<p>(<b>A</b>) For details of the bicistronic I-<i>Sce</i>I transgen... more <p>(<b>A</b>) For details of the bicistronic I-<i>Sce</i>I transgene construct refer to [65]. (<b>B</b>) MEFs derived from GS mice were cultured in media supplemented with TET at 2μg/mL for 48 hours. Total protein extracts were harvested and analyzed by Western blotting. By 48 hours post-TET, detectable quantities of I-<i>Sce</i>I endonuclease can be observed. As a negative controls, total protein extracts were harvested from cultured E14 ES cells or uncultured MEFs from GS mice. Loading control: Western blotting for β-actin.</p
<p>(<b>A</b>) In the young mouse cohort (age<5.5 months), negative controls ... more <p>(<b>A</b>) In the young mouse cohort (age<5.5 months), negative controls are shown in red bars (n=5), and +TET are shown in grey bars (n=16). Organs with statistically significant increased numbers of GFP+ cells groups are indicated by ** above the error bars. (<b>B</b>) In the older mouse cohort (age>8 months), negative controls are shown in red bars (n=11) and +TET are shown in black bars (n=31). (<b>C</b>) Comparison of +TET young mice (grey bars) versus +TET old mice (black bars) from A and B. Organs with statistically significant different numbers of GFP+ cells by age are indicated by ** above the error bars. For all panels, H=heart, P=pancreas, Li=liver, K=kidney, S=spleen, Lu=lung, T=thymus.</p
<p>(<b>A</b>) For each construct schematic, the numbers of bases are indicated ... more <p>(<b>A</b>) For each construct schematic, the numbers of bases are indicated to show the lengths of homology between the two as well as the relative positions of the engineered I-<i>Sce</i>I restriction sites. The 3’UTR sequences of the two constructs do not share homology and are indicated as a hatched box of 1270 bp for 1S-GFP and a grey box of 535 bp for 2S-GFP; these non-homologous sequences allow for PCR amplification specific to each transgene. Nested PCR primer pairs used for verification of intact construct sequences and for analysis of GFP+ hematopoietic colonies are indicated. Primers 1F-4R followed by 2F-3R amplify sequence flanking the I-<i>Sce</i>I site in 1S-GFP. Primers 1F-7R followed by 5F-6R amplify sequence flanking the I-<i>Sce</i>I site in 2S-GFP. (<b>B</b>) Southern blotting to estimate copy number utilized a GFP ORF DNA fragment of 3.1 kb and diluted to pg amounts that approximated 0, 0.2, 1.0, and 5.0 copies per genome spiked into 10µg non-transgenic mouse DNA. Genomic DNA from single transgenic mice (either 1S-GFP or 2S-GFP) was digested with restriction endonucleases within the GFP promoter and ORF of both transgenes to yield a 3.1 kb fragment. Band intensities are consistent with 4-5 copies of 1S-GFP and 2-4 copies of 2S-GFP, and were confirmed with Q-PCR data on the same samples (data not shown). (<b>C</b>) PCR reactions flanking each DSB site in the two GFP constructs confirm intact I-SceI recognition sites. Nested PCR as described in Materials amplified each transgene shown in the left side lane of each image. Digestion with I-<i>Sce</i>I endonuclease produced the expected sizes indicated in the middle lane of each image. Right side Marker lane PhiX.</p
<p>Colonies were scored by inverted fluorescent microscopy and faint background fluorescenc... more <p>Colonies were scored by inverted fluorescent microscopy and faint background fluorescence of negative controls was subtracted out of total repair frequency. Representative phase contrast and fluorescent microscopy images of GFP+ recombinants from bone marrow CFC assay. Granulocyte-erythrocyte-macrophage-megakaryocyte (GEMM), Granulocyte-macrophage (CFU-GM), Granulocyte (CFU-G), Macrophage (CFU-M), Pre-B cell (Pre-B), and Burst forming unit-erythroid (BFU-E). Magnification 400X.</p
<p>(<b>A</b>) Phase contrast and matched fluorescent microscopy images of MEFs ... more <p>(<b>A</b>) Phase contrast and matched fluorescent microscopy images of MEFs in culture—magnification 400X. Top row-untreated MEFs. Second row-96 hrs post-electroporation with I-<i>Sce</i>I expression plasmid. Third and fourth rows-96 hrs after addition of tetracycline to the culture medium (+TET). (<b>B</b>) Representative FACS plot of MEFs with GFP positivity in log scale on the x axis plotted against number of cells on the y axis. Upper plot--untreated MEFs. Lower plot-- +TET treated MEFs. In this sample, the GFP+ population is 12.4%. (<b>C</b>) Confirmation of GFP+ cells after FACS single cell sorting for GFP+ MEFs. Cells within the GFP+ gate indicated in B lower panel were sorted and then viewed by fluorescent microscopy—magnification 400X.</p
