scholarly journals Modeling the developmental origins of pediatric cancer to improve patient outcomes

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
James F. Amatruda
Keyword(s):  
Patient Outcomes ◽  
Pediatric Cancer ◽  
Molecular Mechanisms ◽  
Cellular Transformation ◽  
Genetic Changes ◽  
Current Therapies ◽  
Physician Scientist ◽  
Improve Patient ◽  
Generation Sequencing

ABSTRACT In the treatment of children and adolescents with cancer, multimodal approaches combining surgery, chemotherapy and radiation can cure most patients, but may cause lifelong health problems in survivors. Current therapies only modestly reflect increased knowledge about the molecular mechanisms of these cancers. Advances in next-generation sequencing have provided unprecedented cataloging of genetic aberrations in tumors, but understanding how these genetic changes drive cellular transformation, and how they can be effectively targeted, will require multidisciplinary collaboration and preclinical models that are truly representative of the in vivo environment. Here, I discuss some of the key challenges in pediatric cancer from my perspective as a physician-scientist, and touch on some promising new approaches that have the potential to transform our understanding of these diseases.

scholarly journals The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA—Salvaging the Gold Standards with Combination Therapy

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 762
Author(s):  
Taylor Morrisette ◽  
Sara Alosaimy ◽  
Jacinda C. Abdul-Mutakabbir ◽  
Razieh Kebriaei ◽  
Michael J. Rybak
Keyword(s):  
Combination Therapy ◽  
Patient Outcomes ◽  
Treatment Option ◽  
Standard Treatment ◽  
Primary Treatment ◽  
Alternative Approach ◽  
Improve Patient ◽  
Substantial Morbidity

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.

scholarly journals The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Aging: Implications in Obesity and Cardiovascular Disease

2018 ◽  
Vol 19 (7) ◽  
pp. 2139 ◽  
Author(s):  
David Bartlett ◽  
Richard Miller ◽  
Scott Thiesfeldt ◽  
Hari Lakhani ◽  
Joseph Shapiro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Patient Outcomes ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
General Decline ◽  
Pumping Function ◽  
Improve Patient

Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and metabolic abnormalities, exacerbating adipocyte dysfunction, cardiovascular diseases, and associated complications at the same time. In recent years, robust have established the implication of Na/K-ATPase signaling in causing oxidative stress and alterations in cellular mechanisms, in addition to its distinct pumping function. Understanding the underlying molecular mechanisms and exploring the possible sources of pro-oxidants may allow for developing therapeutic targets in these processes and formulate novel intervention strategies for patients susceptible to aging and associated complications, such as obesity and cardiovascular disease. The attenuation of oxidative stress with targeted treatment options can improve patient outcomes and significantly reduce economic burden.

scholarly journals Multiple Mitogen-Activated Protein Kinase Signaling Pathways Connect the Cot Oncoprotein to the c-junPromoter and to Cellular Transformation

2000 ◽  
Vol 20 (5) ◽  
pp. 1747-1758 ◽  
Author(s):  
Mario Chiariello ◽  
Maria Julia Marinissen ◽  
J. Silvio Gutkind
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cellular Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Activated T Cells ◽  
Mapk Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein

ABSTRACT The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-κB-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38γ (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-junproto-oncogene.

Investigating the Biological and Molecular Mechanisms Underpinning the Engraftment/Selection Advantage Conferred to Hematopoietic Stem Cells by HOXB4.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2101-2101
Author(s):  
Michael D. Milsom ◽  
Laura Hollins ◽  
Dorothy Gagen ◽  
Lorna B. Woolford ◽  
Leslie J. Fairbairn
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Vitro Analysis

Abstract We have recently demonstrated that co-expression of HOXB4 enables the enhanced delivery of HSC harbouring a second therapeutic trans-gene. Nonetheless, it is of great importance to elaborate the current knowledge about the mechanism of HOXB4 action in order to both evaluate the safety implications of its use in a clinical strategy, and to gain greater insight into the regulation of HSC self-renewal/expansion. To these ends we have performed an extensive in vitro analysis of the consequences of HOXB4 overexpression in primary murine BMC and in a murine multipotent myeloid progenitor cell line (FDCP-mix). We demonstrate for the first time in murine cells, that ectopic HOXB4 reduces the responsiveness of murine hematopoietic cells to differentiation stimuli. Furthermore, by performing a detailed investigation into the kinetics of FDCP-mix differentiation, we reveal that HOXB4 overexpression results in a specific differentiation delay as opposed to an outright block. We propose that an analogous delay is in operation in repopulating cells in order that the shift to increased assymetrical self-renewal, a requirement for stem cell expansion, is achieved. Notwithstanding this, it is clear that any perturbation in differentiation constitutes an increased risk of cellular transformation if this technology were transferred to a clinical setting. In order to further define the repercussions of ectopic HOXB4 delivery, we have developed a retroviral vector which encodes an activatable version of HOXB4. We have shown that this vector is able to mediate an in vitro differentiation delay in primary murine BMC and FDCP-mix as well as enable enhanced engraftment of BMC in vivo, both dependent upon the addition of the estrogen analogue; tamoxifen. Using this system, we are currently examining the effect of ectopic HOXB4 on the transcriptome of FDCP-mix cells, in addition to performing an in depth study into the biological mechanisms affected by HOXB4 overexpression in BMC in vivo. We envisage that these model systems will be particularly amenable to the manipulation required for target gene identification/validation.

