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Trends in Molecular Medicine

Nadya Lumelsky, Morgan O'Hayre, Preethi Chander, Lillian Shum, Martha J Somerman
The promise of tissue engineering and regenerative medicine to reduce the burden of disease and improve quality of life are widely acknowledged. Traditional tissue engineering and regenerative medicine approaches rely on generation of tissue constructs in vitro for subsequent transplantation or injection of exogenously manipulated cells into a host. While promising, few such therapies have succeeded in clinical practice. Here, we propose that recent advances in stem cell and developmental biology, immunology, bioengineering, and material sciences, position us to develop a new generation of in vivo regenerative medicine therapies, which we term autotherapies...
September 10, 2018: Trends in Molecular Medicine
Arantzazu Alfranca, Miguel R Campanero, Juan Miguel Redondo
Lentiviral vectors (LVs) transduce quiescent cells and provide stable integration to maintain transgene expression. Several approaches have been adopted to optimize LV safety profiles. Similarly, LV targeting has been tailored through strategies including the modification of envelope components, the use of specific regulatory elements, and the selection of appropriate administration routes. Models of aortic disease based on a single injection of pleiotropic LVs have been developed that efficiently transduce the three aorta layers in wild type mice...
September 10, 2018: Trends in Molecular Medicine
Ralitsa R Madsen, Bart Vanhaesebroeck, Robert K Semple
PIK3CA is one of the most commonly mutated genes in solid cancers. PIK3CA mutations are also found in benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). As in cancer, PIK3CA mutations in PROS arise postzygotically, but unlike in cancer, these mutations arise during embryonic development, with their timing and location critically influencing the resulting disease phenotype. Recent evidence indicates that phosphoinositide 3-kinase (PI3K) pathway inhibitors undergoing trials in cancer can provide a therapy for PROS...
September 6, 2018: Trends in Molecular Medicine
Yu Sun, Jean-Philippe Coppé, Eric W-F Lam
Cellular senescence is a process that results in irreversible cell-cycle arrest, and is thought to be an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic and signaling features, together referred to as the senescence-associated secretory phenotype (SASP). The SASP is implicated in several aging-related pathologies, including various malignancies. Accumulating evidence argues that cellular senescence acts as a double-edged sword in human cancer, and new agents and innovative strategies to tackle senescent cells are in development pipelines to counter the adverse effects of cellular senescence in the clinic...
August 25, 2018: Trends in Molecular Medicine
Rajashekar Varma Kadumuri, Sarath Chandra Janga
Innovations in epitranscriptomics have resulted in the identification of more than 160 RNA modifications to date. These developments, together with the recent discovery of writers, readers, and erasers of modifications occurring across a wide range of RNAs and tissue types, have led to a surge in integrative approaches for transcriptome-wide mapping of modifications and protein-RNA interaction profiles of epitranscriptome players. RNA modification maps and crosstalk between them have begun to elucidate the role of modifications as signaling switches, entertaining the notion of an epitranscriptomic code as a driver of the post-transcriptional fate of RNA...
August 14, 2018: Trends in Molecular Medicine
Madalina E Carter-Timofte, Søren R Paludan, Trine H Mogensen
In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity...
August 13, 2018: Trends in Molecular Medicine
Dana V Foss, Ross C Wilson
Despite the unparalleled therapeutic promise of genome editing, its curative power is currently limited by the substantial difficulty in delivering DNA-cutting enzymes to the cells in need of correction. A recent study demonstrates the potential for the delivery of pre-assembled genome-editing enzymes in the form of ribonucleoprotein complexes, which were used to rescue a mouse model of fragile X syndrome (FXS).
August 10, 2018: Trends in Molecular Medicine
Luca Peruzzotti-Jametti, Stefano Pluchino
The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation...
August 9, 2018: Trends in Molecular Medicine
Aislyn Schalck, Chantale Bernatchez, Nicholas Navin
The role of tissue-resident memory T (TRM ) cells in breast cancer progression has been difficult to study. Savas et al. [1] (Nat. Med. 2018;24:986-993) used single-cell RNA sequencing to identify TRM cells in triple-negative breast cancer patients and demonstrated their prognostic value for predicting survival.
August 1, 2018: Trends in Molecular Medicine
Mohamad Hamieh, Michel Sadelain
In a recent study, Fraietta and colleagues identified chimeric antigen receptor (CAR) T cell biomarkers that may predict the success or failure of CAR therapy in patients with refractory chronic lymphoblastic leukemia (CLL). These findings open new prospects for improving T cell product manufacturing and the management of patients with CLL undergoing T cell-based therapies.
September 2018: Trends in Molecular Medicine
Jan M Deussing, Eduardo Arzt
Depression is a prime contributor to global disease burden with 300 million affected patients worldwide. The persistent lack of progress with regards to pharmacotherapy stands in stark contrast to the pandemic magnitude of the disease. Alterations of inflammatory pathways in depressed patients, including altered circulating pro-inflammatory cytokines, have been put forward as a potential pathophysiological mechanism. The P2X7 receptor (P2X7R) plays an important role regulating the release of interleukin-1β and other cytokines...