<p>The number of GFP+ cells in each organ of analyzed mice was determined. Establishment of... more <p>The number of GFP+ cells in each organ of analyzed mice was determined. Establishment of gates is described in text. From FACS analysis, the average number of GFP+ recombinant cells per million cells and the standard deviation of each was calculated for seven organs and represented in bar graph form. Negative controls are shown in red bars (n=8), and +TET are shown in green bars (n=47). H=heart, P=pancreas, Li=liver, K=kidney, S=spleen, Lu=lung, T=thymus. Organs with statistically significant increased numbers of GFP+ cells groups are indicated by ** above the error bars.</p
Abstract: Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxy... more Abstract: Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the c... more Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the chemotherapeutic drug etoposide may promote infant acute leukemia. Several studies have shown that common dietary bioflavonoids as well as benzene metabolites can induce DNA double strand breaks (DSB) and inhibit topoII. The goal of this study was to determine the relative potential for bioflavonoids genistein and quercetin, and possible leukemogenic compounds p-benzoquinone and dipyrone to promote rearrangements between the MLL and AF9 breakpoint cluster regions within specific hematopoietic cell subpopulations. A murine embryonic stem (ES) cell line containing two Green Fluorescent Protein (GFP) DSB-inducible recombination reporter substrates was differentiated in vitro into embryoid bodies (EB) containing hematopoietic stem cells (HSC) followed by differentiation into myeloid progenitor subpopulations. Following exposure to genistein, quercetin, p-benzoquinone, or dipyrone at each of t...
Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is ... more Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is variable. Data on biological predictors of response is limited. Cytidine deaminase (CDA) inactivates HMAs. Increased CDA activity may lead to HMA resistance. Using core pathway analysis, we identified nucleophosmin 1 (NPM1) indirectly influences CDA expression. We hypothesized that responses to HMAs occur in the setting of decreased CDA expression regulated by NPM1 and investigated the relationship between NPM1 status, CDA expression, single nucleotide polymorphisms (SNPs) in CDA, and HMA response in pts with AML. AML pts with banked samples who received HMA-based therapy between 1/2014 to 12/2018 were reviewed. Responses following at least 2 cycles of HMA were categorized as responders (R) or non-responders (NR). Pt, disease, NPM1 status, and treatment characteristics were summarized. CDA gene and protein expression was examined in bone marrow and peripheral blood samples at diagnosis u...
Three annotated splice variants for CSF3R, the gene encoding the receptor for granulocyte colony-... more Three annotated splice variants for CSF3R, the gene encoding the receptor for granulocyte colony-stimulating factor (G-CSF) that critically regulates neutrophil production, have been described. Splice variant 1 (CSF3R-V1, also known as wild-type) is the most highly expressed and widely studied. Splice variant 4 (CSF3R-V4) is generated through use of cryptic 5' and 3' splice sites in the last exon of CSF3R, and produces a frame shift that results in early termination of the receptor. Increased expression of this splice variant has been reported in some patients with de novo AML. This splice variant induces a hyperproliferative phenotype and delayed receptor internalization by a mechanism similar to that reported in patients with severe congenital neutropenia transforming to AML with acquired CSF3R mutations. Although expression of the CSF3R-V3 splice variant was reported some 20 years ago in placenta, nothing is currently known about its expression in primary human hematopoie...