scholarly journals Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sheila Castro-Sánchez ◽  
Paula Suarez-Bregua ◽  
Rossina Novas ◽  
María Álvarez-Satta ◽  
Jose L. Badano ◽  
...  
Keyword(s):  
Wild Type ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Genetic Changes ◽  
Bardet Biedl Syndrome ◽  
Main Challenge ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Human Wild Type

Abstract The multiple genetic approaches available for molecular diagnosis of human diseases have made possible to identify an increasing number of pathogenic genetic changes, particularly with the advent of next generation sequencing (NGS) technologies. However, the main challenge lies in the interpretation of their functional impact, which has resulted in the widespread use of animal models. We describe here the functional modelling of seven BBS loci variants, most of them novel, in zebrafish embryos to validate their in silico prediction of pathogenicity. We show that target knockdown (KD) of known BBS (BBS1, BB5 or BBS6) loci leads to developmental defects commonly associated with ciliopathies, as previously described. These KD pleiotropic phenotypes were rescued by co-injecting human wild type (WT) loci sequence but not with the equivalent mutated mRNAs, providing evidence of the pathogenic effect of these BBS changes. Furthermore, direct assessment of cilia located in Kupffer’s vesicle (KV) showed a reduction of ciliary length associated with all the studied variants, thus confirming a deleterious effect. Taken together, our results seem to prove the pathogenicity of the already classified and unclassified new BBS variants, as well as highlight the usefulness of zebrafish as an animal model for in vivo assays in human ciliopathies.

scholarly journals Molecular Basis of p53 Functional Inactivation by the Leukemic Protein MLL-ELL

2003 ◽  
Vol 23 (12) ◽  
pp. 4230-4246 ◽  
Author(s):  
Dmitri Wiederschain ◽  
Hidehiko Kawai ◽  
JiJie Gu ◽  
Ali Shilatifard ◽  
Zhi-Min Yuan
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Cellular Transformation ◽  
Wild Type ◽  
Efficient Inhibitor ◽  
C Terminus ◽  
Functional Inactivation ◽  
Necessary And Sufficient ◽  
First Time

ABSTRACT The Eleven Lysine-rich Leukemia (ELL) gene undergoes translocation and fuses in frame to the Multiple Lineage Leukemia (MLL) gene in a substantial proportion of patients suffering from acute forms of leukemia. Molecular mechanisms of cellular transformation by the MLL-ELL fusion are not well understood. Although both MLL-ELL and wild-type ELL can reduce functional activity of p53 tumor suppressor, our data reveal that MLL-ELL is a much more efficient inhibitor of p53 than is wild-type ELL. We also demonstrate for the first time that ELL extreme C terminus [ELL(eCT)] is required for the recruitment of p53 into MLL-ELL nuclear foci and is both necessary and sufficient for the MLL-ELL inhibition of p53-mediated induction of p21 and apoptosis. Finally, our results demonstrate that MLL-ELL requires the presence of intact ELL(eCT) in order to disrupt p53 interactions with p300/CBP coactivator and thus significantly reduce p53 acetylation in vivo. Since ELL(eCT) has recently been shown to be both necessary and sufficient for MLL-ELL-mediated transformation of normal blood progenitors, our data correlate ELL(eCT) contribution to MLL-ELL transformative effects with its ability to functionally inhibit p53.

scholarly journals Molecular Mechanisms of Coxsackievirus Persistence in Chronic Inflammatory Myopathy: Viral RNA Persists through Formation of a Double-Stranded Complex without Associated Genomic Mutations or Evolution

