Mutant pattern of p53 predicts local recurrence and poor survival rate in gastric cancer

Background. TP53 mutation is a poor prognostic factor for various organ malignancies such as colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, lung adenocarcinoma and clinical pathologists previously evaluated it using immunohistochemistry for p53. The clinicopathologic significance of p53 expression in gastric cancer remains unclear due to inconsistent classification methods. Methods. Immunohistochemistry for p53 protein was performed using tissue microarray blocks generated from 725 cases of gastric cancer, and p53 expression was divided into three staining patterns using a semiquantitative ternary classifier: heterogeneous (wild type), overexpression, and absence (mutant pattern). Results. Mutant pattern of p53 expression had a male predominance, greater frequency in cardia/fundus, higher pT stage, frequent lymph node metastasis, local recurrence clinically, and more differentiated histology microscopically compared with wild type. In survival analysis, p53 mutant pattern was associated with worse recurrent-free survival and overall survival rates, and significance was maintained in subgroup analysis of early versus advanced gastric cancers. In Cox regression analysis, p53 mutant pattern was a significant predicting factor for local recurrence (relative risk (RR=4.882, p<0.001)) and overall survival (RR=2.040, p=0.007). The p53 mutant pattern remained significant for local recurrence (RR=2.934, p=0.018) in multivariate analyses. Conclusions. Mutant p53 pattern on immunohistochemistry was a significant prognostic factor for local recurrence and poor overall survival in gastric cancer

High BMI1 Expression with Low CD8+ and CD4+ T Cell Activity Could Promote Breast Cancer Cell Survival: A Machine Learning Approach

BMI1 is known to play a key role in the regulation of stem cell self-renewal in both endogenous and cancer stem cells. High BMI1 expression has been associated with poor prognosis in a variety of human tumors. The aim of this study was to reveal the correlations of BMI1 with survival rates, genetic alterations, and immune activities, and to validate the results using machine learning. We investigated the survival rates according to BMI1 expression in 389 and 789 breast cancer patients from Kangbuk Samsung Medical Center (KBSMC) and The Cancer Genome Atlas, respectively. We performed gene set enrichment analysis (GSEA) with pathway-based network analysis, investigated the immune response, and performed in vitro drug screening assays. The survival prediction model was evaluated through a gradient boosting machine (GBM) approach incorporating BMI1. High BMI1 expression was correlated with poor survival in patients with breast cancer. In GSEA and in in silico flow cytometry, high BMI1 expression was associated with factors indicating a weak immune response, such as decreased CD8+ T cell and CD4+ T cell counts. In pathway-based network analysis, BMI1 was directly linked to transcriptional regulation and indirectly linked to inflammatory response pathways, etc. The GBM model incorporating BMI1 showed improved prognostic performance compared with the model without BMI1. We identified telomerase inhibitor IX, a drug with potent activity against breast cancer cell lines with high BMI1 expression. We suggest that high BMI1 expression could be a therapeutic target in breast cancer. These results could contribute to the design of future experimental research and drug development programs for breast cancer

The Effect of Intravenous Dexamethasone and Dexmedetomidine on Analgesia Duration of Supraclavicular Brachial Plexus Block: A Randomized, Four-Arm, Triple-Blinded, Placebo-Controlled Trial

Intravenous dexamethasone and dexmedetomidine, in conjunction with peripheral nerve blockade, have each been reported to prolong the duration of analgesia. This study tested whether combined use further prolongs analgesia duration after supraclavicular brachial plexus block (BPB) in patients undergoing orthopedic upper extremity surgery. One hundred twenty patients were randomized 1:1:1:1 to Control (saline bolus and midazolam infusion [0.05 mg/kg loading, 20 &micro;g/kg/h thereafter]); DMED (saline bolus and dexmedetomidine infusion [1 &mu;g/kg loading, 0.4 &mu;g/kg/h thereafter]); DEXA (dexamethasone [10 mg] bolus and midazolam infusion); and DMED-DEXA (dexmedetomidine infusion and dexamethasone bolus) groups. The primary outcome was the duration of postoperative analgesia, defined as the time from the end of the BPB to the first dose of analgesia via a patient-controlled device. Median (interquartile range) times to first dose of analgesia in the Control, DMED, DEXA, and DMED-DEXA groups were 8.1 (6.2&ndash;11.6), 9.0 (8.1&ndash;11.3), 10.7 (8.1&ndash;20.5), and 13.2 (11.5&ndash;19.1) hours, respectively (p &lt; 0.001). Pairwise comparisons showed significant prolongation of analgesia in the DEXA included groups compared with the non-DEXA included groups (DEXA vs. control, p = 0.045; DEXA vs. DMED, p = 0.045; DMED-DEXA vs. control, p &lt; 0.001; DMED-DEXA vs. DMED, p &lt; 0.001). A mixed effect model showed that dexamethasone was the only significant factor for the prolongation of analgesia (p &lt; 0.001). Intravenous dexamethasone prolonged the analgesia duration of supraclavicular BPB after orthopedic upper extremity surgery. The concurrent use of mild to moderate sedation dose of intravenous dexmedetomidine in addition to intravenous dexamethasone showed no additional benefit to the prolongation of analgesia

Nuclear Expression Loss of SSBP2 Is Associated with Poor Prognostic Factors in Colorectal Adenocarcinoma

