Leishmania are parasitic protozoa that cause a wide spectrum of diseases collectively known as th... more Leishmania are parasitic protozoa that cause a wide spectrum of diseases collectively known as the leishmaniases. Sexual reproduction in Leishmania has been proposed as an important source of genetic diversity and has been formally demonstrated to occur inside the sand fly vector midgut.
Background: Pilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies... more Background: Pilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours. Methods: RNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization. Results: In this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, ...
Page 1. 3D Visualization of Relation Clusters from OWL Ontologies Jahangheer S. Shaik a , Cartik ... more Page 1. 3D Visualization of Relation Clusters from OWL Ontologies Jahangheer S. Shaik a , Cartik R. Kothari b , David J. Russomanno a , and M. Yeasin a aDepartment of Electrical and Computer Engineering Herff College ...
... function based on higher order statistics which consider the deviations from normality for ra... more ... function based on higher order statistics which consider the deviations from normality for ranking the marker genes from two sample microarray experiments. ...
Automated brain tumor segmentation and detection are immensely important in medical diagnostics b... more Automated brain tumor segmentation and detection are immensely important in medical diagnostics because it provides information associated to anatomical structures as well as potential abnormal tissue necessary to delineate appropriate surgical planning. In this work, we propose a ...
BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAI... more BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary...
BackgroundSiglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins... more BackgroundSiglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins involved in immune regulation. NC318 is a first-in-class humanized IgG1κ monoclonal antibody that blocks S15-mediated immune suppression.MethodsThe Phase 1 dose-escalation study was a classical 3+3 design in 15 tumor types (n=49). Phase 2 (n=47) was conducted at 400 mg q2w in 4 tumor types. Inclusion criteria included subjects with advanced/metastatic solid tumors refractory or resistant to currently available therapies with a TPS PD-L1 score <50%. The median number of previous therapies was ≥3, including checkpoint inhibitors (figure 1).ResultsNC318 was well tolerated with no novel immunologic or safety signals observed. Disease control rate amongst evaluable population (n=83) is 38% {1 CR, 3 PR and 28 SD (stable disease)}. Median duration of disease control is 24 weeks (16–48 weeks) amongst 20 subjects achieving a minimal 16-week duration of stable disease. Two NSCLC subjects (1CR ...
We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mamma... more We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mammalian target of rapamycin (mTOR; a conserved serine/threonine kinase critical for immune regulation and cellular growth) in human dendritic cells (DC) and we have proposed that this mTOR inhibition is associated with the DC dysfunction seen in filarial infections. Extracellular vesicles (EVs) contain many proteins and nucleic acids including microRNAs (miRNAs) that might affect a variety of intracellular pathways. Thus, EVs secreted from mf may elucidate the mechanism by which the parasite is able to modulate the host immune response during infection. EVs, purified from mf of Brugia malayi and confirmed by size through nanoparticle tracking analysis, were assessed by miRNA microarrays (accession number GSE157226) and shown to be enriched (>2-fold, p-value<0.05, FDR = 0.05) for miR100, miR71, miR34, and miR7. The microarray analysis compared mf-derived EVs and mf supernatant. After c...
Collagens are a primary component of the extracellular matrix and are functional ligands for the ... more Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich ar...
Collagens are a primary component of the extracellular matrix and are functional ligands for the ... more Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1). Leukocyte associated immunoglobulin-like receptor-2 (LAIR-2) is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 and that LAIR-2 could release LAIR-1 mediated immune suppression. Analysis of public datasets shows high LAIR-2 expression being associated with a favorable outcome in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 reduces tumor growth and increases T cell expansion and effector function in humanized tumor models. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a powerful new stra...
A cryptic sexual reproductive cycle in Leishmania has been inferred through population genetic st... more A cryptic sexual reproductive cycle in Leishmania has been inferred through population genetic studies revealing the presence of hybrid genotypes in natural isolates, with attempts made to decipher sexual strategies by studying complex chromosomal inheritance patterns. A more informative approach is to study the products of controlled, laboratory-based experiments where known strains or species are crossed in the sand fly vector to generate hybrid progeny. These hybrids can be subsequently studied through high resolution sequencing technologies and software suites such as PAINT that disclose inheritance patterns including ploidies, parental chromosome contributions and recombinations, all of which can inform the sexual strategy. In this work, we discuss the computational methods in PAINT that can be used to interpret the sexual strategies adopted specifically by aneuploid organisms and summarize how PAINT has been applied to the analysis of experimental hybrids to reveal meiosis-lik...
