano, Verónica C. Martínez Allo, Anabela M. Cutine, Gabriel A. Rabinovich, Karina V. Mariño
Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin–glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention.
Human Endogenous Retroviruses in Neurological Diseases Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-15 Patrick Küry, Avindra Nath, Alain Créange, Antonina Dolei, Patrice Marche, Julian Gold, Gavin Giovannoni, Hans-Peter Hartung, Hervé Perron
The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.
Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancers Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-09 Julian A. Gingold, Dandan Zhu, Dung-Fang Lee, Ahmed Kaseb, Jian Chen
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), the two most common primary liver cancers, represent the second most common cancer-related cause of death worldwide, with most cases being diagnosed at an advanced stage. Recent genome-wide studies have helped to elucidate the molecular pathogenesis and genetic heterogeneity of liver cancers. This review of the genetic landscape of HCC and iCCA discusses the most recent findings from genomic profiling and the current understanding of the pathways involved in the initiation and progression of liver cancer. We highlight recent insights gained from metabolic profiling of HCC and iCCA. This knowledge will be key to developing clinically useful diagnostic/prognostic profiles, building targeted molecular and immunologic therapies, and ultimately curing these complex and heterogeneous diseases.
Mechanisms of Tissue Injury in Lupus Nephritis Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-08 Giovanna Flores-Mendoza, Stephanie P. Sansón, Santiago Rodríguez-Castro, José C. Crispín, Florencia Rosetti
Disease heterogeneity remains a major challenge for the understanding of systemic lupus erythematosus (SLE). Recent work has revealed the important role of nonimmune factors in the development of end-organ damage involvement, shifting the current paradigm that views SLE as a disease inflicted by a disturbed immune system on passive target organs. Here, we discuss the pathogenesis of lupus nephritis in a comprehensive manner, by incorporating the role that target organs play by withstanding and modulating the local inflammatory response. Moreover, we consider the effects that genetic variants exert on immune and nonimmune cells in order to shape the phenotype of the disease in each affected individual.
Therapeutic Perspectives for Interferons and Plasmacytoid Dendritic Cells in Rheumatoid Arthritis Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-05 Ramzi Nehmar, Alexandre Mariotte, Aurore de Cauwer, Jean Sibilia, Seiamak Bahram, Philippe Georgel
Rheumatoid arthritis (RA) is a multifactorial immune disease exhibiting diverse clinical responses to specific therapeutic agents. Such heterogeneity reflects variable activation of signaling pathways. Consequently, RA physiopathology has been linked to many immune cells and factors, with controversial observations for interferons (IFNs). In this opinion article, we review the roles of these cytokines and the cells that produce them in light of recent data: clinical observations showing that expression of IFN-dependent genes does not reflect RA activity and RA mouse models in which the stimulation of IFN-dependent pathways provided disease protection. We suggest that epicutaneous stimulation of the IFN network is an attractive possibility to limit neutrophil infiltration or activation, thus providing therapeutic benefits to RA patients refractory to current therapies.
Nitric Oxide Signaling in T Cell-Mediated Immunity Trends Mol. Med. (IF 10.732) Pub Date : 2018-03-05 Almudena García-Ortiz, Juan M. Serrador
Nitric oxide (NO) is a key messenger in the pathogenesis of inflammation, linking innate and adaptive immunity. By targeting signaling molecules, NO from inducible NO synthase (iNOS) and endothelial (e)NOS affects T helper cell differentiation and the effector functions of T lymphocytes, and is a potential target for therapeutic manipulation. In this review we discuss the regulatory actions exerted by NO on T cell functions, focusing on S-nitrosylation as an important post-translational modification by which NO acts as a signaling molecule during T cell-mediated immunity. We also present recent findings showing novel mechanisms through which NO regulates the activation of human T cells, and consider their potential in strategies to treat tumoral, allergic, and autoimmune diseases.
Neuronal Cilia: Another Player in the Melanocortin System Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-28 Luis Varela, Tamas L. Horvath
Melanocortin receptors play crucial roles in multiple physiological processes. Melanocortin receptor 4 (MC4R) is expressed in key brain regions, and MC4R gene mutations can cause severe obesity. However, the cellular biology of MC4R is less well understood owing to the lack of reliable methods to visualize its location. Recently, Siljee and colleagues localized MC4R to the cilia of the neurons within the hypothalamus and showed that cilial expression of MC4R is crucial for the control of metabolic phenotype.
