Here, we report that B-cell lymphoma 2 (Bcl-2) is a novel target molecule of aspirin in breast cancer cells. Aspirin influenced the formation of a complex by Bcl-2 and FKBP38 and induced the nuclear translocation of Bcl-2 and its phosphorylation. These events inhibited cancer cell proliferation and subsequently enhanced MCF-7 breast cancer cell apoptosis. Bcl-2 knockdown using small interfering RNA (siRNA) delayed apoptotic cell death, which correlated with increased proliferation following aspirin exposure. In contrast, Bcl-2 overexpression enhanced the onset of aspirin-induced apoptosis, which was also associated with a significant increase in Bcl-2 phosphorylation in the nucleus. Therefore, this study may provide novel insight into the molecular mechanism of aspirin, particularly its anticancer effects in Bcl-2- and estrogen receptor-positive breast cancer cells.
Active Transport, Cell Nucleus/drug effects ; *Apoptosis ; Aspirin/*pharmacology ; Cell Nucleus/*metabolism ; Humans ; MCF-7 Cells ; Phosphorylation ; Protein Binding ; Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism ; Tacrolimus Binding Proteins/metabolism

Background: and Objective: The use of potentially inappropriate medications (PIMs) increases the risk of negative health outcomes, including drug-related admissions. Tools for structured medication review have been developed to ensure optimal medication use and safety. Here, we aimed to evaluate medication use review (MUR) tools for community-dwelling older patients. Methods: We performed a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and MetaAnalyses Statement (PRISMA). We searched PubMed, Embase, and the Cochrane Library from 1991 to 2020, excluding tools that are specifically applied to hospitalized patients or nursing home residents. We identified the most common inappropriate medications, drug-disease interactions, drug-drug interactions and prescribing omissions presented among tools. Results: From among 9,788 identified reports screened, 60 met our inclusion criteria; finally, 27 were eligible for data analysis considering originality and up-to-dateness. Most tools presented explicit criteria (93%), and only one was specific to community-dwelling elderly. The most common PIM was tricyclic antidepressants. Use of diltiazem and verapamil in patients with heart failure and the combination of nonsteroidal anti-inflammatory analgesics and warfarin were the most frequent disease-specific PIM and druginteraction, respectively. Conclusions Although several medication review tools have been developed for older adults, specific guidelines for community-dwelling populations remain limited. Furthermore, the list of PIMs differed among available tools. In future, specific but integrating MUR tools need to be developed for clinical practice considering this population.

Background: and Objective: The use of potentially inappropriate medications (PIMs) increases the risk of negative health outcomes, including drug-related admissions. Tools for structured medication review have been developed to ensure optimal medication use and safety. Here, we aimed to evaluate medication use review (MUR) tools for community-dwelling older patients. Methods: We performed a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and MetaAnalyses Statement (PRISMA). We searched PubMed, Embase, and the Cochrane Library from 1991 to 2020, excluding tools that are specifically applied to hospitalized patients or nursing home residents. We identified the most common inappropriate medications, drug-disease interactions, drug-drug interactions and prescribing omissions presented among tools. Results: From among 9,788 identified reports screened, 60 met our inclusion criteria; finally, 27 were eligible for data analysis considering originality and up-to-dateness. Most tools presented explicit criteria (93%), and only one was specific to community-dwelling elderly. The most common PIM was tricyclic antidepressants. Use of diltiazem and verapamil in patients with heart failure and the combination of nonsteroidal anti-inflammatory analgesics and warfarin were the most frequent disease-specific PIM and druginteraction, respectively. Conclusions Although several medication review tools have been developed for older adults, specific guidelines for community-dwelling populations remain limited. Furthermore, the list of PIMs differed among available tools. In future, specific but integrating MUR tools need to be developed for clinical practice considering this population.

In order to develop an anti-human TNF-alpha mAb, mice were immunized with recombinant human TNF-alpha. A murine mAb, TSK114, which showed the highest binding activity for human TNF-alpha was selected and characterized. TSK114 specifically bound to human TNF-alpha without cross-reactivity with the homologous murine TNF-alpha and human TNF-beta TSK114 was found to be of IgG1 isotype with kappa light chain. The nucleotide sequences of the variable regions of TSK114 heavy and light chains were determined and analyzed for the usage of gene families for the variable (V), diversity (D), and joining (J) segments. Kinetic analysis of TSK114 binding to human TNF-alpha by surface plasmon resonance technique revealed a binding affinity (KD) of ~5.3 pM, which is about 1,000- and 100-fold higher than those of clinically relevant infliximab (Remicade) and adalimumab (Humira) mAbs, respectively. TSK114 neutralized human TNF-alpha-mediated cytotoxicity in proportion to the concentration, exhibiting about 4-fold greater efficiency than those of infliximab and adalimumab in WEHI 164 cells used as an in vitro model system. These results suggest that TSK114 has the potential to be developed into a therapeutic TNF-alpha-neutralizing antibody with picomolar affinity.
Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry/genetics/*immunology ; Antibody Affinity/*immunology ; Antibody Specificity ; Base Sequence ; Blotting, Western ; Cell Line ; Cytotoxicity, Immunologic ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoglobulin Variable Region/genetics ; Kinetics ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Neutralization Tests ; Sequence Analysis, Protein ; Tumor Necrosis Factor-alpha/*immunology