809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by ... more 809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by deposition of misfolded light chains in various organ systems with an average survival of 1–2 years. AL is also the most common form of systemic amyloidosis with 1200–3200 newly diagnosed cases reported annually in the United States. Very little is known regarding specific genomic aberrations associated with AL-amyloidosis. Aside from the light chain selection, no phenotypic or genetic features have been identified that distinguish AL amyloidosis from other plasma cell dyscrasias. Understanding the genetics of AL and the molecular mechanisms involved in amyloid formation may lead to early diagnosis and the identification of novel drug targets and therapies. We therefore have attempted to study the genomic landscape of AL patients and MM for comparison. Genomic copy number and loss of heterozygosity (LOH) analyses were performed on DNA derived from tumor (CD138 sorted cells) and matched g...
Mosaic aneuploidy prevalent in organisms such as Leishmania and Fungi and in genomes of some neur... more Mosaic aneuploidy prevalent in organisms such as Leishmania and Fungi and in genomes of some neurological disorders and cancers manifest as non-integer haplotypes due to heterogeneity in somy across a population of cells. Thus, the tools designed for strictly haploid or diploid genomes are insufficient to study them. We addressed this issue by upgrading our population genetics tool POPSICLE for aneuploid genomes and studied the population structure of 50 strains of Leishmania to understand genetic diversity and the sexual strategies that predispose to that diversity. Leishmania showed enormous diversity but a dichotomic nature of extreme zygosities. To understand this dichotomy, we specifically studied two species, L. tropica that contained strains with both hetero and homozygosities and L. major that were mainly homozygous. The homozygosity in L. tropica was a consequence of extreme inbreeding while heterozygosity was due to recent hybridizations involving two different genotypes. ...
The advent of new sequencing technologies has provided access to genome-wide markers which may be... more The advent of new sequencing technologies has provided access to genome-wide markers which may be evaluated for their association with phenotypes. Recent studies have leveraged these technologies and sequenced hundreds and sometimes thousands of strains to improve the accuracy of genotype-phenotype predictions. Sequencing of thousands of strains is not practical for many research groups which argues for the formulation of new strategies to improve predictability using lower sample sizes and more cost-effective methods. We introduce here a novel computational algorithm called POPSICLE that leverages the local genetic variations to infer blocks of shared ancestries to construct complex evolutionary relationships. These evolutionary relationships are subsequently visualized using chromosome painting, as admixtures and as clades to acquire general as well as specific ancestral relationships within a population. In addition, POPSICLE evaluates the ancestral blocks for their association w...
Leishmania are parasitic protozoa that cause a wide spectrum of diseases collectively known as th... more Leishmania are parasitic protozoa that cause a wide spectrum of diseases collectively known as the leishmaniases. Sexual reproduction in Leishmania has been proposed as an important source of genetic diversity and has been formally demonstrated to occur inside the sand fly vector midgut.
Background: Pilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies... more Background: Pilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours. Methods: RNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization. Results: In this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, ...
Page 1. 3D Visualization of Relation Clusters from OWL Ontologies Jahangheer S. Shaik a , Cartik ... more Page 1. 3D Visualization of Relation Clusters from OWL Ontologies Jahangheer S. Shaik a , Cartik R. Kothari b , David J. Russomanno a , and M. Yeasin a aDepartment of Electrical and Computer Engineering Herff College ...
... function based on higher order statistics which consider the deviations from normality for ra... more ... function based on higher order statistics which consider the deviations from normality for ranking the marker genes from two sample microarray experiments. ...
Automated brain tumor segmentation and detection are immensely important in medical diagnostics b... more Automated brain tumor segmentation and detection are immensely important in medical diagnostics because it provides information associated to anatomical structures as well as potential abnormal tissue necessary to delineate appropriate surgical planning. In this work, we propose a ...
BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAI... more BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary...
BackgroundSiglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins... more BackgroundSiglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins involved in immune regulation. NC318 is a first-in-class humanized IgG1κ monoclonal antibody that blocks S15-mediated immune suppression.MethodsThe Phase 1 dose-escalation study was a classical 3+3 design in 15 tumor types (n=49). Phase 2 (n=47) was conducted at 400 mg q2w in 4 tumor types. Inclusion criteria included subjects with advanced/metastatic solid tumors refractory or resistant to currently available therapies with a TPS PD-L1 score <50%. The median number of previous therapies was ≥3, including checkpoint inhibitors (figure 1).ResultsNC318 was well tolerated with no novel immunologic or safety signals observed. Disease control rate amongst evaluable population (n=83) is 38% {1 CR, 3 PR and 28 SD (stable disease)}. Median duration of disease control is 24 weeks (16–48 weeks) amongst 20 subjects achieving a minimal 16-week duration of stable disease. Two NSCLC subjects (1CR ...