A New Chapter in Genetic Medicine: RNA Editing and its Role in Disease Pathogenesis Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-23 Khatuna Gagnidze, Violeta Rayon-Estrada, Sheila Harroch, Karen Bulloch, F. Nina Papavasiliou
The transfer of genomic information from DNA to mRNA to protein usually occurs with high fidelity, but can also be subverted by a programmed RNA sequence alteration termed ‘RNA editing’, involving deamination of adenosine to inosine (decoded as guanosine), or of cytosine to uracil. These sequence changes can lead to cellular heterogeneity by generating variable sets of transcripts within otherwise identical cells. Recent studies have demonstrated that editing is most prevalent in cells and tissues with high propensity for plasticity. Within those, RNA editing reproducibly targets transcripts of related function, altering the outcomes of entire pathways at once. In ongoing work, changes in patterns of editing have been correlated with neuronal disease pathogenesis, suggesting that RNA editing harbors diagnostic potential.
Macrophages Remember Cheeseburgers and Promote Inflammation via NLRP3 Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-23 Luke A.J. O’Neill, Zbigniew Zaslona
In a recent study, Christ and colleagues identify a key role for NLRP3/IL-1beta in the induction of innate immune memory in monocytes by the Western diet, promoting atherosclerosis and inflammatory diseases.
Untapped Reserves: Controlling Primordial Follicle Growth Activation Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-13 Amanda Kallen, Alex J. Polotsky, Joshua Johnson
Even with the benefit of assisted reproductive technologies (ART), many women are unable to conceive and deliver healthy offspring. One common cause of infertility is the inability to produce eggs capable of contributing to live birth. This can occur despite standard-of-care treatment to maximize the recovery of eggs from growing ovarian follicles. Dormant primordial follicles in the human ovary are a ‘reserve ’ that can be exploited clinically to overcome this problem. We discuss how controlling primordial follicle growth activation (PFGA) can produce increased numbers of high-quality eggs available for fertility treatment(s). We consider the state of the art in interventions used to control PFGA, and consider genetic and epigenetic strategies on the horizon that might improve compromised oocyte quality to increase live births.
Manufacturing Exosomes: A Promising Therapeutic Platform Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-12 Ivano Luigi Colao, Randolph Corteling, Daniel Bracewell, Ivan Wall
Extracellular vesicles, in particular the subclass exosomes, are rapidly emerging as a novel therapeutic platform. However, currently very few clinical validation studies and no clearly defined manufacturing process exist. As exosomes progress towards the clinic for treatment of a vast array of diseases, it is important to define the engineering basis for their manufacture early in the development cycle to ensure they can be produced cost-effectively at the appropriate scale. We hypothesize that transitioning to defined manufacturing platforms will increase consistency of the exosome product and improve their clinical advancement as a new therapeutic tool. We present manufacturing technologies and strategies that are being implemented and consider their application for the transition from bench-scale to clinical production of exosomes.
Therapeutic Targeting of Long Non-Coding RNAs in Cancer Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-12 Gayatri Arun, Sarah D. Diermeier, David L. Spector
Long non-coding RNAs (lncRNAs) represent a significant population of the human transcriptome. Many lncRNAs exhibit cell- and/or tissue/tumor-specific expression, making them excellent candidates for therapeutic applications. In this review we discuss examples of lncRNAs that demonstrate the diversity of their function in various cancer types. We also discuss recent advances in nucleic acid drug development with a focus on oligonucleotide-based therapies as a novel approach to inhibit tumor progression. The increased success rates of nucleic acid therapeutics provide an outstanding opportunity to explore lncRNAs as viable therapeutic targets to combat various aspects of cancer progression.
In Vivo Imaging of Single Mammalian Cells in Development and Disease Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-10 Melanie D. White, Ziqing W. Zhao, Nicolas Plachta
Live imaging has transformed biomedical sciences by enabling visualization and analysis of dynamic cellular processes as they occur in their native contexts. Here, we review key recent efforts applying in vivo optical imaging with single-cell resolution to mammalian systems ranging from embryos to adult tissues and organs. We highlight insights into active processes regulating cell fate and morphogenesis during embryonic development, how neuronal circuitry and non-neuronal cell types contribute to neurological functions, and how novel imaging-based approaches enable the dissection of neurological disorders and cancer with high spatio-temporal resolution. The convergence of technical advancements in accessing, visualizing, and manipulating individual cells provides an unprecedented lens to probe mammalian cellular dynamics in vivo in both physiological and pathological states.
