MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer.

We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (

Diphenhydramine against cisplatin nephrotoxicity

Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes nephrotoxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced nephrotoxicity is currently available. This study identified that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced nephrotoxicity based on the results of the analysis of medical big data. We evaluated the actual efficacy of diphenhydramine via in vitro and in vivo experiments in a mouse model. Diphenhydramine inhibited cisplatin-induced cell death in renal proximal tubular cells. Mice administered cisplatin developed kidney injury with renal dysfunction (plasma creatinine: 0.43 ± 0.04 mg/dl vs 0.15 ± 0.01 mg/dl, p<0.01) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and mitogen-activated protein kinases activation; however, most of these symptoms were suppressed by treatment with diphenhydramine. Further, the renal concentration of cisplatin was attenuated in diphenhydramine-treated mice (platinum content: 70.0 ± 3.3 µg/g dry kidney weight vs 53.4 ± 3.6 µg/g dry kidney weight, p<0.05). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. Moreover, a retrospective clinical study of 1467 cancer patients treated with cisplatin showed that patients who had used diphenhydramine exhibited less acute kidney injury than patients who had not used diphenhydramine (6.1 % vs 22.4 %, p<0.05). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced nephrotoxicity

MUC4 and MUC1 Expression in Adenocarcinoma of the Stomach Correlates with Vessel Invasion and Lymph Node Metastasis: An Immunohistochemical Study of Early Gastric Cancer

<div><p>We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (<em>P</em><0.0001; <em>P</em> = 0.0021; <em>P</em><0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, <em>P</em> = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, <em>P</em> = 0.001) and lymph node metastasis (r = 0.296, <em>P</em> = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, <em>P</em> = 0.032) and venous invasion (r = 0.377, <em>P</em> = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.</p> </div

The difference in antibody specificity between anti-human MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8.

<p>A: MUC4 mRNA was detected in the two gastric cancer cell lines, SNU-16 and NCI-N87. PANC1 and CAPAN1 cells were used as a negative and positive control, respectively. B: Cell lysates of SNU-16 and NCI-N87 were immunoblotted and detected by the indicated antibodies, respectively. A-tubulin served as a loading control. C: Formalin-fixed SNU-16 and NCI-N87 cells were processed for immunocytochemistry using the MAbs, 8G7 and 1G8, respectively. Original magnification ×400.</p

Semiquantitative evaluation of mucin expression in gastric carcinoma for each histological type (negative, none of the carcinoma cells stained; faint, >0% to <5% of carcinoma cells stained; 1+, ≥5% to <25%; 2+, ≥25% to <50%; 3+, ≥50% to <75%; and 4+: ≥75% stained.

<p>The detailed number and percentage of positively stained neoplastic cells using the scoring system were summarized in Table S1. MUC4/8G7, MUC4/1G8 and MUC1/DF3 expressions were were significantly higher in the well differentiated types (pap+tub1) than in the poorly differentiated type (por1+por2) (<i>P</i><0.0001, <i>P</i> = 0.0021 and <i>P</i><0.0001, respectively) (arrows). In tub1, expression rates of MUC4/8G7 and MUC4/1G8 were significantly higher than that of MUC1/DF3 (<i>P</i> = 0.0106 and <i>P</i> = 0.039, respectively) (*1). In por2, the expression rate of MUC4/1G8 was significantly higher than that of MUC4/8G7 (<i>P</i> = 0.0286) or that of MUC1/DF3 (<i>P</i> = 0.0005) (*2). In sig, the expression rate of MUC4/1G8 was significantly higher than that of MUC4/8G7 (<i>P</i> = 0.0158) or that of MUC1/DF3 (sig, <i>P</i> = 0.0019) (*3). In the other histolgical types (pap, tub2, muc and por1), there was no significant difference in the expression rates among MUC4/8G7, MUC4/1G8 and MUC1/DF3.</p

Clinicopathological studies using anti-MUC4 monoclonal antibodies, 8G7 and 1G8.

<p>Clinicopathological studies using anti-MUC4 monoclonal antibodies, 8G7 and 1G8.</p