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Background: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. Methods: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. Results: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for ‘copy-number’ status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined ‘high-risk’ group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. Conclusions: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables ( P ≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts ( P =0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted.

Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.

Immunohistochemical (IHC) testing for HER2/neu is becoming the standard of care for guiding adjuvant treatment of gastric carcinoma with trastuzumab. To assess interlaboratory variation in IHC staining and interpretation across multiple laboratories. A tissue microarray consisting of 45 cores from 28 gastric cancers was distributed to 37 laboratories for HER2/neu assessment. The IHC results were compared against expert scores at an academic institution and correlated with in situ hybridization results from the originating specimen. Interlaboratory agreement was calculated using Cohen κ statistic. The survey demonstrated several variations in IHC methods, including the primary antibodies in use. There was excellent agreement among laboratories in HER2/neu(+) (IHC 3(+)) cases (κ = 0.80 ± 0.01) and very good agreement among laboratories in HER2/neu(-) (IHC 0 or 1(+)) cases (κ = 0.58 ± 0.01). Less agreement was observed among laboratories when scoring equivocal (IHC 2(+)) cases (κ = 0.22 ± 0.01). Sensitivity and specificity of HER2/neu IHC were 99% and 100%, respectively, when measured against expert review and consensus score as a reference standard. There is substantial interlaboratory agreement in the interpretation of HER2/neu IHC despite variability in protocols. Although HER2/neu IHC is a highly sensitive and specific test, primary antibody selection may significantly affect IHC results. Furthermore, gastric tumors require a unique scoring system and expertise in interpretation. Intratumoral heterogeneity has a significant effect on HER2/neu scoring by IHC. Ongoing quality assurance exercises among laboratories will help ensure optimized HER2/neu testing.

The teleost warm temperature acclimation related 65 kDa protein (Wap65) is a plasma glycoprotein with the potential roles in heat adaptation, heme recycling, immune response and copper metabolism. It is most homologous to the mammalian hemopexin, which is the plasma transporter of heme. A full-length cDNA clone of the Wap65 gene, 1,534 bp in size, was isolated from the fish ayu (Plecoglossus altivelis). Its deduced amino acid sequence of 439 residues had 60.4-65.4% and 38.3-47.3% identical to fish Wap65-2-type and Wap65-1-type sequences, respectively. In phylogenetic analysis, aWap65 grouped tightly with those fish Wap65-2-type sequences. In healthy control fish, the highest mRNA signal for aWap65 was from the liver, moderately high in brain and gill, and but weaker in spleen, kidney, muscle, heart and intestine. In Listonella anguillarum-infected fish, aWap65 transcripts were significantly increased in liver, while no obvious changes in other tissues at 12 hpi. However, aWap65 transcripts were significantly increased in various tissues at 24 hpi when hemolysis developing, suggesting that aWap65 might be involved in the immune response of ayu.

Background Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test. Methods DNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data. Results Gastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have ≥3 driver mutations detected (11% vs. 2%, p = 0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma. Conclusions Panel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.

Adsorption behavior of the iron impregnated, weakly basic resin D301 (Fe-D301) for removal of 2-naphthalenesulfonic acid (2-NSA) from aqueous solution was studied by using a fixed-bed column. The effects of process variables such as bed height, flow rate, and coexisting ions were investigated. The results indicated that the breakpoint and exhaustion point increased with increasing bed height and decreased with increasing 2-NSA flowrate. Experimental data showed a strong fit to the Bed Depth Service Time model. The coexisting ions in the 2-NSA solution had a clear effect on the breakthrough volume. The high extent of recovery of 2-NSA with good reproducibility provided an effective method for the separation of 2-NSA by the adsorbent Fe-D301.

Aim： Free fatty acid-induced lipotoxicity plays a crucial role in the progression of nonalcoholic fatty liver disease （NAFLD）. In the present study we investigated the effects of a high-fat diet and free fatty acids on the autophagic process in hepatocytes in vivo and in vitro and the underlying mechanisms. Methods： LC3-II expression, a hallmark of autophagic flux, was detected in liver specimens from patients with non-alcoholic steatohepatitis （NASH） as well as in the livers of C57BL/6 mice fed a high-fat diet （HFD） up to 16 weeks. LC3-II expression was also analyzed in human SMMC-7721 and HepG2 hepatoma cells exposed to palmitic acid （PA）, a saturated fatty acid. PA-induced apoptosis was detected by Annexin V staining and specific cleavage of PARP in the presence and absence of different agents. Results： LC3-II expression was markedly increased in human NASH and in liver tissues of HFD-fed mice. Treatment of SMMC-7721 cells with PA increased LC3-II expression in time- and dose-dependent manners, whereas the unsaturated fatty acid oleic acid had no effect. Inhibition of autophagy with 3MA sensitized SMMC-7721 cells to PA-induced apoptosis, whereas activation of autophagy by rapamycin attenuated PA-induced PARP cleavage. The autophagy-associated proteins Beclin1 and Atg5 were essential for PA-induced autophagy in SMMC-7721 cells. Moreover, pretreatment with SP600125, an inhibitor of JNK, effectively abrogated PA-mediated autophagy and apoptosis. Specific knockdown of JNK2, but not JNK1, in SMMC-7721 cells significantly suppressed PA-induced autophagy and enhanced its pro-apoptotic activity; whereas specific knockdown of JNK1 had the converse effect. Similar results were obtained when HepG2 cells were tested. Conclusion： JNK1 promotes PA-induced lipoapoptosis, whereas JNK2 activates pro-survival autophagy and inhibits PA lipotoxicity. Our results suggest that modulation of autophagy may have therapeutic benefits in the treatment of lipid-related metabolic diseases.