Functional Neurocircuits and Neuroimaging Biomarkers of Tobacco Use Disorder Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-10 Matthew T. Sutherland, Elliot A. Stein
Drug abuse and addiction remain major public health issues, exemplified by the opioid epidemic currently devastating the United States. Treatment outcomes across substance use disorders remain unacceptably poor, wherein drug discovery/development for this multifaceted neuropsychiatric disorder focuses on single molecular-level targets. Rather, our opinion is that a systems-level neuroimaging perspective is crucial for identifying novel therapeutic targets, biomarkers to stratify patients, and individualized treatment strategies. Focusing on tobacco use disorder, we advocate a brain systems-level perspective linking two abuse-related facets (i.e., statelike withdrawal and traitlike addiction severity) with specific neurocircuitry (insula- and striatum-centered networks). To the extent that precise neurocircuits mediate distinct facets of abuse, treatment development must adopt not only a systems-level perspective, but also multi-intervention rather than mono-intervention practices.
Cannabinoid Markers in Biological Fluids and Tissues: Revealing Intake Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-10 Marilyn A. Huestis, Michael L. Smith
Understanding cannabis and synthetic cannabinoid intake history is vital for treating drug dependence, investigating cannabinoid effects, and providing information to healthcare personnel, medical examiners, and public health officials; this is particularly relevant today with cannabis medicalization and legalization. Required information includes identifying exposure, time of use, frequency of use, relapse, withdrawal, and predicting cannabinoid effects. Recent controlled cannabinoid administration studies enable the development of models and markers to better identify patterns of intake and exposure. Future challenges include developing behavioral markers of cannabis impairment, bringing to market breathalyzers for cannabinoid detection, and identifying markers of recent cannabis intake in diverse biological matrices. We posit that biological monitoring of cannabinoids and metabolites will improve the characterization of cannabis and synthetic cannabinoid intake history.
Inflammasome, Inflammation, and Tissue Homeostasis Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-09 Vijay A.K. Rathinam, Francis Ka-Ming Chan
Organismal fitness demands proper response to neutralize the threat from infection or injury. At the mammalian intestinal epithelium barrier, the inflammasome coordinates an elaborate tissue repair response marked by the induction of antimicrobial peptides, wound-healing cytokines, and reparative proliferation of epithelial stem cells. The inflammasome in myeloid and intestinal epithelial compartments exerts these effects in part through maintenance of a healthy microbiota. Disease-associated mutations and elevated expression of certain inflammasome sensors have been identified. In many cases, inhibition of inflammasome activity has dramatic effects on disease outcome in mouse models of experimental colitis. Here, we discuss recent studies on the role of distinct inflammasome sensors in intestinal homeostasis and how this knowledge may be translated into a therapeutic setting.
Aldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-06 Helen M. Heymann, Adriana M. Gardner, Eric R. Gross
Alcohol use disorder (AUD) screening frequently involves questionnaires complemented by laboratory work to monitor alcohol use and/or evaluate AUD-associated complications. Here we suggest that measuring aldehyde-induced DNA and protein adducts produced during alcohol metabolism may lead to earlier detection of AUD and AUD-associated complications compared with existing biomarkers. Use of aldehyde-induced adducts to monitor AUD may also be important when considering that approximately 540 million people bear a genetic variant of aldehyde dehydrogenase 2 (ALDH2) predisposing this population to aldehyde-induced toxicity with alcohol use. We posit that measuring aldehyde-induced adducts may provide a means to improve precision medicine approaches, taking into account lifestyle choices and genetics to evaluate AUD and AUD-associated complications.
Biosignature Discovery for Substance Use Disorders Using Statistical Learning Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-04 James W. Baurley, Christopher S. McMahan, Carolyn M. Ervin, Bens Pardamean, Andrew W. Bergen
There are limited biomarkers for substance use disorders (SUDs). Traditional statistical approaches are identifying simple biomarkers in large samples, but clinical use cases are still being established. High-throughput clinical, imaging, and ‘omic’ technologies are generating data from SUD studies and may lead to more sophisticated and clinically useful models. However, analytic strategies suited for high-dimensional data are not regularly used. We review strategies for identifying biomarkers and biosignatures from high-dimensional data types. Focusing on penalized regression and Bayesian approaches, we address how to leverage evidence from existing studies and knowledge bases, using nicotine metabolism as an example. We posit that big data and machine learning approaches will considerably advance SUD biomarker discovery. However, translation to clinical practice, will require integrated scientific efforts.
Bone Talk: Activated Osteoblasts Promote Lung Cancer Growth Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-03 Emilis Bružas, Mikala Egeblad
Cancer cells can directly stimulate the generation and recruitment of tumor-supportive bone marrow-derived cells (BMDCs), including neutrophils, via secreted factors. A new study demonstrates that lung tumors also remotely activate bone-residing osteoblasts, which in turn promote neutrophil production. This is a multistep mechanism of establishing a supportive tumor microenvironment.
