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Trends in Molecular Medicine

Alexandre Detappe, Mark Bustoros, Tarek H Mouhieddine, P Peter Ghoroghchian
In the past decades, considerable progress has been made in our understanding and treatment of multiple myeloma. Several challenges remain including our abilities to longitudinally image tumor responses to treatment, to combine various therapeutic agents with different mechanisms of action but with overlapping toxicities, and to efficiently harness the power of the immune system to augment remission and/or to induce permanent cures. Nanomedicine may help to address many of these outstanding issues, affording novel diagnostic capabilities and offering disruptive technologies that promise to revolutionize treatment...
May 14, 2018: Trends in Molecular Medicine
Douglas E Brash, Leticia C P Goncalves, Etelvino J H Bechara
Quantum mechanics rarely extends to molecular medicine. Recently, the pigment melanin was found to be susceptible to chemiexcitation, in which an electron is chemically excited to a high-energy molecular orbital. In invertebrates, chemiexcitation causes bioluminescence; in mammals, a higher-energy process involving melanin transfers energy to DNA without photons, creating the lethal and mutagenic cyclobutane pyrimidine dimer that can cause melanoma. This process is initiated by NO and O2 - radicals, the formation of which can be triggered by ultraviolet light or inflammation...
May 8, 2018: Trends in Molecular Medicine
Ruslan Rust, Anna-Sophie Hofer, Martin E Schwab
Patients who survive a stroke have an increased risk for recurrent vascular events. The mechanisms underlying the events are barely understood. A recent study suggests that stroke-enhanced atherosclerosis is induced through brain-released alarmins, which lead to systemic vascular inflammation and plaque formation. Interfering with these processes may lead to novel therapeutic approaches.
May 7, 2018: Trends in Molecular Medicine
Rejane Rua, Dorian B McGavern
The central nervous system (CNS) is an immunologically specialized tissue protected by a blood-brain barrier. The CNS parenchyma is enveloped by a series of overlapping membranes that are collectively referred to as the meninges. The meninges provide an additional CNS barrier, harbor a diverse array of resident immune cells, and serve as a crucial interface with the periphery. Recent studies have significantly advanced our understanding of meningeal immunity, demonstrating how a complex immune landscape influences CNS functions under steady-state and inflammatory conditions...
May 3, 2018: Trends in Molecular Medicine
Yared Hailemichael, Manisha Singh, Willem Overwijk
In a recent study, Kooreman and colleagues identify a set of genes expressed in both induced pluripotent stem cells (iPSCs) and cancer cells. Vaccination of mice with iPSCs induces prophylactic and therapeutic anticancer immunity to shared antigens, opening a possible avenue towards rapid generation of iPSC-based, personalized cancer vaccines.
May 3, 2018: Trends in Molecular Medicine
Aarti Narang, Binhai Zheng
A recent study indicates that reducing fibrotic scarring by genetically abrogating the proliferation of type A pericytes promotes axon regeneration and functional recovery after spinal cord injury. Questions remain regarding the identity of the cells being manipulated and the balance between the beneficial and detrimental effects of fibrotic scarring.
May 2, 2018: Trends in Molecular Medicine
Stephanie L Moon, Nahum Sonenberg, Roy Parker
A key site of translation control is the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α), which reduces the rate of GDP to GTP exchange by eIF2B, leading to altered translation. The extent of eIF2α phosphorylation within neurons can alter synaptic plasticity. Phosphorylation of eIF2α is triggered by four stress-responsive kinases, and as such eIF2α is often phosphorylated during neurological perturbations or disease. Moreover, in some cases decreasing eIF2α phosphorylation mitigates neurodegeneration, suggesting that this could be a therapeutic target...
April 28, 2018: Trends in Molecular Medicine
Hyunah Lee, Sandrine Thuret
The hippocampus has been described as one of the few sites in the mammalian brain capable of generating new cells continuously throughout life. Two recent studies that report contradicting findings on adult human hippocampal neurogenesis, however, reminds us of the caveats and challenges of studying this phenomenon in postmortem tissues.
April 23, 2018: Trends in Molecular Medicine
Andreea-Manuela Mirea, Cees J Tack, Triantafyllos Chavakis, Leo A B Joosten, Erik J M Toonen
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD...