1275 Infant acute leukemias account for ∼30% of all malignancy seen in childhood across the Weste... more 1275 Infant acute leukemias account for ∼30% of all malignancy seen in childhood across the Western world. They are aggressive and characterized by rapid onset shortly after birth. The majority of these (∼80% ALL and ∼60% AML) have rearrangements involving the MLL gene. Although MLL fusion to more than 75 genes have been identified, AF9 is one of its most common translocation partners. MLL breakpoint sequences associated with infant acute leukemia are similar to those in secondary AML following exposure to the topoisomerase II (topoII) poison etoposide. This similarity led to the hypothesis that exposure during preganancy to biochemically similar compounds may promote infant acute leukemia. Some studies have shown an epidemiological link between bioflavonoid intake and increased incidence of MLL-rearranged infant leukemias. These bioflavonoids have also been shown to inhibit topoII in in vitro DNA cleavage assays and produce MLL rearrangements by inverse PCR in mice. Hundreds of unr...
Conventional delivery of chemotherapeutic agents leads to multiple systemic side effects and toxi... more Conventional delivery of chemotherapeutic agents leads to multiple systemic side effects and toxicity, limiting the doses that can be used. The development of targeted therapies to selectively deliver anti-cancer agents to tumor cells without damaging neighboring unaffected cells would lead to higher effective local doses and improved response rates. Aptamers are single-stranded oligonucleotides that bind to target molecules with both high affinity and high specificity. The high specificity exhibited by aptamers promotes localization and uptake by specific cell populations, such as tumor cells, and their conjugation to anti-cancer drugs has been explored for targeted therapy. Advancements in the development of polymeric nanoparticles allow anti-cancer drugs to be encapsulated in protective nonreactive shells for controlled drug delivery with reduced toxicity. The conjugation of aptamers to nanoparticle-based therapeutics may further enhance direct targeting and personalized medicine. Here we present how the combinatorial use of aptamer and nanoparticle technologies has the potential to develop &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;smart bombs&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for targeted cancer treatment, highlighting recent pre-clinical studies demonstrating efficacy for the direct targeting to particular tumor cell populations. However, despite these pre-clinical promising results, there has been little progress in moving this technology to the bedside.
Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiat... more Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiation. Although dysregulation of several HOX genes in ovarian cancer has been reported, little is known about HOXC6 expression in epithelial ovarian cancer. In this report, analysis of laser capture microdissected samples determined HOXC6 expression patterns in normal versus malignant serous ovarian carcinoma tissues. HOXC6 protein was quantified by ELISA in parallel serum samples and further validated in a larger cohort of serum samples collected from women with and without serous ovarian carcinoma. These data demonstrate significant downregulation of HOXC6 in serous ovarian cancer.
International journal of molecular sciences, Jan 22, 2015
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cel... more Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Objective: The Homeobox (HOX) family of genes consists of 39 genes encoding transcription factors... more Objective: The Homeobox (HOX) family of genes consists of 39 genes encoding transcription factors important to morphogenesis and cell differentiation. Usually inactive in normal differentiated tissues, dysregulation of HOX genes has been reported in several malignancies. HOX genes have been linked to genes important in malignant transformation including vascular endothelial growth factor, Ras, interleukin-8, and fibroblast growth factor. We have previously reported up-regulation of HOXA2, HOXA7 and HOXB7 in ovarian cancer. Little is known about HOXC6 gene expression in ovarian cancer. In this study we evaluated HOXC6 expression in normal and malignant human ovarian tissue to characterize expression of HOXC6 in serous ovarian cancer. Methods: Microarray analysis of mRNA from LCM captured cells from human ovarian tissues was performed on 11 samples of normal, and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human EXON 1.0 ST microarray to distinguish the...