Pulmonary Comorbidity in Lung Cancer Trends Mol. Med. (IF 10.732) Pub Date : 2018-02-01 Feixiong Cheng, Joseph Loscalzo
Pulmonary hypertension (PH) is caused by many disorders that affect the pulmonary vasculature. A recent study has provided evidence that pulmonary vascular remodeling and PH can be observed in lung cancer, and this may be associated with tumor cell–immune cell inflammatory crosstalk. These findings highlight the pressing need to understand better and manage pulmonary vascular comorbidities in lung cancer.
Targeting Obesity and Cachexia: Identification of the GFRAL Receptor–MIC-1/GDF15 Pathway Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-09 Samuel N. Breit, Vicky Wang-Wei Tsai, David A. Brown
Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFβ) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor α family, as the receptor for MIC-1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome.
Sensing the Breaks: Cytosolic Chromatin in Senescence and Cancer Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10 Raffaella Di Micco
Cellular senescence constitutes a stable growth arrest characterized by DNA damage response (DDR) activation and by the senescence-associated secretory phenotype (SASP). SASP, through its paracrine effects, stimulates the immune system for senescence eradication. Similarly, chemotherapy-treated cancers activate an interferon-mediated response to induce anti-tumor immunity. Recent studies now uncover a new role for the innate DNA sensing pathway in the recognition of cytosolic chromatin in senescence and cancer.
Inflammation and Autism: From Maternal Gut to Fetal Brain Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-06 Ivan Osokine, Adrian Erlebacher
Maternal immune activation (MIA) during pregnancy is associated with an increased risk of behavioral disorders in the offspring of affected mothers. Two recent studies highlight how maternal inflammation disrupts inhibitory interneuron networks and suggest that the maternal gut microbiome may be a contributing risk factor for MIA-induced behavioral abnormalities.
CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-12 Laura A. Vella, Ramin S. Herati, E. John Wherry
CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host–pathogen interaction.
Post-translational Mechanisms of Host Subversion by Bacterial Effectors Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-14 Nichollas E. Scott, Elizabeth L. Hartland
Bacterial effector proteins are a specialized class of secreted proteins that are translocated directly into the host cytoplasm by bacterial pathogens. Effector proteins have diverse activities and targets, and many mediate post-translational modifications of host proteins. Effector proteins offer potential in novel biotechnological and medical applications as enzymes that may modify human proteins. Here, we discuss the mechanisms used by effectors to subvert the human host through blocking, blunting, or subverting immune mechanisms. This capacity allows bacteria to control host cell function to support pathogen survival, replication and dissemination to other hosts. In addition, we highlight that knowledge of effector protein activity may be used to develop chemical inhibitors as a new approach to treat bacterial infections.
Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10 Grainne M. O’Kane, Ashton A. Connor, Steven Gallinger
Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options.
NEMO Links Nuclear Factor-κB to Human Diseases Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-08 Gunter Maubach, Michael Naumann
The nuclear factor (NF)-κB essential modulator (NEMO) is a key regulator in NF-κB-mediated signaling. By transmitting extracellular or intracellular signals, NEMO can control NF-κB-regulated genes. NEMO dysfunction is associated with inherited diseases such as incontinentia pigmenti (IP), ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), and some cancers. We focus on molecular studies, human case reports, and mouse models emphasizing the significance of NEMO molecular interactions and modifications in health and diseases. This knowledge opens new opportunities to engineer suitable drugs that may putatively target precise NEMO functions attributable to various diseases, while leaving other functions intact, and eliminating cytotoxicity. Indeed, with the advent of novel gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9, treating some inherited diseases may in the long run, become a reality.
Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10 Loredana Cifaldi, Franco Locatelli, Emiliano Marasco, Lorenzo Moretta, Vito Pistoia
Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy.
Partners in Crime: Phenolic Glycolipids and Macrophages Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-29 Alok Kumar Singh, William R. Bishai
Two recent articles advance our understanding of mycobacterial pathogenesis, revealing key roles for bacterially derived phenolic glycolipids (PGLs). In leprosy, Mycobacterium leprae PGL-1 uniquely subverts local macrophages to produce neurotoxic nitric oxide (NO), leading to nerve demyelination. In a related model, Mycobacterium marinum PGL stimulates the recruitment of growth-conducive monocytes to sites of initial infection as an early immune evasion strategy.
Checkpoint Blockade Plus Oncolytic Virus: A Hot Therapeutic Cancer Strategy Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-11 Caroline Robert
How can we transform an immune desert into a ‘hot tumor’ that is prone to respond to anti-programmed death (PD)-1 immunotherapy? This might be possible by injecting an oncolytic virus, engineered to induce local immune stimulation, prior to anti-PD-1 therapy. A recent study demonstrated that this combination – evaluated in a Phase Ib metastatic melanoma clinical study – yields promising results.