September 2018: Trends in Molecular Medicine
Mark C de Gooijer, Miriam Guillén Navarro, Rene Bernards, Thomas Wurdinger, Olaf van Tellingen
Glioblastoma is a highly aggressive brain tumor that is characterized by its unparalleled invasiveness. Invasive glioblastoma cells not only escape surgery and focal therapies but also are more resistant to current radio- and chemo-therapeutic approaches. Thus, any curative therapy for this deadly disease likely should include treatment strategies that interfere with glioblastoma invasiveness. Understanding glioblastoma invasion mechanisms is therefore critical. We discuss the strengths and weaknesses of various glioblastoma invasion models and conclude that robust experimental evidence has been obtained for a pro-invasive role of Ephrin receptors, Rho GTPases, and casein kinase 2 (CK2)...
September 2018: Trends in Molecular Medicine
Baiping Mao, Dolores Mruk, Qingquan Lian, Renshan Ge, Chao Li, Bruno Silvestrini, C Yan Cheng
Studies have proven that per- and polyfluoroalkyl substances are harmful to humans, most notably perfluorooctanesulfonate (PFOS). PFOS induces rapid disorganization of actin- and microtubule (MT)-based cytoskeletons in primary cultures of rodent and human Sertoli cells, perturbing Sertoli cell gap junction communication, thereby prohibiting Sertoli cells from maintaining cellular homeostasis in the seminiferous epithelium to support spermatogenesis. PFOS perturbs several signaling proteins/pathways, such as FAK and mTORC1/rpS6/Akt1/2...
September 2018: Trends in Molecular Medicine
Lindsey K Symons, Jessica E Miller, Vanessa R Kay, Ryan M Marks, Kiera Liblik, Madhuri Koti, Chandrakant Tayade
Endometriosis is a chronic, inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissue outside of the uterine cavity. Although the etiology of endometriosis remains elusive, immunological dysfunction has been proposed as a critical facilitator of ectopic lesion growth following retrograde menstruation of endometrial debris. However, it is not clear whether this immune dysfunction is a cause or consequence of endometriosis. Thus, here we provide in-depth insights into our current understanding of the immunopathophysiology of endometriosis and highlight challenges and opportunities for future research...
September 2018: Trends in Molecular Medicine
Minhong Shen, Yibin Kang
The tumor microenvironment contains heterogeneous populations of stromal cells with important roles in cancer progression and metastasis. In a recent study published in Nature Medicine, pSTAT3+ reactive astrocytes were found to promote brain metastasis by altering the tumor microenvironment, and represent a promising target for the treatment of brain metastasis.
September 2018: Trends in Molecular Medicine
Miguel Foronda, Lukas E Dow
Two recent reports show that, in some contexts, CRISPR-mediated genome editing can lead to a p53-mediated stress response and cell-cycle arrest. These findings may help to explain why CRISPR-mediated genetic manipulation in different cell types leads to dissimilar outcomes, and highlights the need for a better understanding of the factors that influence effective genome editing in vitro and in vivo.
September 2018: Trends in Molecular Medicine
Nona M Jiang, Maureen Cowan, Shannon N Moonah, William A Petri
Inflammatory mediators affect the brain during development. Neurodevelopmental disorders such as autism spectrum disorders, cognitive impairment, cerebral palsy, epilepsy, and schizophrenia have been linked to early life inflammation. Recent advances have shown the effects of systemic inflammation on children's neurodevelopment. We discuss the potential mechanisms by which inflammatory molecules can exert their effects on the developing brain and consider the roles of MHC class I molecules, the HPA axis, glial cells, and monoamine metabolism...
September 2018: Trends in Molecular Medicine
Kevin G Chen, Barbara S Mallon, Kyeyoon Park, Pamela G Robey, Ronald D G McKay, Michael M Gottesman, Wei Zheng
Use of human pluripotent stem cells (hPSCs) and their differentiated derivatives have led to recent proof-of-principle drug discoveries, defining a pathway to the implementation of hPSC-based drug discovery (hPDD). Current hPDD strategies, however, have inevitable conceptual biases and technological limitations, including the dimensionality of cell-culture methods, cell maturity and functionality, experimental variability, and data reproducibility. In this review, we dissect representative hPDD systems via analysis of hPSC-based 2D-monolayers, 3D culture, and organoids...
September 2018: Trends in Molecular Medicine
Beiyun C Liu, Joseph Sarhan, Alexander Poltorak
Most genetic ablations of interferon (IFN) signaling abolish both the experimentally induced IFN response and constitutive IFN, whose effects are well established in autoimmunity but understudied during infection. In host-pathogen interactions, most IFN-mediated responses are attributed to infection-driven IFN. However, IFNs confer their activity by regulating networks of interferon-stimulated genes (ISGs), a process that requires de novo transcription and translation of both IFN and downstream ISGs through feedback of IFN receptor signaling...
August 2018: Trends in Molecular Medicine
David L Elion, Rebecca S Cook
Chemotherapy is the most commonly prescribed treatment for patients with aggressive and lethal triple negative breast cancers (TNBCs), which often develop chemoresistance. A recent study combined single nucleus sequencing, single cell RNA sequencing, and evolutionary biology to understand how tumor cells use genetic and phenotypic diversity to evade the selective pressures of neoadjuvant chemotherapy.
August 2018: Trends in Molecular Medicine
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