CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer

The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.United States. National Institutes of Health (R01CA148688)United States. National Institutes of Health (R01CA148688S1)United States. National Institutes of Health (R01CA179483-01)United States. National Institutes of Health (CA109901)United States. National Institutes of Health (HG002668)United States. National Institutes of Health (R21HG006778)American Cancer Society (RSG-12-247-TBG)United States. Department of Defense (PR120741A)Friends for Life Neuroblastoma Foundatio

From cacti to carnivores: Improved phylotranscriptomic sampling and hierarchical homology inference provide further insight into the evolution of Caryophyllales

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143660/1/ajb21069.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143660/2/ajb21069_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143660/3/ajb21069-sup-0002-AppendixS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143660/4/ajb21069-sup-0005-AppendixS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143660/5/ajb21069-sup-0001-AppendixS1.pd

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers

Sequencing of the Sea Lamprey (Petromyzon marinus) Genome Provides Insights into Vertebrate Evolution

Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ∼500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Biopolymer Coatings for Biomedical Applications

Biopolymer coatings exhibit outstanding potential in various biomedical applications, due to their flexible functionalization. In this review, we have discussed the latest developments in biopolymer coatings on various substrates and nanoparticles for improved tissue engineering and drug delivery applications, and summarized the latest research advancements. Polymer coatings are used to modify surface properties to satisfy certain requirements or include additional functionalities for different biomedical applications. Additionally, polymer coatings with different inorganic ions may facilitate different functionalities, such as cell proliferation, tissue growth, repair, and delivery of biomolecules, such as growth factors, active molecules, antimicrobial agents, and drugs. This review primarily focuses on specific polymers for coating applications and different polymer coatings for increased functionalization. We aim to provide broad overview of latest developments in the various kind of biopolymer coatings for biomedical applications, in order to highlight the most important results in the literatures, and to offer a potential outline for impending progress and perspective. Some key polymer coatings were discussed in detail. Further, the use of polymer coatings on nanomaterials for biomedical applications has also been discussed, and the latest research results have been reported

Calcium phosphate coating on dental composite resins by a laser-assisted biomimetic process

Objectives: Dental composite resins with better biocompatibility and osteoconductivity have been sought in endodontic treatments. This study aimed to develop a technique to produce the osteoconductive resin surfaces through calcium phosphate (CaP) coating using a laser-assisted biomimetic (LAB) process. Methods: Light-cured, acrylic-based composite resins were used as substrates. The resin substrate was subjected to a LAB process comprising Nd:YAG pulsed laser irradiation in a supersaturated CaP solution. The LAB-processed substrate was immersed for 3 days in a simulated body fluid (SBF) for the preliminary osteoconductivity assessment. Results: After irradiation for 30 min, the resin surfaces were partly coated with a newly formed CaP layer. The coating layer contained hydroxyapatite as the main crystalline phase and the coating coverage depended on the laser wavelength and the type of resin. The LAB-processed CaP-coated surface exhibited apatite-forming ability in SBF. Conclusions: LAB process is effective for CaP coating on light-cured dental composite resins and improving their osteoconductivity. Clinical significance: The LAB process is a potential new tool to create a cementum-like osteoconductive surface on dental composite resins

PVP Assisted Synthesis of Hydroxyapatite Nanorods with Tunable Aspect Ratio and Bioactivity

Highly crystalline and reasonably uniform hydroxyapatite (HA) nanorods were prepared by polyvinylpyrrolidone (PVP) assisted hydrothermal synthesis which produces high aspect ratio (length/width) nanorods. The aspect ratio of the nanorods was higher in the presence of PVP and increased with increasing concentrations of PVP. X-ray diffraction (XRD) analysis showed that the HA nanorods were of the hexagonal apatite phase. High resolution transmission electron microscopy (HRTEM) and selected area electron diffraction (SAED) patterns confirmed that the nanorods grew in the c-axis direction (preferred orientation). The calculated lattice spacing was ∼0.35 nm which is the c-axis value of hexagonal HA. Morphological variations of pristine and PVP added HA were evaluated by field emission scanning electron microscopy (FESEM) and TEM, which revealed that the presence of PVP greatly increased the aspect ratio of the HA nanorods. The formation mechanism of the PVP assisted HA was studied and a possible reaction model was given. Cell viability analysis by in vitro studies showed encouraging results for the high aspect ratio nanorods and indicated a possibility for tuning the activity based on controlling the aspect ratio

Antibacterial Coatings for Titanium Implants: Recent Trends and Future Perspectives

Titanium and its alloys are widely used as implant materials for biomedical devices owing to their high mechanical strength, biocompatibility, and corrosion resistance. However, there is a significant rise in implant-associated infections (IAIs) leading to revision surgeries, which are more complicated than the original replacement surgery. To reduce the risk of infections, numerous antibacterial agents, e.g., bioactive compounds, metal ions, nanoparticles, antimicrobial peptides, polymers, etc., have been incorporated on the surface of the titanium implant. Various coating methods and surface modification techniques, e.g., micro-arc oxidation (MAO), layer-by-layer (LbL) assembly, plasma electrolytic oxidation (PEO), anodization, magnetron sputtering, and spin coating, are exploited in the race to create a biocompatible, antibacterial titanium implant surface that can simultaneously promote tissue integration around the implant. The nature and surface morphology of implant coatings play an important role in bacterial inhibition and drug delivery. Surface modification of titanium implants with nanostructured materials, such as titanium nanotubes, enhances bone regeneration. Antimicrobial peptides loaded with antibiotics help to achieve sustained drug release and reduce the risk of antibiotic resistance. Additive manufacturing of patient-specific porous titanium implants will have a clear future direction in the development of antimicrobial titanium implants. In this review, a brief overview of the different types of coatings that are used to prevent implant-associated infections and the applications of 3D printing in the development of antibacterial titanium implants is presented