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Trends in Molecular Medicine

P Degan, E Cappelli, S Regis, S Ravera
Fanconi anemia is a rare, cancer-prone disease with mutations in 22 genes. The primary defect results in altered DNA repair mechanisms that fuel a severe proinflammatory condition in the bone marrow, leading to cellular depletion of the hematopoietic system and eventually to bone marrow failure. During the past three decades, a plethora of dysfunctions have been highlighted in the Fanconi anemia phenotype, but recent research allows us to glimpse an even more complex scenario where defective lipid metabolism could have important consequences in hematopoietic stem cell differentiation...
February 7, 2019: Trends in Molecular Medicine
Eli Y Adashi, I Glenn Cohen, Jacob H Hanna, Azim M Surani, Katsuhiko Hayashi
The implications of scientific breakthroughs are rarely faced up to in advance of their realization. Stem cell-derived human gametes, a disruptive technology in waiting, are likely to recapitulate this historic pattern absent active intervention. Herein we call for the conduct of thoughtful ante hoc deliberations on the prospect of stem cell-derived human gametes with an eye toward minimizing potential untoward post hoc regulatory or statutory impositions.
February 6, 2019: Trends in Molecular Medicine
Matthew DeBerge, Sanjiv J Shah, Lisa Wilsbacher, Edward Thorp
There is a growing number of individuals living with heart failure (HF) with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). Long-term prognosis remains poor in both cases, especially in HFpEF, which is rising in incidence and lacks effective therapeutics. In both HFrEF and HFpEF, there is evidence that elevated inflammatory biomarkers, implicating innate immune cells such as macrophages, are associated with worsened clinical outcomes. Macrophage subsets are active in both inflammatory and reparative processes, yet our understanding of the causative roles for these cells in HF development and progression is incomplete...
February 5, 2019: Trends in Molecular Medicine
Claudia Willmes
No abstract text is available yet for this article.
February 5, 2019: Trends in Molecular Medicine
Eóin C O'Brien, Rachel M McLoughlin
Staphylococcus aureus is an opportunistic pathogen, which can readily develop antibiotic resistance and result in severe disease. To combat antibiotic resistance, new treatment strategies are being developed with a particular focus on vaccine development. S. aureus vaccines that target humoral immunity alone do not provide sufficient protection from all disease phenotypes associated with this pathogen. Recent studies have identified the requirement for cellular immunity to provide a robust immune response to this infection...
January 31, 2019: Trends in Molecular Medicine
Guido Moll, James A Ankrum, Julian Kamhieh-Milz, Karen Bieback, Olle Ringdén, Hans-Dieter Volk, Sven Geissler, Petra Reinke
Intravascular infusion is the most popular route for therapeutic multipotent mesenchymal stromal/stem cell (MSC) delivery in hundreds of clinical trials. Meta-analysis has demonstrated that bone marrow MSC infusion is safe. It is not clear if this also applies to diverse new cell products derived from other sources, such as adipose and perinatal tissues. Different MSC products display varying levels of highly procoagulant tissue factor (TF) and may adversely trigger the instant blood-mediated inflammatory reaction (IBMIR)...
January 30, 2019: Trends in Molecular Medicine
Liam J O'Neil, Mariana J Kaplan
Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by a highly coordinated inflammatory response that involves innate and adaptive immunity. One of the hallmarks of RA is an immune response directed at citrullinated peptides that are specifically targeted by anticitrullinated protein antibodies (ACPAs). Among the various mechanisms by which neutrophils may promote immune dysregulation in RA, their ability to extrude neutrophil extracellular traps has recently been implicated in the development of ACPAs...
January 29, 2019: Trends in Molecular Medicine
Amit J Sabnis, Trever G Bivona
Identification of the genomic drivers of cancer has led to the clinical development of targeted therapies that strike at the heart of many malignancies. Nonetheless, many cancers outsmart such precision-medicine efforts, and thus therapeutic resistance contributes significantly to cancer mortality. Attempts to understand the basis for resistance in patient samples and laboratory models has yielded two major benefits: one, more effective chemical inhibitors and rational combination therapies are now employed to prevent or circumvent resistance pathways; and two, our understanding of how oncogenic mutations drive cancer cell survival and oncogene addiction is deeper and broader, highlighting downstream or parallel cellular programs that shape these phenotypes...
January 24, 2019: Trends in Molecular Medicine
Isobel Ronai, Paul E Griffiths
The majority of biomedical and biological research relies on a few molecular biology techniques. Here we show that eight key molecular biology techniques would not exist without basic biological research. We also find that the scientific reward system does not sufficiently value basic biological research into molecular mechanisms.
January 24, 2019: Trends in Molecular Medicine
Ryan P Donahue, Jerry C Hu, Kyriacos A Athanasiou
The temporomandibular joint (TMJ) disc, a fibrocartilaginous structure between the mandible and temporal bone, is implicated in temporomandibular disorders (TMDs). TMDs symptomatically affect approximately 25% of the population; of which, 70% have internal derangement of the disc. Treatments lack efficiency, motivating novel therapies, including tissue-engineering toward TMJ disc regeneration. Recent developments in scaffold-based or scaffold-free approaches, cell sources, and biochemical and mechanical stimulation have resulted in constructs exhibiting native tissue mechanics...
