A conditional RNA Pol II mono-promoter drives HIV-inducible, CRISPR-mediated cyclin T1 suppression and HIV inhibition.

Gene editing using clustered regularly interspaced short palindromic repeats (CRISPR) targeted to HIV proviral DNA has shown excision of HIV from infected cells. However, CRISPR-based HIV excision is vulnerable to viral escape. Targeting cellular co-factors provides an attractive yet risky alternative to render viral escape irrelevant.

Guardant360 Circulating Tumor DNA Assay Is Concordant with FoundationOne Next-Generation Sequencing in Detecting Actionable Driver Mutations in Anti-EGFR Naive Metastatic Colorectal Cancer.

Background: Direct comparisons between Guardant360 (G360) circulating tumor DNA (ctDNA) and FoundationOne (F1) tumor biopsy genomic profiling in metastatic colorectal cancer (mCRC) are limited. We aim to assess the concordance across overlapping genes tested in both F1 and G360 in patients with mCRC.

Materials And Methods: We retrospectively analyzed 75 patients with mCRC who underwent G360 and F1 testing.

Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation.

Background: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL.

LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells.

Methylglyoxal (MGO) is a highly reactive dicarbonyl compound known to induce cellular injury and cytoxicity, including apoptosis in vascular cells. Vascular endothelial cell apoptosis has been implicated in the pathophysiology and progression of atherosclerosis. We investigated whether the advanced glycation end-product inhibitor LR-90 could prevent MGO-induced apoptosis in human umbilical vascular endothelial cells (HUVECs).

Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma.

Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown.

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis.

Two novel dichlorophenyl urea compounds, SR4 and SR9, were synthesized in our laboratory and evaluated for anti-cancer activities. Specifically, we investigated the antiproliferative properties of these new compounds on promyelocytic HL-60 leukemia cells by analyzing their effects on cell differentiation, cell cycle progression and apoptosis. SR4 and SR9 were both cytotoxic to HL-60 cells in a dose-and time-dependent manner, with IC(50) of 1.

Unveiling the methylation status of CpG dinucleotides in the substituted segment of the human p53 knock-in (Hupki) mouse genome.

Methylated cytosines within CpG dinucleotides (mCpGs) along the DNA-binding domain of the TP53 tumor suppressor gene (exons ~5-8) are the single most significant mutational target in human cancers. The human p53 knock-in (Hupki) mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human wild-type TP53 DNA sequences spanning exons 4-9 in both copies of the mouse p53 gene. To date, however, the methylation status of cytosines within CpGs in the substituted segment of the Hupki mouse genome has not been determined.

CD154 expression is associated with neutralizing antibody titer levels postinfluenza vaccination in stem cell transplant patients and healthy adults.

We undertook a prospective longitudinal study to examine humoral and cellular immune responses to influenza vaccination in hematopoietic cell transplant (HCT) patients and healthy adults. Healthy volunteers and HCT patients had blood samples taken prior to influenza vaccination and 30, 90, and 180 days postvaccination. Serum from pre- and postvaccination time points were tested for influenza A IgG and IgM by ELISA as well as tested for neutralizing antibody (NAb) titers via hemagglutination inhibition assay.

Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing.

Tumor-driving mutations in the TP53 gene occur frequently in human cancers. These inactivating mutations arise predominantly from a single-point mutation in the DNA-binding domain of this tumor suppressor gene (i.e.

In vitro recapitulating of TP53 mutagenesis in hepatocellular carcinoma associated with dietary aflatoxin B1 exposure.

Background & Aims: Dietary exposure to aflatoxin B(1) (AFB(1)), in addition to other known factors, increases risk for human hepatocellular carcinoma (HCC). HCCs from AFB(1)-exposed individuals frequently have distinct TP53 mutations, such as G to T transversions in the second guanine of codon 249 (AGG to AGT), and a characteristic mutational spectrum predominated by G:C to T:A mutations.

Methods: To recapitulate the distinctive features of TP53 mutations in AFB(1)-associated HCC, we investigated AFB(1)-induced DNA adduction in relation to mutagenesis in transgenic mouse fibroblasts exposed to AFB(1) in vitro.

DNA-lesion mapping in mammalian cells.

Formation of DNA damage is a crucial event in carcinogenesis. Irreparable DNA lesions have the potential to cause mispairing during DNA replication, thereby giving rise to mutations. Critically important mutations in cancer-related genes, i.

Second-hand smoke and human lung cancer.

Since the early 1980s, there has been growing concern about potential health consequences of exposure to second-hand smoke (SHS). Despite SHS being established as a risk factor for lung cancer development, the estimated risk has remained small yet somehow debatable. Human exposure to SHS is complicated because of temporal variabilities in source, composition, and concentration of SHS.

Sunlight ultraviolet irradiation and BRAF V600 mutagenesis in human melanoma.

The incidence of melanoma, the most lethal form of skin cancer, continues to increase in the Western world. In addition to genetic alterations in high- and low-susceptibility genes identified for melanoma, somatic mutations in BRAF gene occur frequently in human melanoma and are distinctively linked to sun exposure. Of significance is a single hotspot codon, i.

Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells.