Promoting In Vitro Gametogenesis Research with a Social Understanding Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-12 Tetsuya Ishii, Mitinori Saitou
Recent advances in in vitro gametogenesis (IVG), including in humans, have raised ethical concerns regarding the potential misuse and manipulation of ‘artificial embryos’. However, basic research on IVG is expected to be of immense scientific and social value provided that the ethical, legal, and social issues are carefully considered.
Biomarker Potential of Extracellular miRNAs in Duchenne Muscular Dystrophy Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-05 Anna M.L. Coenen-Stass, Matthew J.A. Wood, Thomas C. Roberts
miRNAs are small, noncoding RNAs that not only regulate gene expression within cells, but might also constitute promising extracellular biomarkers for a variety of pathologies, including the progressive muscle-wasting disorder Duchenne Muscular Dystrophy (DMD). A set of muscle-enriched miRNAs, the myomiRs (miR-1, miR-133, and miR-206) are highly elevated in the serum of patients with DMD and in dystrophin-deficient animal models. Furthermore, circulating myomiRs might be used as pharmacodynamic biomarkers, given that their levels can be restored towards wild-type levels following exon skipping therapy in dystrophic mice. The relationship between muscle pathology and extracellular myomiR release is complex, and incompletely understood. Here, we discuss current progress leading towards the clinical utility of extracellular miRNAs as putative DMD biomarkers, and their possible contribution to muscle physiology.
TRPV1: A Potential Therapeutic Target in Type 2 Diabetes and Comorbidities? Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-11 Dorte X. Gram, Jens J. Holst, Arpad Szallasi
With an estimated 422 million affected patients worldwide in 2016, type 2 diabetes (T2D) has reached pandemic proportions and represents a major unmet medical need. T2D is a polygenic disease with a chronic, low-grade inflammatory component. Second-generation transient receptor potential vanilloid-1 (TRPV1) antagonists are potent anti-inflammatory agents with proven clinical safety. In rodent models of T2D, TRPV1 blockade was shown to halt disease progression and improve glucose metabolism. Thus, we propose that TRPV1 antagonists merit further study as novel therapeutic approaches to potentially treat T2D and its comorbidities.
A Maternal Functional Module in the Mammalian Oocyte-To-Embryo Transition Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-06 Xukun Lu, Zheng Gao, Dandan Qin, Lei Li
Prior to zygotic genome activation, early mammalian development relies on maternal-effect genes to orchestrate the oocyte-to-embryo transition. Recently, a subcortical maternal complex (SCMC) was identified to be essential for mouse preimplantation development. The SCMC integrates multiple proteins encoded by maternal-effect genes and appears to be functionally conserved across mammalian species. In addition, mutations in human SCMC genes are associated with certain human reproductive disorders. Here, we highlight recent advances in the biology of the SCMC and propose that this complex may be a representative example of maternal functional modules in mammalian oocyte-to-embryo transition. These findings may provide further insights into the molecular regulation of mammalian early embryogenesis, with possible implications for human early embryonic development and reproduction medicine.
Oxygen, Metabolism, and Regeneration: Lessons from Mice Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-05 Ellen Heber-Katz
The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians, and their ability to regenerate, to a mammalian context. We identified the ancient hypoxia-inducible factor (HIF)-1α pathway, operating through prolyl hydroxylase domain proteins (PHDs), as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans.
TNFR2: A Novel Target for Cancer Immunotherapy Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-12 Éva S. Vanamee, Denise L. Faustman
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but exhibit variable efficacy and relapse and can induce autoimmunity. Tumor necrosis factor (TNF) receptor 2 (TNFR2) is a signaling molecule found on the surface of a subset of potent regulatory T cells (Tregs) that can activate the proliferation of these cells through nuclear factor kappa B (NF-κB). TNFR2 is also abundantly expressed on the surface of many human tumors. We propose that blocking TNFR2 might target abundant TNFR2+ tumor-infiltrating Tregs and directly kill TNFR2-expressing tumors. We also posit that TNFR2 inhibitors might potentially constitute safer and more targeted alternatives to ICI cancer treatment because the expression of TNFR2 on immune cells, concentrated in the tumor microenvironment of various cancers, appears to be more selective than that of checkpoint molecules.
Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-06 Stephen L. Pinkosky, Pieter H.E. Groot, Narendra D. Lalwani, Gregory R. Steinberg
Chronic overnutrition and a sedentary lifestyle promote imbalances in metabolism, often manifesting as risk factors for life-threating diseases such as atherosclerotic cardiovascular disease (ASCVD) and nonalcoholic fatty liver disease (NAFLD). Nucleocytosolic acetyl-coenzyme A (CoA) has emerged as a central signaling node used to coordinate metabolic adaptations in response to a changing nutritional status. ATP-citrate lyase (ACL) is the enzyme primarily responsible for the production of extramitochondrial acetyl-CoA and is thus strategically positioned at the intersection of nutrient catabolism and lipid biosynthesis. Here, we discuss recent findings from preclinical studies, as well as Mendelian and clinical randomized trials, demonstrating the importance of ACL activity in metabolism, and supporting its inhibition as a potential therapeutic approach to treating ASCVD, NAFLD, and other metabolic disorders.
