Antibody Design and Humanization via In Silico Modeling.

Antibody humanization process converts any nonhuman antibody sequence into humanized antibodies. This can be achieved using different methods of antibody design and engineering. This chapter will primarily focus on antibody design using a homology model followed by framework shuffling of murine to human germline sequence for humanization.

Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse.

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn.

MUC1-C is a target in lenalidomide resistant multiple myeloma.

Lenalidomide (LEN) acts directly on multiple myeloma (MM) cells by inducing cereblon-mediated degradation of interferon regulatory factor 4, Ikaros (IKZF)1 and IKZF3, transcription factors that are essential for MM cell survival. The mucin 1 (MUC1) C-terminal transmembrane subunit (MUC1-C) oncoprotein is aberrantly expressed by MM cells and protects against reactive oxygen species (ROS)-mediated MM cell death. The present studies demonstrate that targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is more than additive with LEN in downregulating the WNT/β-catenin pathway, suppressing MYC, and inducing late apoptosis/necrosis.

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia.

Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression.

MUC1-C drives MYC in multiple myeloma.

Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples.

Structure guided homology model based design and engineering of mouse antibodies for humanization.

No universal strategy exists for humanizing mouse antibodies, and most approaches are based on primary sequence alignment and grafting. Although this strategy theoretically decreases the immunogenicity of mouse antibodies, it neither addresses conformational changes nor steric clashes that arise due to grafting of human germline frameworks to accommodate mouse CDR regions. To address these issues, we created and tested a structure-based biologic design approach using a de novo homology model to aid in the humanization of 17 unique mouse antibodies.

BRCA1 expression is epigenetically repressed in sporadic ovarian cancer cells by overexpression of C-terminal binding protein 2.

Introduction: Ovarian cancer is the leading cause of mortality from gynecological malignancy despite advancements in novel therapeutics. We have recently demonstrated that the transcriptional co-repressor C-terminal binding protein 2 (CtBP2) is overexpressed in epithelial ovarian carcinoma.

Materials And Methods: Reverse-transcribed cDNA from CtBP2 wild-type and knockdown ovarian cancer cell lines was hybridized to Affymetrix Gene 1.

Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss.

The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span.

CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Although recent studies have provided significant new insights into mechanisms by which CtBP regulates transcription, the biological function of CtBP remains incompletely understood. Here, we report that genetic inactivation of the Caenorhabditis elegans homolog, ctbp-1, results in life span extension, which is suppressed by reintroduction of the ctbp-1 genomic DNA encoding wild-type but not NAD(H)-binding defective CTBP-1 protein.

Michael adducts--source for biologically potent heterocycles.

A new class of pyrimidinetriones, thioxopyrimidinediones, pyrazolidinediones and isoxazolidinediones were prepared from (E)-1,4-diarylbut-2-ene-1,4-diones. All the new compounds synthesized were screened for antimicrobial activity.

Altered hippocampal gene expression 2 days after general anesthesia in rats.

We profiled changes in gene expression in the hippocampus 2 days after a 4 h general anesthetic with isoflurane and nitrous oxide. Eighteen month old Fisher 344 rats were anesthetized for 4 h with 1.2% isoflurane and 70% nitrous oxide (N=9) whereas control rats breathed 30% oxygen for 4 h (N=9).