We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mamma... more We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mammalian target of rapamycin (mTOR; a conserved serine/threonine kinase critical for immune regulation and cellular growth) in human dendritic cells (DC) and we have proposed that this mTOR inhibition is associated with the DC dysfunction seen in filarial infections. Extracellular vesicles (EVs) contain many proteins and nucleic acids including microRNAs (miRNAs) that might affect a variety of intracellular pathways. Thus, EVs secreted from mf may elucidate the mechanism by which the parasite is able to modulate the host immune response during infection. EVs, purified from mf of Brugia malayi and confirmed by size through nanoparticle tracking analysis, were assessed by miRNA microarrays (accession number GSE157226) and shown to be enriched (>2-fold, p-value<0.05, FDR = 0.05) for miR100, miR71, miR34, and miR7. The microarray analysis compared mf-derived EVs and mf supernatant. After c...
Collagens are a primary component of the extracellular matrix and are functional ligands for the ... more Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich ar...
Collagens are a primary component of the extracellular matrix and are functional ligands for the ... more Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1). Leukocyte associated immunoglobulin-like receptor-2 (LAIR-2) is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 and that LAIR-2 could release LAIR-1 mediated immune suppression. Analysis of public datasets shows high LAIR-2 expression being associated with a favorable outcome in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 reduces tumor growth and increases T cell expansion and effector function in humanized tumor models. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a powerful new stra...
A cryptic sexual reproductive cycle in Leishmania has been inferred through population genetic st... more A cryptic sexual reproductive cycle in Leishmania has been inferred through population genetic studies revealing the presence of hybrid genotypes in natural isolates, with attempts made to decipher sexual strategies by studying complex chromosomal inheritance patterns. A more informative approach is to study the products of controlled, laboratory-based experiments where known strains or species are crossed in the sand fly vector to generate hybrid progeny. These hybrids can be subsequently studied through high resolution sequencing technologies and software suites such as PAINT that disclose inheritance patterns including ploidies, parental chromosome contributions and recombinations, all of which can inform the sexual strategy. In this work, we discuss the computational methods in PAINT that can be used to interpret the sexual strategies adopted specifically by aneuploid organisms and summarize how PAINT has been applied to the analysis of experimental hybrids to reveal meiosis-lik...
809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by ... more 809 Immunoglobulin light chain amlyloidosis (AL) is a rare plasma cell disorder characterized by deposition of misfolded light chains in various organ systems with an average survival of 1–2 years. AL is also the most common form of systemic amyloidosis with 1200–3200 newly diagnosed cases reported annually in the United States. Very little is known regarding specific genomic aberrations associated with AL-amyloidosis. Aside from the light chain selection, no phenotypic or genetic features have been identified that distinguish AL amyloidosis from other plasma cell dyscrasias. Understanding the genetics of AL and the molecular mechanisms involved in amyloid formation may lead to early diagnosis and the identification of novel drug targets and therapies. We therefore have attempted to study the genomic landscape of AL patients and MM for comparison. Genomic copy number and loss of heterozygosity (LOH) analyses were performed on DNA derived from tumor (CD138 sorted cells) and matched g...
Mosaic aneuploidy prevalent in organisms such as Leishmania and Fungi and in genomes of some neur... more Mosaic aneuploidy prevalent in organisms such as Leishmania and Fungi and in genomes of some neurological disorders and cancers manifest as non-integer haplotypes due to heterogeneity in somy across a population of cells. Thus, the tools designed for strictly haploid or diploid genomes are insufficient to study them. We addressed this issue by upgrading our population genetics tool POPSICLE for aneuploid genomes and studied the population structure of 50 strains of Leishmania to understand genetic diversity and the sexual strategies that predispose to that diversity. Leishmania showed enormous diversity but a dichotomic nature of extreme zygosities. To understand this dichotomy, we specifically studied two species, L. tropica that contained strains with both hetero and homozygosities and L. major that were mainly homozygous. The homozygosity in L. tropica was a consequence of extreme inbreeding while heterozygosity was due to recent hybridizations involving two different genotypes. ...
The advent of new sequencing technologies has provided access to genome-wide markers which may be... more The advent of new sequencing technologies has provided access to genome-wide markers which may be evaluated for their association with phenotypes. Recent studies have leveraged these technologies and sequenced hundreds and sometimes thousands of strains to improve the accuracy of genotype-phenotype predictions. Sequencing of thousands of strains is not practical for many research groups which argues for the formulation of new strategies to improve predictability using lower sample sizes and more cost-effective methods. We introduce here a novel computational algorithm called POPSICLE that leverages the local genetic variations to infer blocks of shared ancestries to construct complex evolutionary relationships. These evolutionary relationships are subsequently visualized using chromosome painting, as admixtures and as clades to acquire general as well as specific ancestral relationships within a population. In addition, POPSICLE evaluates the ancestral blocks for their association w...
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