Single-stranded DNA binding protein 2 (SSBP2) is involved in DNA damage response and may induce growth arrest in cancer cells, having a potent tumor suppressor role. SSBP2 is ubiquitously expressed and the loss of its expression has been reported in various tumor types. However, the correlation between SSBP2 expression and colorectal cancer (CRC) prognosis remains unclear. SSBP2 nuclear expression was evaluated immunohistochemically in 48 normal colonic mucosae, 47 adenomas, 391 primary adenocarcinomas, and 131 metastatic carcinoma tissue samples. The clinicopathological factors, overall survival (OS), and recurrence-free survival were evaluated, and associations with the clinicopathological parameters were analyzed in 391 colorectal adenocarcinoma patients. A diffuse nuclear SSBP2 expression was detected in all normal colonic mucosa and adenoma samples. SSBP2 expression loss was observed in 131 (34.3%) primary adenocarcinoma and 100 (76.3%) metastatic carcinoma samples. SSBP2 expression was significantly associated with poor prognostic factors, such as vascular invasion (p = 0.005), high pT category (p = 0.045), and shorter OS (p = 0.038), using univariate survival analysis. Nuclear SSBP2 expression loss was significantly observed in colorectal carcinoma and metastatic carcinoma tissues, being associated with poor prognostic factors. SSBP2 acts as a tumor suppressor and may be used as a CRC prognostic biomarker

MiRAR—miRNA Activity Reporter for Living Cells

microRNA (miRNA) activity and regulation are of increasing interest as new therapeutic targets. Traditional approaches to assess miRNA levels in cells rely on RNA sequencing or quantitative PCR. While useful, these approaches are based on RNA extraction and cannot be applied in real-time to observe miRNA activity with single-cell resolution. We developed a green fluorescence protein (GFP)-based reporter system that allows for a direct, real-time readout of changes in miRNA activity in live cells. The miRNA activity reporter (MiRAR) consists of GFP fused to a 3&prime; untranslated region containing specific miRNA binding sites, resulting in miRNA activity-dependent GFP expression. Using qPCR, we verified the inverse relationship of GFP fluorescence and miRNA levels. We demonstrated that this novel optogenetic reporter system quantifies cellular levels of the tumor suppressor miRNA let-7 in real-time in single Human embryonic kidney 293 (HEK 293) cells. Our data shows that the MiRAR can be applied to detect changes in miRNA levels upon disruption of miRNA degradation pathways. We further show that the reporter could be adapted to monitor another disease-relevant miRNA, miR-122. With trivial modifications, this approach could be applied across the miRNome for quantification of many specific miRNA in cell cultures, tissues, or transgenic animal models

Clinicopathologic Significance of Extranodal Tumor Extension in Colorectal Adenocarcinoma with Regional Lymph Node Metastasis

Background. This study investigated the clinicopathologic significance of extranodal tumor extension in colorectal adenocarcinoma with lymph node metastasis. Method. Included were 419 patients who underwent curative resection for primary colorectal adenocarcinoma. Results. Extranodal tumor extension was observed more frequently in tumors with ulceroinfiltrative gross type (p=0.026), higher histologic grade (p=0.012), high grade tumor budding (p=0.003), vascular invasion (p<0.001), perineural invasion (p=0.015), tumor deposit (p<0.001), high ratio of metastatic/total lymph nodes (p<0.001), and high pN stage (p<0.001). Overall survival was significantly different between an extranodal tumor extension (−) group and an extranodal tumor extension (+) group for both N1 (p=0.022) and N2 homogeneous staging (p=0.007). Both overall (p=0.002) and disease-free survival (p=0.001) were significantly different between the two groups in an N1a homogeneous group and overall survival was significantly different (p=0.016) in an N2b homogeneous group. Conclusion. Our study demonstrated that extranodal tumor extension was a useful prognostic factor for colorectal adenocarcinoma with lymph node metastasis, especially in homogeneous pN staging groups

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma

Background Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. Methods Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. Results Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05). Conclusions Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone

Immunohistochemical Expression of Dual-Specificity Protein Phosphatase 4 in Patients with Colorectal Adenocarcinoma

The role of dual-specificity protein phosphatase 4 (DUSP4) appears to vary with the type of malignant tumors and is still controversial. The purpose of our study was to clarify the exact role of DUSP4 expression in colorectal adenocarcinoma. We constructed tissue microarrays and investigated DUSP4 expression by immunohistochemistry. DUSP4 was more frequently expressed in adenocarcinomas and lymph node/distant metastases compared to that in normal colorectal tissues and tubular adenomas (P<0.001). Mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (P<0.001). DUSP4 expression was significantly correlated with older age (P=0.017), male gender (P=0.036), larger tumor size (P=0.014), nonmucinous tumor type (P=0.023), and higher T stage (P=0.040). Kaplan-Meier survival curves revealed a significant effect of DUSP4 expression on both overall survival and disease-free survival in AJCC stage I (P=0.008 and P=0.003, resp., log-rank test) and male gender (P=0.017 and P=0.049, resp., log-rank test). DUSP4 protein is frequently upregulated in colorectal adenocarcinoma and may play an important role in carcinogenesis and cancer progression and may be a marker of adverse prognosis