January 21, 2019: Trends in Molecular Medicine
Abhay P Sagare, Melanie D Sweeney, Amy R Nelson, Zhen Zhao, Berislav V Zlokovic
Recent studies revealed that cellular prion protein on neurons bind Alzheimer's amyloid-β oligomers, causing neurotoxic effects. A new article in Cell Reports by Gunther and colleagues (Cell Rep. 2019; 26:145-158) shows that an orally administered cellular prion protein antagonist can rescue synaptic and cognitive deficits in Alzheimer's mice overexpressing amyloid-β.
January 17, 2019: Trends in Molecular Medicine
Peter Kühnen, Heiko Krude, Heike Biebermann
The melanocortin-4 receptor (MC4R) - embedded in the leptin-melanocortin pathway - is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency...
January 11, 2019: Trends in Molecular Medicine
Miguel Quiros, Asma Nusrat
The intestinal mucosa serves as a highly selective barrier that allows the absorption of nutrients and water while restricting microbiota access to tissues. This barrier is compromised in inflammatory conditions such as infectious colitis and inflammatory bowel disease (IBD). In response to mucosal injury, there is a temporal recruitment of leukocytes that crosstalk with epithelial cells to orchestrate repair. Specialized pro-resolving mediators (SPMs) play an important role in the resolution of inflammation and epithelial repair...
January 11, 2019: Trends in Molecular Medicine
Dorit Trudler, Stuart A Lipton
Direct cell reprogramming, the process by which a somatic cell is converted to another cell type, can potentially circumvent epigenetic changes and proliferative stages resulting from de-differentiation. Recently, Matsuda et al. (Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion; Neuronin in press) demonstrated that expression of transcription factor NeuroD1 can convert mouse microglia to neurons, both in vitro and in vivo.
January 2, 2019: Trends in Molecular Medicine
Stephen F Carter, Karl Herholz, Pedro Rosa-Neto, Luc Pellerin, Agneta Nordberg, Eduardo R Zimmer
Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available...
January 2, 2019: Trends in Molecular Medicine
Peter Bedner, Christian Steinhäuser
The etiology of temporal lobe epilepsy is unclear, but proinflammatory molecules and disturbed neuron-glia communications are emerging as potential causers. A recent study (Nikolic et al. Glia 2018; revealed that pathologically elevated tumor necrosis factor α contributes to epileptogenesis, by boosting hyperexcitation through an autocrine mechanism involving purinergic signaling, astrocyte glutamate release, and modulation of neuronal transmitter release.
December 20, 2018: Trends in Molecular Medicine
Sofie Voet, Marco Prinz, Geert van Loo
Microglia are the resident macrophages of the central nervous system (CNS). They have important physiological functions in maintaining tissue homeostasis but also contribute to CNS pathology. Microglia respond to changes in the microenvironment, and the resulting reactive phenotype can be very diverse, with both neuroinflammatory and neuroprotective properties, illustrating the plasticity of these cells. Recent progress in understanding the autoimmune neuroinflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis suggests major roles for microglia in the disease, which have drastically changed our view on the function of microglia in MS...
December 18, 2018: Trends in Molecular Medicine
Hana Yeh, Tsuneya Ikezu
Microglia are the resident immune cells that maintain brain homeostasis and contribute to neurodegenerative disorders. Recent studies of microglia at transcriptomic and epigenetic levels revealed specific molecular pathways that regulate microglia development, maturation, and reactive states. The transcription factor PU.1 plays a key role in regulating several microglial functions. Environmental factors such as microbiota, early life stress, and maternal immune activation can dysregulate PU.1 and innate immune response...
December 18, 2018: Trends in Molecular Medicine
Hervé Puy, Jean-Charles Deybach, Laurent Gouya
The potential of mRNA to produce therapeutic and protective protein levels is a promising approach for the treatment of a large number of diseases. In a recent study published in Nature Medicine (Published online October 8, 2018., the intravenous delivery of human porphobilinogen deaminase (PBGD) mRNA, targeting the liver, demonstrated its efficacy and safety to replace the defective PBGD protein in preclinical models of acute intermittent porphyria.
December 6, 2018: Trends in Molecular Medicine
Andreas Kurtz, Magdi Elsallab, Ralf Sanzenbacher, Mohamed Abou-El-Enein
The biomedical field has witnessed remarkable advances in analytical tools and technologies that have expanded our understanding of healthy and diseased human tissue and, at the same time, enable extensive molecular characterization of living cells. The volume of scientific data generated is expanding in an unprecedented manner; however, these data remain scattered across research groups worldwide. Access to various data sources in a systematic fashion could hugely benefit the progress of nascent fields such as stem cell-based therapeutics...
November 26, 2018: Trends in Molecular Medicine
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