Effects of maternal HFD during lactation on the weight, caloric intake, fat mass/body weight ratio and blood pressure of the female offspring.

<p>(A) Body weight; (B) calorific intake; (C) fat mass/body ratio; and systolic blood pressure at 12 (D) and 24 (E) weeks of age. OCC: offspring from CD-fed dams suckled by CD-fed dams; OHC: offspring from HFD-fed dams suckled by CD-fed dams; OCH: offspring from CD-fed dams suckled by HFD-fed dams; OHH: offspring from HFD-fed dams suckled by HFD-fed dams. The results are shown as the mean ± SEM (<i>n</i> = 6 litter per group). *<i>P</i><0.01 compared with the OCC mice and ^#<i>P</i><0.01 compared with the OHC mice.</p

Maternal characteristics and neonatal weights.

<p>CD; control diet, HFD; high fat diet, mean ± SEM,</p><p>*p<0.01 vs. CD-fed pregnant mice.</p

Effects of maternal HFD during lactation on glucose intolerance and insulin resistance in the offspring.

<p>GTT (A; male, C; female), ITT (B; male, D; female) at 24 weeks and HOMA-IR at 12 (E) and 24 (F) weeks of age. OCC: offspring from CD-fed dams suckled by CD-fed dams; OHC: offspring from HFD-fed dams suckled by CD-fed dams; OCH: offspring from CD-fed dams suckled by HFD-fed dams; OHH: offspring from HFD-fed dams suckled by HFD-fed dams. The results are shown as the mean ± SEM (<i>n</i> = 6 litter per group). *<i>P</i><0.01, ** <i>P</i><0.05 compared with the OCC mice and ^#<i>P</i><0.01 compared with the OHC mice, ^$<i>P</i><0.01 between male and female offspring in OHH group.</p

Effects of maternal HFD during lactation on modifications to H3K9 and H4K20 in the promoter regions of the <i>leptin</i> and <i>adiponectin</i> genes in the adipose tissue of the offspring.

<p>OCC: offspring from CD-fed dams suckled by CD-fed dams; OHC: offspring from HFD-fed dams suckled by CD-fed dams; OCH: offspring from CD-fed dams suckled by HFD-fed dams; OHH: offspring from HFD-fed dams suckled by HFD-fed dams. The results are shown as the mean ± SEM (<i>n</i> = 6 litter per group). *<i>P</i><0.01 compared with the OCC mice.</p

Effects of maternal HFD during lactation on neonatal leptin concentrations (A; male, B; female) and adipose leptin mRNA expression (C) in the offspring.

<p>OCC: offspring from CD-fed dams suckled by CD-fed dams; OHC: offspring from HFD-fed dams suckled by CD-fed dams; OCH: offspring from CD-fed dams suckled by HFD-fed dams; OHH: offspring from HFD-fed dams suckled by HFD-fed dams. The results are shown as the mean ± SEM (<i>n</i> = 6 litter per group). *<i>P</i><0.01, **<i>P</i><0.05 compared with the OCC mice and ^#<i>P</i><0.01 compared with the OHC mice, ^$<i>P</i><0.01 between male and female offspring in OHH group.</p

Effects of maternal HFD during lactation on leptin and adiponectin gene expression in white adipose tissue of the offspring.

<p>The white mesenteric adipose tissues were removed from male and female offspring at 12 (A, B) and 24 weeks (C, D) of age. OCC: offspring from CD-fed dams suckled by CD-fed dams; OHC: offspring from HFD-fed dams suckled by CD-fed dams; OCH: offspring from CD-fed dams suckled by HFD-fed dams; OHH: offspring from HFD-fed dams suckled by HFD-fed dams. The results are shown as the mean ± SEM (<i>n</i> = 6 litter per group). *<i>P</i><0.01 compared with the OCC mice and ^#<i>P</i><0.01 compared with the OHC mice.</p

Clinical impact of endometrial cancer stratified by genetic mutational profiles, <i>POLE</i> mutation, and microsatellite instability

<div><p>Background</p><p>The molecular characterization of endometrial cancer (EC) can facilitate identification of various tumor subtypes. Although EC patients with <i>POLE</i> mutations reproducibly demonstrate better prognosis, the outcome of patients with microsatellite instability (MSI) remains controversial. This study attempted to interrogate whether genetic stratification of EC can identify distinct subsets with prognostic significance.</p><p>Materials and methods</p><p>A cohort of 138 EC patients who underwent surgical resection with curative intent was enrolled. Sanger sequencing was used to evaluate mutations in the <i>POLE</i> and <i>KRAS</i> genes. MSI analysis was performed using four mononucleotide repeat markers and methylation status of the <i>MLH1</i> promoter was measured by a fluorescent bisulfite polymerase chain reaction (PCR). Protein expression for mismatch repair (MMR) proteins was evaluated by immunohistochemistry (IHC).</p><p>Results</p><p>Extensive hypermethylation of the <i>MLH1</i> promoter was observed in 69.6% ECs with MLH1 deficiency and 3.5% with MMR proficiency, but in none of the ECs with loss of other MMR genes (<i>P</i> < .0001). MSI-positive and <i>POLE</i> mutations were found in 29.0% and 8.7% EC patients, respectively. Our MSI analysis showed a sensitivity of 92.7% for EC patients with MMR deficiency, and a specificity of 97.9% for EC patients with MMR proficiency. In univariate and multivariate analyses, <i>POLE</i> mutations and <i>MSI</i> status was significantly associated with progression-free survival (<i>P</i> = 0.0129 and 0.0064, respectively) but not with endometrial cancer-specific survival.</p><p>Conclusions</p><p>This study provides significant evidence that analyses of proofreading <i>POLE</i> mutations and MSI status based on mononucleotide repeat markers are potentially useful biomarkers to identify EC patients with better prognosis.</p></div

Molecular and clinic-pathological features of 138 ECs.

<p>(A) Molecular and clinic–pathological landscape of 138 ECs. Genetic analysis, focusing on frequent hotspot mutations in the POLE gene, and MSI status result in the identification of three molecular subgroups: (1) <i>POLE</i>-mutant, (2) MSI and (3) non-MSI. (B) Progression-free survival and endometrial cancer-specific survival of 138 EC patients stratified by genetic profiles. <i>P</i> values were calculated by the log-rank test.</p

Association between clinic-pathological features and EC patients stratified by genetic mutational profiles.

<p>Association between clinic-pathological features and EC patients stratified by genetic mutational profiles.</p

Detection of MSI and distribution of number of MSIs in 138 EC patients.

<p>(A) Example of MSI and non-MSI cases analyzed by four mononucleotide repeat markers (BAT26, NR21, NR27, and CAT25). (B) Association between MSI, <i>POLE</i> mutation, <i>MLH-1</i> promoter methylation and MMR protein expression. The number of mononucleotide repeat markers showing MSI are shown by color.</p