11 research outputs found
Low-Molecular-Weight Organo- and Hydrogelators Based on Cyclo(l‑Lys‑l‑Glu)
Four cyclo(l-Lys-l-Glu) derivatives (<b>3</b>–<b>6</b>) were synthesized from the coupling reaction
of protecting l-lysine with l-glutamic acid followed
by the cyclization, deprotection, and protection reactions. They can
efficiently gelate a wide variety of organic solvents or water. Interestingly,
a spontaneous chemical reaction proceeded in the organogel obtained
from <b>3</b> in acetone exhibiting not only visual color alteration
but also increasing mechanical strength with the progress of time
due to the formation of Schiff base. Moreover, <b>6</b> bearing
a carboxylic acid and Fmoc group displayed a robust hydrogelation
capability in PBS solution. Transmission electron microscopy (TEM)
and scanning electron microscopy (SEM) revealed the characteristic
gelation morphologies of 3D fibrous network structures in the resulting
organo- and hydrogels. FT-IR and fluorescence analyses indicated that
the hydrogen bonding and π–π stacking play as major
driving forces for the self-assembly of these cyclic dipeptides as
low-molecular-weight gelators. X-ray diffraction (XRD) measurements
and computer modeling provided information on the molecular packing
model in the hydrogelation state of <b>6</b>. A spontaneous
chemical reaction proceeded in the organogel obtained from <b>3</b> in acetone exhibiting visual color alteration and increasing mechanical
strength. <b>6</b> bearing an optimized balance of hydrophilicity
to lipophilicity gave rise to a hydrogel in PBS with MGC at 1 mg/mL
Biologically Derived Nanoarchitectonic Coatings for the Engineering of Hemostatic Needles
Bleeding after venipuncture could cause blood loss, hematoma,
bruising,
hemorrhagic shock, and even death. Herein, a hemostatic needle with
antibacterial property is developed via coating of biologically derived
carboxymethyl chitosan (CMCS) and Cirsium setosum extract (CsE). The rapid transition from films of the coatings to
hydrogels under a wet environment provides an opportunity to detach
the coatings from needles and subsequently seal the punctured site.
The hydrogels do not significantly influence the healing process of
the puncture site. After hemostasis, the coatings on hemostatic needles
degrade in 72 h without inducing a systemic immune response. The composition
of CMCS can inhibit bacteria of Gram-negative Escherichia
coli and Gram-positive Staphylococcus
aureus by destroying the membrane of bacteria. The
hemostatic needle with good hemostasis efficacy, antibacterial property,
and safety is promising for the prevention of bleeding-associated
complications in practical applications
Image3_Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia.jpeg
As effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of Artemis would cause chromosome breaks during maturation of RAG-expressing T- and B-cells. Though this would block generation of new B- and T-cells temporarily, it could be oncologically beneficial for reducing the proliferation of B-ALL and T-ALL cells by causing chromosome breaks in these RAG-expressing tumor cells. Currently, pharmacological inhibition is not available for Artemis. According to gene expression analyses from 207 children with high-risk pre-B acute lymphoblastic leukemias high Artemis expression is correlated with poor outcome. Therefore, we evaluated four compounds (827171, 827032, 826941, and 825226), previously generated from a large Artemis targeted drug screen. A biochemical assay using a purified Artemis:DNA-PKcs complex shows that the Artemis inhibitors 827171, 827032, 826941, 825226 have nanomolar IC50 values for Artemis inhibition. We compared these 4 compounds to a DNA-PK inhibitor (AZD7648) in three patient-derived B-ALL cell lines (LAX56, BLQ5 and LAX7R) and in two mature B-cell lines (3301015 and 5680001) as controls. We found that pharmacological Artemis inhibition substantially decreases proliferation of B-ALL cell lines while normal mature B-cell lines are not markedly affected. Inhibition of DNA-PKcs (which regulates Artemis) using the DNA-PK inhibitor AZD7648 had minor effects on these same primary patient-derived ALL lines, indicating that inhibition of V(D)J hairpin opening requires direct inhibition of Artemis, rather than indirect suppression of the kinase that regulates Artemis. Our data provides a basis for further evaluation of pharmacological Artemis inhibition of proliferation of B- and T-ALL.</p
DataSheet1_Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia.docx
As effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of Artemis would cause chromosome breaks during maturation of RAG-expressing T- and B-cells. Though this would block generation of new B- and T-cells temporarily, it could be oncologically beneficial for reducing the proliferation of B-ALL and T-ALL cells by causing chromosome breaks in these RAG-expressing tumor cells. Currently, pharmacological inhibition is not available for Artemis. According to gene expression analyses from 207 children with high-risk pre-B acute lymphoblastic leukemias high Artemis expression is correlated with poor outcome. Therefore, we evaluated four compounds (827171, 827032, 826941, and 825226), previously generated from a large Artemis targeted drug screen. A biochemical assay using a purified Artemis:DNA-PKcs complex shows that the Artemis inhibitors 827171, 827032, 826941, 825226 have nanomolar IC50 values for Artemis inhibition. We compared these 4 compounds to a DNA-PK inhibitor (AZD7648) in three patient-derived B-ALL cell lines (LAX56, BLQ5 and LAX7R) and in two mature B-cell lines (3301015 and 5680001) as controls. We found that pharmacological Artemis inhibition substantially decreases proliferation of B-ALL cell lines while normal mature B-cell lines are not markedly affected. Inhibition of DNA-PKcs (which regulates Artemis) using the DNA-PK inhibitor AZD7648 had minor effects on these same primary patient-derived ALL lines, indicating that inhibition of V(D)J hairpin opening requires direct inhibition of Artemis, rather than indirect suppression of the kinase that regulates Artemis. Our data provides a basis for further evaluation of pharmacological Artemis inhibition of proliferation of B- and T-ALL.</p