Despite the predominance of ultraviolet A (UVA) relative to UVB in terrestrial sunlight, solar mutagenesis in humans and rodents is characterized by mutations specific for UVB. We have investigated the kinetics of repair of UVA- and UVB-induced DNA lesions in relation to mutagenicity in transgenic mouse fibroblasts irradiated with equilethal doses of UVA and UVB in comparison to simulated-sunlight UV (SSL). We have also analyzed mutagenesis-derived carcinogenesis in sunlight-associated human skin cancers by compiling the published data on mutation types found in crucial genes in nonmelanoma and melanoma skin cancers.

Lack of mutagenicity of acrolein-induced DNA adducts in mouse and human cells.

Acrolein is an endogenous metabolite and a ubiquitous environmental pollutant. Recently, it has been suggested that acrolein is a major etiologic agent for tobacco smoking-related lung cancer. Despite the known DNA-damaging effects of acrolein, its mutagenicity to mammalian cells remains uncertain.

Riboflavin activated by ultraviolet A1 irradiation induces oxidative DNA damage-mediated mutations inhibited by vitamin C.

An increasingly popular theory ascribes UVA (>320-400 nm) carcinogenicity to the ability of this wavelength to trigger intracellular photosensitization reactions, thereby giving rise to promutagenic oxidative DNA damage. We have tested this theory both at the genomic and nucleotide resolution level in mouse embryonic fibroblasts carrying the lambda phage cII transgene. We have also tested the hypothesis that inclusion of a cellular photosensitizer (riboflavin) can intensify UVA-induced DNA damage and mutagenesis, whereas addition of an antioxidant (vitamin C) can counteract the induced effects.

A review of mechanisms of acrylamide carcinogenicity.

The fact that acrylamide, a proven rodent carcinogen, is present in significant quantities (up to several mg/kg of foodstuff) in a wide range of commonly consumed human foods is alarming. Attempts to determine a possible involvement of dietary acrylamide in human cancers have not been conclusive, however. To resolve the carcinogenicity of acrylamide to humans, the as yet unknown mechanism of action of acrylamide needs to be unraveled.

Nuclear receptors in stem cell biology.

Batteries of transcription factors have been proposed to control stem cell self-renewal and lineage progression by eliciting cascades of gene expression. Nuclear receptors provide an ideal model to study the transcriptional regulation of gene expression because they can activate as well as repress gene expression through ligand binding and recruitment of transcriptional coactivators or corepressors. Recent progress in defining specific roles of some nuclear receptors and their coregulators in stem cell self-renewal and differentiation provides a first glimpse of the regulatory events involved and is the beginning of a very promising area of research.

Fibrates inhibit aldose reductase activity in the forward and reverse reactions.

Fibrates such as bezafibrate, gemfibrozil, clofibric acid, ciprofibrate and fenofibrate, are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha), and are used as therapeutic agents in the treatment of hyperlipidemia. Synthesis and accumulation of sorbitol in cells due to aldose reductase (AR) activity is implicated in secondary diabetic complications. In pursuit of finding a lead compound identification to design an effective AR inhibitor employing fragment-based design-like approach, we found that this class of compounds and their nearest neighbors could inhibit AR.

Investigating DNA adduct-targeted mutagenicity of tamoxifen: preferential formation of tamoxifen-DNA adducts in the human p53 gene in SV40 immortalized hepatocytes but not endometrial carcinoma cells.

Tamoxifen is a widely used drug for chemotherapy and chemoprevention of breast cancer worldwide. Tamoxifen therapy is, however, associated with an increased incidence of endometrial cancer. The carcinogenicity of tamoxifen is ascribed to its genotoxic and estrogen agonist effects.

Biological consequences of 8-methoxypsoralen-photoinduced lesions: sequence-specificity of mutations and preponderance of T to C and T to a mutations.

Psoriatic patients undergoing psoralen plus ultraviolet radiation (PUVA) therapy are susceptible for squamous cell carcinoma and melanoma of the skin. To investigate the etiological relevance of PUVA for these diseases, we performed mutation spectrometry on the cII transgene in mouse embryonic fibroblasts treated with a single or split PUVA dose (PUVA-I or PUVA-II, respectively). Both treatments were significantly mutagenic as they increased the cII mutant frequency up to 3.

Retention of conformational flexibility in HIV-1 Rev-RNA complexes.

Sequence-specific recognition between HIV-1 Rev and viral RNA mediates the nuclear export of the viral mRNA and thus is important for the viral life cycle. HIV Rev binds to its viral RNA target with high affinity and specificity and also binds to an in vitro selected RNA aptamer that has a significantly different sequence from the viral RNA target with a 6-fold higher affinity than its natural target. The high-resolution structures of HIV Rev Arg-rich motif (ARM) in complexes with the wild-type RNA and the RNA aptamer reveal that, despite the significantly different RNA sequences, the two complexes share similar structural features and the protein-RNA interactions are mediated mostly by the Arg side chains in Rev ARM.

Similar mutagenicity of photoactivated porphyrins and ultraviolet A radiation in mouse embryonic fibroblasts: involvement of oxidative DNA lesions in mutagenesis.

Ultraviolet A (UVA) radiation is implicated in the etiology of human skin cancer. However, the underlying mechanism of carcinogenicity for UVA is not fully delineated. A mutagenic role for UVA has been suggested, which involves activation of endogenous photosensitizers generating oxidative DNA damage.