1999 ◽  
Vol 73 (12) ◽  
pp. 10113-10121 ◽  
Author(s):  
Patricia E. Tam ◽  
Ronald P. Messner
Keyword(s):  
Persistent Infection ◽  
Viral Genome ◽  
Molecular Mechanisms ◽  
Infectious Virus ◽  
Inflammatory Myopathy ◽  
Viral Rna ◽  
Genetic Changes ◽  
Reverse Transcription Pcr

ABSTRACT Enterovirus infection and persistence have been implicated in the pathogenesis of certain chronic muscle diseases. In vitro studies suggest that persistent enteroviruses mutate, evolving into forms that are less lytic and display altered tropism, but it is less clear whether these mechanisms operate in vivo. In this study, persistent coxsackievirus RNA from the muscle of mice afflicted with chronic inflammatory myopathy (CIM) was characterized and compared with RNA from a virus that had established a persistent infection of G8 mouse myoblasts for 30 passages in vitro. Competitive strand-specific reverse transcription-PCR and susceptibility to RNase I treatment revealed that plus- and minus-strand viral RNAs were present at nearly equivalent levels in muscle and that they persisted in a double-stranded conformation. All regions of the viral genome persisted and were amplified as a series of seven overlapping fragments. Restriction endonuclease fingerprinting coupled with sequencing indicated that there was no evolution of the viral genome associated with its persistence in muscle. This contrasted with the productive persistent infection that was established in myoblast cultures, where plus-strand RNA predominated and persistent virus developed distinct mutations. In vitro persistence proceeded by a carrier culture mechanism and was completely dependent on production of infectious virus, since persistent viral RNA was not detected in cultures subjected to antibody-mediated curing. These experiments demonstrate that persistence of coxsackievirus RNA in muscle is not facilitated by distinct genetic changes in the virus that give rise to replication-defective forms but occurs primarily through production of stable double-stranded RNA that is produced as the acute viral infection resolves. The data suggest a mechanism for coxsackievirus persistence in myofibers and perhaps other nondividing cells whereby cells that survive infection could harbor persistent viral RNA for extended times without producing detectable levels of infectious virus.

In vivo dosimetry; essential or unnecessary?

2011 ◽  
Vol 11 (1) ◽  
pp. 55-61
Author(s):  
Jenna L Leman
Keyword(s):  
Patient Outcomes ◽  
Medical Officer ◽  
Intensity Modulated Radiotherapy ◽  
In Vivo Dosimetry ◽  
Timely Manner ◽  
Knowing That ◽  
Arc Therapy ◽  
Improve Patient ◽  
Delivered Dose

AbstractIntroduction: The radiotherapy profession has learned from errors made during treatment planning and delivery. Quality assurance in radiotherapy (QART) procedures are implemented to reduce the risk of an error occuring. The chief medical officer, along with others, has recommended that the QART of all departments includes in vivo dosimetry (IVD) to ensure that the delivered dose equals the planned dose.Why we need IVD: A lot of effort goes into field verification and it is just as vital that dosimetry is verified. Overdose to normal tissue can cause devastating side effects, even death, whilst tumour underdose may compromise control. Without IVD, there is no way of knowing that a patient is receiving an overdose until it is too late. Underdoses are unlikely to manifest without IVD. IVD allows radiotherapists and physicists to correct for dose errors in a timely manner.Why IVD is unnecessary: Radiotherapy accidents are rare. Implementing IVD is expensive, time consuming and takes resources away from developing techniques which will improve patient outcomes. Current IVD methods are not suitable for modern techniques such as intensity modulated radiotherapy (IMRT).Discussion: IVD appears to be a useful QART tool, particularly as dose escalation techniques develop allowing a higher dose to be delivered to the tumour. Departments may be unwilling to spend time and money on an IVD system that is costly and time consuming if it cannot perform IVD on modern techniques. Electronic portal imaging devices (EPIDs) can be utilised to perform IVD on complex techniques, such as IMRT and arc therapy, which current IVD methods cannot, however there is currently no EPID IVD system available commercially.Conclusion: Ideally, all departments would conduct IVD on all new patients. IVD has proven to be an important QART tool, however, until technology is developed to allow EPID to include IVD, the procedure is not likely to be implemented countrywide.

Combined Approaches to the Skull Base for Intracranial Extension of Tumors via Perineural Spread can Improve Patient Outcomes

2016 ◽  
Vol 77 (S 01) ◽  
Author(s):  
Sheri Palejwala ◽  
Jonnae Barry ◽  
Crystal Rodriguez ◽  
Chandni Parikh ◽  
Stephen Goldstein ◽  
...  
Keyword(s):  
Skull Base ◽  
Patient Outcomes ◽  
Intracranial Extension ◽  
Perineural Spread ◽  
Improve Patient
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