Disparities in Colorectal Cancer Incidence among Asian and Pacific Islander Populations in Guam, Hawai'i, and the United States.

Colorectal cancer (CRC) ranks among the three most common cancers in Guam (GU), Hawai'i (HI), and the mainland United States (US). CRC prevalence in these areas is high among Filipinos, and indigenous CHamorus and Native Hawaiians; however, data on these populations are frequently aggregated in epidemiological studies, which can mask true CRC disparities. We examined CRC cumulative incidence rates (CIRs) among CHamorus in GU, Filipinos in GU, HI, and the US, and Native Hawaiians in HI and the US. CRC CIRs were calculated for two age groups (20-49 years; early onset, and 50-79 years; senior) and four time periods (2000-2004, 2005-2009, 2010-2014, and 2015-2019), stratified by ethnicity, sex, and location. Data analyzed included all invasive CRC cases reported to the Surveillance, Epidemiology, and End Results 9-Registry (n = 166,666), the Hawai'i Tumor Registry (n = 10,760), and the Guam Cancer Registry (n = 698) between 2000 and 2019. Senior CIRs were highest in HI and lowest in GU throughout all time periods, with a downward trend observed for senior CIRs in the US and HI, but not GU. This downward trend held true for all ethnic groups, except for CHamorus in GU, females in GU, and females of CHamoru ethnicity in GU. In contrast, early onset CIRs increased across all locations, sexes, and ethnic groups, except for Filipinos in HI and males of Filipino ethnicity in HI. Our findings provide crucial insights for future research and policy development aimed at reducing the burden of CRC among indigenous populations.

Functional significance of serine 13 in the active site of glutathione S-transferase F3 from Oryza sativa.

Plant glutathione S-transferase (GST, EC 2.5.1.18) is an enzyme that detoxifies various electrophilic compounds including herbicides and organic pollutants by catalyzing the formation of conjugates with reduced glutathione (GSH). Although the structure and function of the GST subunits in rice, an important food in Asia, are not well understood, they are crucial for herbicide development. To investigate the role of active site residues in rice Phi-class GSTF3 (OsGSTF3), evolutionarily conserved serine residues were replaced with alanine using site-directed mutagenesis to obtain the mutants S13A, S38A, S69A, and S169A. These four mutants were expressed in Escherichia coli and purified to electrophoretic homogeneity using immobilized GSH affinity chromatography. Mutation of Ser13 to Ala resulted in substantial reductions in specific activities and kcat/Km values for the GSH-[1-chloro-2,4-dinitrobenzene (CDNB)] conjugation reaction. In contrast, mutations of Ser38, Ser69, and Ser169 to Ala had little effect on the activities and kinetic parameters. Additionally, the mutation of Ser13 to Ala significantly affected the KmGSH and I50 values of S-hexylglutathione and S-(2,4-dinitrophenyl)glutathione, which compete with GSH and the product of GSH-CDNB conjugation, respectively. A pH-log (kcat/KmCDNB) plot was used to estimate the pKa value of GSH in the enzyme-GSH complex of the wild-type enzyme, which was approximately 6.9. However, the pKa value of GSH in the enzyme-GSH complex of the S13A mutant was approximately 8.7, which was about 1.8 pK units higher than that of the wild-type enzyme. OsGSTF3 was also crystallized for crystallographic study, and the structure analyses revealed that Ser13 is located in the active site and that its side chain is in close proximity to the thiol group of glutathione bound in the enzyme. Based on these substitution effects on kinetic parameters, the dependence of kinetic parameters on the pH and 3-dimensional structure, it was suggested that Ser13 in rice OsGSTF3 is the residue responsible for catalytic activity by lowering the pKa of GSH in the enzyme-GSH complex and enhancing the nucleophilicity of the GSH thiol in the active site.

MEK inhibition enhances efficacy of bacillus Calmette-Guérin on bladder cancer cells by reducing release of Toll-like receptor 2-activated antimicrobial peptides.

Bacillus Calmette-Guérin (BCG) is one of the standard treatment options for non-muscle-invasive bladder cancer. The details of the biological defense mechanisms against BCG remain unclear. Here, we investigated whether BCG-induced release of antimicrobial peptides (AMPs; e.g., human ß-defensin-2, -3, and cathelicidin) is involved with mitogen-activated protein kinase (MAPK) pathways, and investigated the enhanced anticancer effect of BCG through the down-regulation of Toll-like receptors (TLRs) and MAPK pathways in bladder cancer cells. BCG-infected bladder cancer cells produced AMPs as a defense mechanism against BCG, which were reduced by MEK inhibitors by blocking phosphorylation of extracellular signal-regulated kinase (ERK1/2 or MEK) and c-Jun. MEK inhibitors enhanced inhibition of bladder cancer cell growth by decreased binding of c-Jun, p65 and Pol II to the activated protein-1 promoter. Knockdown of TLR2 and TLR4 reduced ERK phosphorylation. Knockdown of TLR 2 decreased release of AMPs, which was similar to the efficacy of MEK inhibitor on BCG-infected cells. BCG-infected bladder cancer cells were more prone to induction of AMP release following TLR2 activation via ERK and c-Jun pathway mediators. In conclusion, our data suggest that the BCG-induced release of AMPs in bladder cancer cells is a promising molecular target for enhancing the immunotherapeutic efficacy of BCG in bladder cancer patients.