<p>(<b>A</b>) For details of the bicistronic I-<i>Sce</i>I transgen... more <p>(<b>A</b>) For details of the bicistronic I-<i>Sce</i>I transgene construct refer to [65]. (<b>B</b>) MEFs derived from GS mice were cultured in media supplemented with TET at 2μg/mL for 48 hours. Total protein extracts were harvested and analyzed by Western blotting. By 48 hours post-TET, detectable quantities of I-<i>Sce</i>I endonuclease can be observed. As a negative controls, total protein extracts were harvested from cultured E14 ES cells or uncultured MEFs from GS mice. Loading control: Western blotting for β-actin.</p
<p>(<b>A</b>) In the young mouse cohort (age<5.5 months), negative controls ... more <p>(<b>A</b>) In the young mouse cohort (age<5.5 months), negative controls are shown in red bars (n=5), and +TET are shown in grey bars (n=16). Organs with statistically significant increased numbers of GFP+ cells groups are indicated by ** above the error bars. (<b>B</b>) In the older mouse cohort (age>8 months), negative controls are shown in red bars (n=11) and +TET are shown in black bars (n=31). (<b>C</b>) Comparison of +TET young mice (grey bars) versus +TET old mice (black bars) from A and B. Organs with statistically significant different numbers of GFP+ cells by age are indicated by ** above the error bars. For all panels, H=heart, P=pancreas, Li=liver, K=kidney, S=spleen, Lu=lung, T=thymus.</p
<p>(<b>A</b>) For each construct schematic, the numbers of bases are indicated ... more <p>(<b>A</b>) For each construct schematic, the numbers of bases are indicated to show the lengths of homology between the two as well as the relative positions of the engineered I-<i>Sce</i>I restriction sites. The 3’UTR sequences of the two constructs do not share homology and are indicated as a hatched box of 1270 bp for 1S-GFP and a grey box of 535 bp for 2S-GFP; these non-homologous sequences allow for PCR amplification specific to each transgene. Nested PCR primer pairs used for verification of intact construct sequences and for analysis of GFP+ hematopoietic colonies are indicated. Primers 1F-4R followed by 2F-3R amplify sequence flanking the I-<i>Sce</i>I site in 1S-GFP. Primers 1F-7R followed by 5F-6R amplify sequence flanking the I-<i>Sce</i>I site in 2S-GFP. (<b>B</b>) Southern blotting to estimate copy number utilized a GFP ORF DNA fragment of 3.1 kb and diluted to pg amounts that approximated 0, 0.2, 1.0, and 5.0 copies per genome spiked into 10µg non-transgenic mouse DNA. Genomic DNA from single transgenic mice (either 1S-GFP or 2S-GFP) was digested with restriction endonucleases within the GFP promoter and ORF of both transgenes to yield a 3.1 kb fragment. Band intensities are consistent with 4-5 copies of 1S-GFP and 2-4 copies of 2S-GFP, and were confirmed with Q-PCR data on the same samples (data not shown). (<b>C</b>) PCR reactions flanking each DSB site in the two GFP constructs confirm intact I-SceI recognition sites. Nested PCR as described in Materials amplified each transgene shown in the left side lane of each image. Digestion with I-<i>Sce</i>I endonuclease produced the expected sizes indicated in the middle lane of each image. Right side Marker lane PhiX.</p
<p>Colonies were scored by inverted fluorescent microscopy and faint background fluorescenc... more <p>Colonies were scored by inverted fluorescent microscopy and faint background fluorescence of negative controls was subtracted out of total repair frequency. Representative phase contrast and fluorescent microscopy images of GFP+ recombinants from bone marrow CFC assay. Granulocyte-erythrocyte-macrophage-megakaryocyte (GEMM), Granulocyte-macrophage (CFU-GM), Granulocyte (CFU-G), Macrophage (CFU-M), Pre-B cell (Pre-B), and Burst forming unit-erythroid (BFU-E). Magnification 400X.</p
<p>(<b>A</b>) Phase contrast and matched fluorescent microscopy images of MEFs ... more <p>(<b>A</b>) Phase contrast and matched fluorescent microscopy images of MEFs in culture—magnification 400X. Top row-untreated MEFs. Second row-96 hrs post-electroporation with I-<i>Sce</i>I expression plasmid. Third and fourth rows-96 hrs after addition of tetracycline to the culture medium (+TET). (<b>B</b>) Representative FACS plot of MEFs with GFP positivity in log scale on the x axis plotted against number of cells on the y axis. Upper plot--untreated MEFs. Lower plot-- +TET treated MEFs. In this sample, the GFP+ population is 12.4%. (<b>C</b>) Confirmation of GFP+ cells after FACS single cell sorting for GFP+ MEFs. Cells within the GFP+ gate indicated in B lower panel were sorted and then viewed by fluorescent microscopy—magnification 400X.</p
