24 research outputs found
A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens
Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers
Social change and the family: Comparative perspectives from the west, China, and South Asia
This paper examines the influence of social and economic change on family structure and relationships: How do such economic and social transformations as industrialization, urbanization, demographic change, the expansion of education, and the long-term growth of income influence the family? We take a comparative and historical approach, reviewing the experiences of three major sociocultural regions: the West, China, and South Asia. Many of the changes that have occurred in family life have been remarkably similar in the three settingsāthe separation of the workplace from the home, increased training of children in nonfamilial institutions, the development of living arrangements outside the family household, increased access of children to financial and other productive resources, and increased participation by children in the selection of a mate. While the similarities of family change in diverse cultural settings are striking, specific aspects of change have varied across settings because of significant pre-existing differences in family structure, residential patterns of marriage, autonomy of children, and the role of marriage within kinship systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45661/1/11206_2005_Article_BF01124383.pd
Characterization and regulation of ADAMTS-16
The ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) family includes 19 secreted proteinases in man. ADAMTS16 is a recently cloned gene expressed at high levels in fetal lung and kidney and adult brain and ovary. The ADAMTS-16 protein currently has no known function. ADAMTS16 is also expressed in human cartilage and synovium where its expression is increased in tissues from osteoarthritis patients compared to normal tissues. In this study, we ascertained that the full length ADAMTS16 mRNA was expressed in chondrocytes and cloned the appropriate cDNA. Stable over-expression of ADAMTS16 in chondrosarcoma cells led to a decrease in cell proliferation and migration, though not adhesion, as well as a decrease in the expression of matrix metalloproteinase-13 (MMP13). The transcription start point of the human ADAMTS16 gene was experimentally identified as 138Ā bp upstream of the translation start ATG and the basal promoter was mapped out to āĀ 1802Ā bp. Overexpression of Egr1 induced ADAMTS16 promoter constructs of āĀ 157/+138 or longer whilst Sp1 induced all ADAMTS16 promoter constructs. Transforming growth factor beta (TGFĪ²) stimulated expression of endogenous ADAMTS16 gene expression in chondrocyte cell lines
Expression and function of matrix metalloproteinase (MMP)-28
Matrix metalloproteinase-28 (MMP-28, epilysin) is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues. In epithelial cells, over-expression of MMP-28 mediates irreversible epithelial to mesenchymal transition concomitant with loss of E-cadherin from the cell surface and an increase in active transforming growth factor beta. We recently reported the expression of MMP-28 in both cartilage and synovium where expression is increased in patients with osteoarthritis
Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase
Hedgehog signaling
is involved in embryonic development
and cancer
growth. Functional activity of secreted Hedgehog signaling proteins
is dependent on N-terminal palmitoylation, making
the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential
drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural
data, we designed and synthesized 37 new analogues which we profiled
alongside 13 previously reported analogues in enzymatic and cellular
assays. Our results show that a central amide linkage, a secondary
amine, and (R)-configuration at the 4-position of
the core are three key factors for inhibitory potency. Several potent
analogues with low- or sub-Ī¼M IC50 against purified
HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and
suppress the SHH signaling pathway. This work identifies IMP-1575
as the most potent cell-active chemical probe for HHAT function, alongside
an inactive control enantiomer, providing tool compounds for validation
of HHAT as a target in cellular assays
Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase
Hedgehog signaling
is involved in embryonic development
and cancer
growth. Functional activity of secreted Hedgehog signaling proteins
is dependent on N-terminal palmitoylation, making
the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential
drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural
data, we designed and synthesized 37 new analogues which we profiled
alongside 13 previously reported analogues in enzymatic and cellular
assays. Our results show that a central amide linkage, a secondary
amine, and (R)-configuration at the 4-position of
the core are three key factors for inhibitory potency. Several potent
analogues with low- or sub-Ī¼M IC50 against purified
HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and
suppress the SHH signaling pathway. This work identifies IMP-1575
as the most potent cell-active chemical probe for HHAT function, alongside
an inactive control enantiomer, providing tool compounds for validation
of HHAT as a target in cellular assays
Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase
Hedgehog signaling
is involved in embryonic development
and cancer
growth. Functional activity of secreted Hedgehog signaling proteins
is dependent on N-terminal palmitoylation, making
the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential
drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural
data, we designed and synthesized 37 new analogues which we profiled
alongside 13 previously reported analogues in enzymatic and cellular
assays. Our results show that a central amide linkage, a secondary
amine, and (R)-configuration at the 4-position of
the core are three key factors for inhibitory potency. Several potent
analogues with low- or sub-Ī¼M IC50 against purified
HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and
suppress the SHH signaling pathway. This work identifies IMP-1575
as the most potent cell-active chemical probe for HHAT function, alongside
an inactive control enantiomer, providing tool compounds for validation
of HHAT as a target in cellular assays