Neoantigen Vaccines Pass the Immunogenicity Test Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-31 Gerald P. Linette, Beatriz M. Carreno
Neoantigens arising from tumor-specific genomic alterations constitute authentic non-self antigens and represent a new class of targets for cancer immunotherapy. Recent reports on various vaccine platforms targeting neoantigens suggest a basis for precision therapies customized to each patient’s tumor mutational profile.
Lung Alveolar Repair: Not All Cells Are Equal Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-01 Charlotte H. Dean, Clare M. Lloyd
The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a ‘Goldilocks zone’ of repair.
Precision Oncology: The Road Ahead Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-05 Daniela Senft, Mark D.M. Leiserson, Eytan Ruppin, Ze’ev A. Ronai
Current efforts in precision oncology largely focus on the benefit of genomics-guided therapy. Yet, advances in sequencing techniques provide an unprecedented view of the complex genetic and nongenetic heterogeneity within individual tumors. Herein, we outline the benefits of integrating genomic and transcriptomic analyses for advanced precision oncology. We summarize relevant computational approaches to detect novel drivers and genetic vulnerabilities, suitable for therapeutic exploration. Clinically relevant platforms to functionally test predicted drugs/drug combinations for individual patients are reviewed. Finally, we highlight the technological advances in single cell analysis of tumor specimens. These may ultimately lead to the development of next-generation cancer drugs, capable of tackling the hurdles imposed by genetic and phenotypic heterogeneity on current anticancer therapies.
NAD+ in Aging: Molecular Mechanisms and Translational Implications Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-09 Evandro F. Fang, Sofie Lautrup, Yujun Hou, Tyler G. Demarest, Deborah L. Croteau, Mark P. Mattson, Vilhelm A. Bohr
The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demands and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD+ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD+ biosynthesis, together with putative mechanisms of NAD+ action against aging, including recent preclinical and clinical trials.
Genome Engineering for Personalized Arthritis Therapeutics Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-05 Shaunak S. Adkar, Jonathan M. Brunger, Vincent P. Willard, Chia-Lung Wu, Charles A. Gersbach, Farshid Guilak
Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis. These technologies, together with cell reprogramming methods, including the use of induced pluripotent stem cells, provide a platform for human disease modeling. We summarize new evidence from genome-wide association studies and genomics that substantiates a genetic basis for arthritis pathogenesis. We also review the potential contributions of genome engineering in the development of new arthritis therapeutics.
On the Whereabouts of HIV-1 Cellular Entry and Its Fusion Ports Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-09 G. Maria Jakobsdottir, Maro Iliopoulou, Rory Nolan, Luis Alvarez, Alex A. Compton, Sergi Padilla-Parra
HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus–cell fusion in vitro may contribute to the development of future therapeutic interventions. Collectively, novel findings underline the need for potent, host-directed therapies that disrupt the earliest stages of the virus life cycle and preclude the emergence of resistant viral variants.
Targeted Immune Interventions for an HIV-1 Cure Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-07 Matthieu Perreau, Riddhima Banga, Giuseppe Pantaleo
Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure. Single intervention strategies have shown promise, albeit with limited efficacy. Consequently, a combination of interventions aiming to stimulate the immune response and prevent new rounds of viral infection and spreading may render the HIV functional cure a feasible goal.
Modifiers of GRN-Associated Frontotemporal Lobar Degeneration Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-07 Eline Wauters, Sara Van Mossevelde, Julie Van der Zee, Marc Cruts, Christine Van Broeckhoven
Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.
T Cell Exhaustion: An Epigenetically Imprinted Phenotypic and Functional Makeover Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-07 Francesca Alfei, Dietmar Zehn
A recent article in Cell demonstrates that the absence of a single DNA methyltransferase, Dnmt3a, prevents cytotoxic T cells from acquiring the hypofunctional or exhausted phenotype typically seen in chronic viral infections and tumors. Upon establishing a causal relationship between exhaustion-associated epigenetic changes and reduced CD8+ T cell function, the authors provided mechanistic evidence that exhaustion constitutes a specific differentiation program.
A Topical Solution to the Sunless Tanning Problem Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-05 Helen T. Michael, Glenn Merlino
Skin cancer is the most commonly diagnosed type of cancer and is strongly associated with UV exposure and skin pigmentation. Recent advances in pharmacologic non-UV tanning methods open the possibility of preventing melanoma and non-melanoma skin cancer, especially in people who do not tan in the sun.