<p>The number of GFP+ cells in each organ of analyzed mice was determined. Establishment of... more <p>The number of GFP+ cells in each organ of analyzed mice was determined. Establishment of gates is described in text. From FACS analysis, the average number of GFP+ recombinant cells per million cells and the standard deviation of each was calculated for seven organs and represented in bar graph form. Negative controls are shown in red bars (n=8), and +TET are shown in green bars (n=47). H=heart, P=pancreas, Li=liver, K=kidney, S=spleen, Lu=lung, T=thymus. Organs with statistically significant increased numbers of GFP+ cells groups are indicated by ** above the error bars.</p
Abstract: Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxy... more Abstract: Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the c... more Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the chemotherapeutic drug etoposide may promote infant acute leukemia. Several studies have shown that common dietary bioflavonoids as well as benzene metabolites can induce DNA double strand breaks (DSB) and inhibit topoII. The goal of this study was to determine the relative potential for bioflavonoids genistein and quercetin, and possible leukemogenic compounds p-benzoquinone and dipyrone to promote rearrangements between the MLL and AF9 breakpoint cluster regions within specific hematopoietic cell subpopulations. A murine embryonic stem (ES) cell line containing two Green Fluorescent Protein (GFP) DSB-inducible recombination reporter substrates was differentiated in vitro into embryoid bodies (EB) containing hematopoietic stem cells (HSC) followed by differentiation into myeloid progenitor subpopulations. Following exposure to genistein, quercetin, p-benzoquinone, or dipyrone at each of t...
Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is ... more Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is variable. Data on biological predictors of response is limited. Cytidine deaminase (CDA) inactivates HMAs. Increased CDA activity may lead to HMA resistance. Using core pathway analysis, we identified nucleophosmin 1 (NPM1) indirectly influences CDA expression. We hypothesized that responses to HMAs occur in the setting of decreased CDA expression regulated by NPM1 and investigated the relationship between NPM1 status, CDA expression, single nucleotide polymorphisms (SNPs) in CDA, and HMA response in pts with AML. AML pts with banked samples who received HMA-based therapy between 1/2014 to 12/2018 were reviewed. Responses following at least 2 cycles of HMA were categorized as responders (R) or non-responders (NR). Pt, disease, NPM1 status, and treatment characteristics were summarized. CDA gene and protein expression was examined in bone marrow and peripheral blood samples at diagnosis u...
Three annotated splice variants for CSF3R, the gene encoding the receptor for granulocyte colony-... more Three annotated splice variants for CSF3R, the gene encoding the receptor for granulocyte colony-stimulating factor (G-CSF) that critically regulates neutrophil production, have been described. Splice variant 1 (CSF3R-V1, also known as wild-type) is the most highly expressed and widely studied. Splice variant 4 (CSF3R-V4) is generated through use of cryptic 5' and 3' splice sites in the last exon of CSF3R, and produces a frame shift that results in early termination of the receptor. Increased expression of this splice variant has been reported in some patients with de novo AML. This splice variant induces a hyperproliferative phenotype and delayed receptor internalization by a mechanism similar to that reported in patients with severe congenital neutropenia transforming to AML with acquired CSF3R mutations. Although expression of the CSF3R-V3 splice variant was reported some 20 years ago in placenta, nothing is currently known about its expression in primary human hematopoie...