Image1_Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia.jpg
As effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of Artemis would cause chromosome breaks during maturation of RAG-expressing T- and B-cells. Though this would block generation of new B- and T-cells temporarily, it could be oncologically beneficial for reducing the proliferation of B-ALL and T-ALL cells by causing chromosome breaks in these RAG-expressing tumor cells. Currently, pharmacological inhibition is not available for Artemis. According to gene expression analyses from 207 children with high-risk pre-B acute lymphoblastic leukemias high Artemis expression is correlated with poor outcome. Therefore, we evaluated four compounds (827171, 827032, 826941, and 825226), previously generated from a large Artemis targeted drug screen. A biochemical assay using a purified Artemis:DNA-PKcs complex shows that the Artemis inhibitors 827171, 827032, 826941, 825226 have nanomolar IC50 values for Artemis inhibition. We compared these 4 compounds to a DNA-PK inhibitor (AZD7648) in three patient-derived B-ALL cell lines (LAX56, BLQ5 and LAX7R) and in two mature B-cell lines (3301015 and 5680001) as controls. We found that pharmacological Artemis inhibition substantially decreases proliferation of B-ALL cell lines while normal mature B-cell lines are not markedly affected. Inhibition of DNA-PKcs (which regulates Artemis) using the DNA-PK inhibitor AZD7648 had minor effects on these same primary patient-derived ALL lines, indicating that inhibition of V(D)J hairpin opening requires direct inhibition of Artemis, rather than indirect suppression of the kinase that regulates Artemis. Our data provides a basis for further evaluation of pharmacological Artemis inhibition of proliferation of B- and T-ALL.</p
Genome-wide patterns of aberrant methylation.
<p>(A) Graphical explanation of how the distribution of M-scores and IQR are transformed into violin distribution plots to enable more efficient visualization and comparison on intra- and inter-sample variability. (B) Distribution of the methylation score (M-score, left) and inter-quartile ranges (IQR, right) at probesets in centromeric, telomeric, and intermediate regions for normal and diseased tissues. Bar width is proportional to the number of data points, and the colors are the same as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003137#pgen-1003137-g001" target="_blank">Figure 1A</a>. (C) Distributions of M-score (left) and IQR (right) are shown for gene-poor, gene-rich, and intermediate regions.</p
The insulator factor CTCF prevents spreading of aberrant methylation.
<p>(A) Methylation heterogeneity depends on the density of CTCF-binding sites. Methylation state (M-score, left) and inter-sample methylation variation (IQR, right) are shown for CTCF-BS-poor, CTCF-BS-rich, and intermediate regions. (B) Spreading of aberrant methylation from genomic position “<i>i</i>” to “<i>i</i>±1” (i.e. two neighboring sites) when at least one CTCF-BS is present (black vertical dotted line) and when no CTCF-BS is present (light grey vertical dotted line) between “<i>i</i>” and “<i>i</i>±1”, for aberrant hypo-methylation (two left panels) and aberrant hyper-methylation (two right panels). The presence of CTCF-BS more efficiently restricts the spreading of aberrant hypo-methylation. (C) A schematic overview showing spreading of abnormal methylation in the absence of CTCF-binding sites in genomic neighborhood.</p
Spreading of aberrant methylation to neighboring probesets in the ABC samples.
<p>(A) A schematic representation of how the genome was divided into blocks of genes to study spreading of altered DNA methylation. (B–C) Analysis of spreading of aberrant methylation within genomic neighborhoods. Loci “<i>i</i>” represent probesets that are significantly hypo- (black) or hyper-methylated (grey) in lymphoma samples compared to normal tissues, and loci “<i>i</i>±<i>j</i>” represent both the (<i>i</i>+<i>j</i>)-th and (<i>i</i>−<i>j</i>)-th neighbors of those probesets. For instance, when we focused on probeset #10 (i.e. <i>i</i> = 10), we analyzed spreading of aberrant methylation at probesets #5, 6, 7, 8, 9, 11, 12, 13, 14 and 15. Panel B displays the change in methylation states while panel C shows the change in IQR (variability between samples).</p
The extent of DNA methylation aberration is predictive of patient survival.
<p>(A) Phylogenetic tree, as estimated based on the correlation of group-averaged M-scores. Departure from normal methylation patterns is correlated with disease severity of the lymphoma samples. (B–C) Kaplan-Meier curves for risk groups defined according to their methylation distance score (i.e. distance from normal B-cells), which reflects how different a sample's methylation profile is from that of NBC or NGC, for all DLBCL (GCB and ABC) samples. (B) Multivariate analysis with the International Prognostic Index (IPI) and distance to NBC. (C) Only IPI.</p
Genomic localization of transcriptional regulators and AICDA associates with sites of aberrant DNA methylation.
<p>(A–D) Methylation heterogeneity of promoters of genes that are targets of master regulators. The panels display the distribution of methylation scores (M-scores) for promoters of target genes of (A) BCL6, (B) MYC, (C) EZH2, and (D) AICDA. (E) A schematic overview showing targeted abnormal promoter methylation by master regulators such as MYC, BCL6, EZH2 and AICDA in the lymphoma subtypes.</p