April 14, 2018: Trends in Molecular Medicine
Jennifer L Guerriero
Macrophages are present in all vertebrate tissues and have emerged as multifarious cells with complex roles in development, tissue homeostasis, and disease. Macrophages are a major constituent of the tumor microenvironment, where they either promote or inhibit tumorigenesis and metastasis depending on their state. Successful preclinical strategies to target macrophages for anticancer therapy are now being evaluated in the clinic and provide proof of concept that targeting macrophages may enhance current therapies; however, clinical success has been limited...
April 11, 2018: Trends in Molecular Medicine
Priya Chatterji, Anil K Rustgi
The intestinal epithelium is highly proliferative and consists of crypt invaginations that house stem cells and villus projections with differentiated cells. There exists a dynamic equilibrium between proliferation, migration, differentiation, and senescence that is regulated by several factors. Among these are RNA binding proteins (RBPs) that bind their targets in a both context dependent and independent manner. RBP-RNA complexes act as rheostats by regulating expression of RNAs both co- and post-transcriptionally...
April 4, 2018: Trends in Molecular Medicine
Ryan P Bennett, Jason D Salter, Harold C Smith
The infectivity of HIV depends on overcoming APOBEC3 (A3) innate immunity, predominantly through the expression of the viral protein Vif, which induces A3 degradation in the proteasome. Disruption of the functional interactions of Vif enables A3 mutagenesis of the HIV genome during viral replication, which can result in a broadly neutralizing antiviral effect. Vif function requires self-association along with interactions with A3 proteins, protein chaperones, and factors of the ubiquitination machinery and these are described here as a potential platform for novel antiviral drug discovery...
March 30, 2018: Trends in Molecular Medicine
Eli Y Adashi, I Glenn Cohen
Mutant mitochondrial DNA gives rise to a broad range of incurable inborn maladies. Prevention may now be possible by replacing the mutation-carrying mitochondria of zygotes or oocytes at risk with donated unaffected counterparts. However, mitochondrial replacement therapy is being held back by theological, ethical, and safety concerns over the loss of human zygotes and the involvement of a donor. These concerns make it plain that the identification, validation, and regulatory adjudication of novel embryo-sparing donor-independent technologies remains a pressing imperative...
March 28, 2018: Trends in Molecular Medicine
Marco Salvetti, Catherine Lubetzki, Raj Kapoor, Giovanni Ristori, Ericka Costa, Mario A Battaglia, Michele Andreaus, Maria Pia Abbracchio, Giuseppe Matarese, Paola Zaratin
The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry.
March 24, 2018: Trends in Molecular Medicine
Sara Lovisa, Raghu Kalluri
The molecular mechanisms underpinning the process of endothelial-to-mesenchymal transition (EndMT) are mostly unknown. Recently Xiong and colleagues explored for the first time the metabolic changes associated with the activation of the mesenchymal program in endothelial cells, and found that reprogramming of fatty acid oxidation pivotally regulates EndMT.
March 21, 2018: Trends in Molecular Medicine
Matthew J Harries, Francisco Jimenez, Ander Izeta, Jonathan Hardman, Sreejith Parameswara Panicker, Enrique Poblet, Ralf Paus
Inflammation-associated, irreversible damage to epithelial stem cells (eSCs) of the hair follicle in their immunologically privileged niche lies at the heart of scarring alopecia, which causes permanent difficult-to-treat hair loss. We propose that the two most common and closely related forms, lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA), provide excellent model diseases for studying the biology and pathology of adult human eSCs in an easily accessible human mini-organ. Emphasising the critical roles for interferon (IFN)-γ and peroxisome proliferator-activated receptor (PPAR)-γ-mediated signalling in immune privilege (IP) collapse and epithelial-mesenchymal transition (EMT) of these eSCs respectively, we argue that these pathways deserve therapeutic targeting in the future management of LPP/FFA and other eSC diseases associated with IP collapse and EMT...
May 2018: Trends in Molecular Medicine
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...
April 2018: Trends in Molecular Medicine
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...
April 2018: Trends in Molecular Medicine
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...
April 2018: Trends in Molecular Medicine
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...
April 2018: Trends in Molecular Medicine
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