1275 Infant acute leukemias account for ∼30% of all malignancy seen in childhood across the Weste... more 1275 Infant acute leukemias account for ∼30% of all malignancy seen in childhood across the Western world. They are aggressive and characterized by rapid onset shortly after birth. The majority of these (∼80% ALL and ∼60% AML) have rearrangements involving the MLL gene. Although MLL fusion to more than 75 genes have been identified, AF9 is one of its most common translocation partners. MLL breakpoint sequences associated with infant acute leukemia are similar to those in secondary AML following exposure to the topoisomerase II (topoII) poison etoposide. This similarity led to the hypothesis that exposure during preganancy to biochemically similar compounds may promote infant acute leukemia. Some studies have shown an epidemiological link between bioflavonoid intake and increased incidence of MLL-rearranged infant leukemias. These bioflavonoids have also been shown to inhibit topoII in in vitro DNA cleavage assays and produce MLL rearrangements by inverse PCR in mice. Hundreds of unr...
Conventional delivery of chemotherapeutic agents leads to multiple systemic side effects and toxi... more Conventional delivery of chemotherapeutic agents leads to multiple systemic side effects and toxicity, limiting the doses that can be used. The development of targeted therapies to selectively deliver anti-cancer agents to tumor cells without damaging neighboring unaffected cells would lead to higher effective local doses and improved response rates. Aptamers are single-stranded oligonucleotides that bind to target molecules with both high affinity and high specificity. The high specificity exhibited by aptamers promotes localization and uptake by specific cell populations, such as tumor cells, and their conjugation to anti-cancer drugs has been explored for targeted therapy. Advancements in the development of polymeric nanoparticles allow anti-cancer drugs to be encapsulated in protective nonreactive shells for controlled drug delivery with reduced toxicity. The conjugation of aptamers to nanoparticle-based therapeutics may further enhance direct targeting and personalized medicine. Here we present how the combinatorial use of aptamer and nanoparticle technologies has the potential to develop &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;smart bombs&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for targeted cancer treatment, highlighting recent pre-clinical studies demonstrating efficacy for the direct targeting to particular tumor cell populations. However, despite these pre-clinical promising results, there has been little progress in moving this technology to the bedside.
Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiat... more Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiation. Although dysregulation of several HOX genes in ovarian cancer has been reported, little is known about HOXC6 expression in epithelial ovarian cancer. In this report, analysis of laser capture microdissected samples determined HOXC6 expression patterns in normal versus malignant serous ovarian carcinoma tissues. HOXC6 protein was quantified by ELISA in parallel serum samples and further validated in a larger cohort of serum samples collected from women with and without serous ovarian carcinoma. These data demonstrate significant downregulation of HOXC6 in serous ovarian cancer.
International journal of molecular sciences, Jan 22, 2015
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cel... more Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Objective: The Homeobox (HOX) family of genes consists of 39 genes encoding transcription factors... more Objective: The Homeobox (HOX) family of genes consists of 39 genes encoding transcription factors important to morphogenesis and cell differentiation. Usually inactive in normal differentiated tissues, dysregulation of HOX genes has been reported in several malignancies. HOX genes have been linked to genes important in malignant transformation including vascular endothelial growth factor, Ras, interleukin-8, and fibroblast growth factor. We have previously reported up-regulation of HOXA2, HOXA7 and HOXB7 in ovarian cancer. Little is known about HOXC6 gene expression in ovarian cancer. In this study we evaluated HOXC6 expression in normal and malignant human ovarian tissue to characterize expression of HOXC6 in serous ovarian cancer. Methods: Microarray analysis of mRNA from LCM captured cells from human ovarian tissues was performed on 11 samples of normal, and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human EXON 1.0 ST microarray to distinguish the...
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