Focusing on the Opioid System for Addiction Biomarker Discovery Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-31 Raoul Belzeaux, Laurence Lalanne, Brigitte L. Kieffer, Pierre-Eric Lutz
Substance use disorders (SUD) and behavioral addictions are devastating conditions that impose a severe burden on all societies, and represent difficult challenges for clinicians. Therefore, biomarkers are urgently needed to help predict vulnerability, clinical course, and response to treatment. Here, we elaborate on the potential for addiction biomarker discovery of the opioid system, particularly within the emerging framework aiming to probe opioid function in peripheral tissues. Mu, delta, and kappa opioid receptors all critically regulate neurobiological and behavioral processes that define addiction, and are also targeted by major pharmacotherapies used in the management of patients with SUD. We propose that opioid biomarkers may have the potential to improve and guide diagnosis and therapeutic decisions in the addiction field.
Using Metabolomics to Investigate Biomarkers of Drug Addiction Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-31 Reza Ghanbari, Susan Sumner
Drug addiction has been associated with an increased risk for cancer, psychological complications, heart, liver, and lung disease, as well as infection. While genes have been identified that can mark individuals at risk for substance abuse, the initiation step of addiction is attributed to persistent metabolic disruptions occurring following the first instance of narcotic drug use. Advances in analytical technologies can enable the detection of thousands of signals in body fluids and excreta that can be used to define biochemical profiles of addiction. Today, these approaches hold promise for determining how exposure to drugs, in the absence or presence of other environmentally relevant factors, can impact human metabolism. We posit that these can lead to candidate biomarkers of drug dependence, treatment, withdrawal, or relapse.
HDAC5 Regulates the Formation of Drug Memories Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-25 Alexander C.W. Smith, Paul J. Kenny
Cocaine-associated environmental cues can precipitate craving and relapse in addicted individuals even after years of abstinence, but the molecular mechanisms by which maladaptive drug memories are generated remain unclear. New findings suggest that histone deacetylase 5 (HDAC5) plays a key role in this process.
Defining Substance Use Disorders: The Need for Peripheral Biomarkers Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-25 Kristopher J. Bough, Jonathan D. Pollock
Addiction is a brain disease, and current diagnostic criteria for substance use disorders (SUDs) are qualitative. Nevertheless, scientific advances are beginning to characterize neurobiological domains. Combining multiple units of measure may provide an opportunity to deconstruct the heterogeneities of a SUD and define endophenotypes by using peripheral biospecimens. There are several recent examples of potential biomarker types that can be examined, together with their categorical applications for SUDs. We propose that, in conjunction with rapidly advancing statistical and mathematical modeling techniques, there is now a unique opportunity for the discovery of composite biomarkers within specific domains of addiction; these may lay the foundation for future biomarker qualification, with important implications for drug development and medical care.
Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-25 Verica Milivojevic, Rajita Sinha
Substance use disorders (SUDs) are marked by heterogeneity in clinical symptomatology and high relapse rates following treatment. Here, we describe specific peripheral and central stress responses associated with the pathophysiology of SUDs. We outline potential stress response measures, including hypothalamus–pituitary–adrenal axis markers, autonomic responses, and central structural and functional brain alterations that could be exploited as putative biomarkers in SUDs. We posit that stress responses can be predictive of both the development of SUDs and their high relapsing nature. We examine their potential as candidate biomarkers, as well as the remaining challenges in developing and implementing their application for the prevention and treatment of SUDs.
Addiction Biomarkers: Dimensional Approaches to Understanding Addiction Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-05 Laura E. Kwako, Warren K. Bickel, David Goldman
Trends towards dimensional approaches in understanding psychiatric disorders may also be applied to addictive disorders. Advances in our understanding of the neurobiology of addiction can inform these efforts. Furthermore, dimensional approaches to addiction, such as the proposed Addictions Neuroclinical Assessment (ANA), may be used in identifying novel addiction biomarkers, and refining ones that currently exist. These biomarkers, derived from both an understanding of the neurobiology of addiction and behavioral phenotypes, represent a departure from traditional markers of alcohol-relevant biomarkers, such as tests of liver function (LFTs). We posit that a potential addiction-relevant biomarker is reinforcer pathology, found to be relevant across addictions to different substances, and which may offer a target for modification through the use of episodic future thinking.
Preparing the Way: Exploiting Genomic Medicine to Stop Smoking Trends Mol. Med. (IF 10.732) Pub Date : 2018-01-04 Laura J. Bierut, Rachel F. Tyndale
Clinical medicine of the future is poised to use an individual’s genomic data to predict disease risk and guide clinical care. The treatment of cigarette smoking and tobacco use disorder represents a prime area for genomics implementation. The genes CHRNA5 and CYP2A6 are strong genomic contributors that alter the risk of heaviness of smoking, tobacco use disorder, and smoking-related diseases in humans. These biomarkers have proven analytical and clinical validity, and evidence for their clinical utility continues to grow. We propose that these biomarkers harbor the potential of enabling the identification of elevated disease risk in smokers, personalizing smoking cessation treatments, and motivating behavioral changes. We must prepare for the integration of genomic applications into clinical care of patients who smoke.
Metabolic Control of CD8+ T Cell Fate Decisions and Antitumor Immunity Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-12 Lianjun Zhang, Pedro Romero
CD8+ T cells are central players in controlling infections and cancer. Longevity, functionality, and metabolic fitness are critical determinants of T cell efficacy in cancer immunotherapy. Tumor-infiltrating CD8+ T cells undergo metabolic ‘exhaustion’ in the nutrient- and oxygen-deprived tumor microenvironment (TME). Thus, reprograming CD8+ T cell metabolism may provide important therapeutic strategies for cancer treatment. Indeed, the adoptive transfer of memory CD8+ T cells with sustained metabolic fitness may yield better antitumor protection in both mouse models and the clinic. Here, we discuss recent progress on how cellular metabolism is linked to CD8+ T cell fate decisions and on how metabolic intermediates can impact gene expression via modulation of the epigenome. We examine the feasibility of developing potential strategies to improve antitumor immunity through the modulation of T cell metabolic activity.
Noncoding RNAs: Master Regulators of Inflammatory Signaling Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-12 Chen Li Chew, Stephanie Ana Conos, Bilal Unal, Vinay Tergaonkar
Inflammatory signaling underlies many diseases, from arthritis to cancer. Our understanding of inflammation has thus far been limited to the world of proteins, because we are only just beginning to understand the role that noncoding RNAs (ncRNA) might play. It is now clear that ncRNA do not constitute transcriptional ‘noise’ but instead harbor physiological functions in controlling signaling pathways. In this review, we cover the newly discovered mechanisms and functions of ncRNAs in the regulation of inflammatory signaling. We also describe advances in experimental techniques allowing this field of research to take root. These findings have opened new avenues for putative therapeutic intervention in inflammatory diseases, which may be seen translated into clinical outcomes in the future.
Is It Our Duty To Hunt for Pathogenic Mutations? Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-12 Roel H.P. Wouters, Rhodé M. Bijlsma, Geert W.J. Frederix, Margreet G.E.M. Ausems, Johannes J.M. van Delden, Emile E. Voest, Annelien L. Bredenoord
Should professionals systematically screen whole-genome sequencing (WGS) data to check for life-threatening mutations? Alternatively, should genome analysis focus on the primary reason for testing – that is, aiming to achieve precision medicine? We present an ethical review of the arguments and compare the act of searching for mutations with disclosing mutations that are discovered incidentally.
Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-09 Natura Myeku, Karen E. Duff
Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction. The range of candidates might address the need for region-, cell-, or even cellular compartment-specific modulation. Given the array of clinical and experimental drugs targeting cAMP/cGMP signaling, we propose that proteasome activators targeting secondary messengers might be exploited as novel agents for the treatment or prevention of some neurodegenerative diseases.
Monitoring Neurodegeneration in Glaucoma: Therapeutic Implications Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-07 Norimitsu Ban, Carla J. Siegfried, Rajendra S. Apte
Glaucoma is one of the leading causes of blindness globally, and is characterized by loss of retinal ganglion cells (RGCs). Because vision loss in glaucoma is not reversible, therapeutic interventions early in disease are highly desirable. However, owing to the current limitations in evaluating glaucomatous neurodegeneration, it is challenging to monitor the disease severity and progression objectively, and to design rational therapeutic strategies accordingly. Therefore, there is a clear need to identify quantifiable molecular biomarkers of glaucomatous neurodegeneration. As such, in our opinion, molecular biomarker(s) that specifically reflect stress or death of RGCs, and which correlate with disease severity, progression, and response to therapy, are highly desirable.
Pregnancy Around the Clock Trends Mol. Med. (IF 10.732) Pub Date : 2017-12-05 Anke Diemert, Petra Clara Arck
A recent study introduced the existence of an ‘immune clock’ in pregnancy; during the course of gestation, peripheral blood cells from pregnant women were analyzed by mass cytometry using a single-cell signaling-based elastic net algorithm. The insights will undoubtedly promote the testing of such a clock – possibly in synergy with other pacemakers – to potentially predict pregnancy complications.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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