The expression of heat shock proteins 27 and 105 in squamous cell carcinoma of the tongue and relationship with clinicopathological index

Introduction: In oral cavity, the tongue is the most common site prone to development of squamous cell carcinoma (SCC). Considering malignant transformation as a cellular stress, the expression of heat shock proteins (HSPs) may be affected in this process. In this study we assessed the expression of HSP105 and HSP27 as two of the most interested stress proteins and investigated their relationship with grade and stage of the tongue SCC. Material and Methods: Fifty-six specimens including 31 early and 25 advanced tongue SCC were gathered. All specimens were graded histologically from I to III. Sixteen sections of normal oral mucosa were used as control group. The cellularity and intensity of HSP105 and HSP27 expression were studied immunohistochemically in both case and control groups. Results were expressed by histochemical score (HSCORE). Results: Significant differences were observed between expression of HSPs and stage of the disease. From early to advanced stage, the expression of HSP105 and HSP27 increased and decreased, respectively. There was no relationship between histological grade of lesion and HSCORE of HSP105 expression (P=0.5), although, HSP27 expression had reverse relationship with the SCC histological grade. Conclusion: HSP27 and HSP105 may be indicated for prognostic purposes in evaluation of tongue SCC. HSP 27 may be used for more accurate microscopic grading of tongue SCC. Increased expression of HSP105 in advanced stage may lead to using this protein for immunotherapy of tongue SCC. © Medicina Oral S. L

Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer

Although expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case–control study within the Nurses’ Health Studies (90 cases, 297 controls), we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results

MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy

Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance

Breast mass as the initial presentation of esophageal carcinoma: a case report

INTRODUCTION: Esophageal cancer is considered as a fatal malignancy. It mostly metastasizes to lung, liver, and bone while breast metastasis has been rarely reported. This is the fifth report of metastatic breast cancer from esophageal cancer, which differs from previous reported cases in terms of initial presentation with metastatic breast mass and no metastatic involvement of other organs. CASE PRESENTATION: We present a 35-year-old Caucasian woman who initially complained of a painful breast mass. Squamous pearls on cytologic evaluation suggested a metastatic lesion. Two months history of dysphagia was extracted through detailed interview with patient and further investigation revealed a stage IV esophageal squamous cell carcinoma. CONCLUSION: In this case, breast lesion as an unusual presentation of esophageal carcinoma emphasizes the great role of thorough medical history taking and cytologic study in evaluating an accidentally detected breast mass. The increasing reports of breast metastasis in patients with esophageal carcinoma necessitate the careful breast examination in visits after treatment of the primary tumor

Pathologic Evaluation of Appendectomy Specimens in Children: Is Routine Histopatholgic Examination Indicated?

Objective:Acute appendicitis is the most common cause of abdominal surgery in children. Similarity between signs and symptoms of appendicitis and other common pediatric illnesses, atypical manifestations of appendicitis in young children, and children's inability to give precise explanation for their symptoms contribute to considerable delay in proper diagnosis and increased rate of perforation. Current study reports the surgical and pathological findings of appendectomies in the largest Children's Hospital in Iran. It also evaluates whether common protocol for pathologic evaluation following appendectomy is beneficial. Methods: Pathologic reports of 947 appendectomies, performed with the presumptive diagnosis of acute appendicitis, were gathered. Correlation between surgical and pathologic findings was assessed. Demographic characteristics of patients between surgical and pathological subgroups were also compared. Findings: The mean age of participants was 6.9±3.5 years. Eighty seven (25.5%) children had abnormal pathological findings and normal surgical report. None of miscellaneous findings including appendicular carcinoid tumor 3 (0.3%), oxyuriasis 2 (0.2%), and mycobacterial infection 4 (0.5%) were recognizable during the surgery. Of all pathologically confirmed cases with perforated appendicitis, 9.7% were not detected during the surgery. Conclusion: In current study, acute appendicitis was the most common pathological diagnosis, however, high normal appendectomy rate along with noticeable proportion of surgically missed perforated appendicitis and unusual histopathologies strongly supported routine histological examination

Image-guided Coring for Large-scale Studies in Molecular Pathology

Sampling of formalin-fixed paraffin-embedded (FFPE) tissue blocks is a critical initial step in molecular pathology. Image-guided coring (IGC) is a new method for using digital pathology images to guide tissue block coring for molecular analyses. The goal of our study is to evaluate the use of IGC for both tissue-based and nucleic acid–based projects in molecular pathology. First, we used IGC to construct a tissue microarray (TMA); second, we used IGC for FFPE block sampling followed by RNA extraction; and third, we assessed the correlation between nuclear counts quantitated from the IGC images and RNA yields. We used IGC to construct a TMA containing 198 normal and breast cancer cores. Histopathologic analysis showed high accuracy for obtaining tumor and normal breast tissue. Next, we used IGC to obtain normal and tumor breast samples before RNA extraction. We selected a random subset of tumor and normal samples to perform computational image analysis to quantify nuclear density, and we built regression models to estimate RNA yields from nuclear count, age of the block, and core diameter. Number of nuclei and core diameter were the strongest predictors of RNA yields in both normal and tumor tissue. IGC is an effective method for sampling FFPE tissue blocks for TMA construction and nucleic acid extraction. We identify significant associations between quantitative nuclear counts obtained from IGC images and RNA yields, suggesting that the integration of computational image analysis with IGC may be an effective approach for tumor sampling in large-scale molecular studies

Breast cancer risk factors in relation to estrogen receptor, progesterone receptor, insulin-like growth factor-1 receptor, and Ki67 expression in normal breast tissue

Studies have suggested that hormone receptor and Ki67 expression in normal breast tissue are associated with subsequent breast cancer risk. We examined the associations of breast cancer risk factors with estrogen receptor (ER), progesterone receptor (PR), insulin-like growth factor-1 receptor (IGF-1R), and Ki67 expression in normal breast tissue. This analysis included 388 women with benign breast disease (ages 17–67 years) in the Nurses’ Health Studies. Immunohistochemical staining was performed on tissue microarrays constructed from benign biopsies containing normal breast epithelium and scored as the percentage of epithelial cells that were positively stained. Ordinal logistic regression (outcomes in tertiles), adjusting for age and potential confounders, was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with risk factors. Alcohol consumption was positively associated (≥2.5 vs.<0.4 drink/wk: OR = 2.69, 95% CI = 1.26–5.75, p-trend = 0.008) and breastfeeding was inversely associated (≥6 months vs. never: OR = 0.11, 95% CI = 0.04–0.35, p-trend = 0.0003) with ER expression. Height (≥66 vs.<64 inches: OR = 2.50, 95% CI = 1.34–4.67, p-trend = 0.005) and BMI at age 18 (≥22 vs.<20 kg/m2: OR = 2.33, 95% CI = 1.18–4.62, p-trend = 0.01) were positively associated with PR expression. Body size at age 5–10 years was inversely associated with Ki67 (Level ≥ 2.5 vs. 1: OR = 0.55, 95% CI = 0.30–1.01, p-trend = 0.03). Premenopausal BMI (≥25 vs.<20 kg/m2) was positively associated with cytoplasmic IGF-1R (OR = 5.06, 95% CI = 1.17–21.8, p-trend = 0.04). Our data suggest that anthropometrics, breastfeeding, and alcohol intake may influence the molecular characteristics of normal breast tissue, elucidating the mechanisms by which these risk factors operate. However, larger studies are required to confirm these results

Extensive rewiring of epithelial-stromal co-expression networks in breast cancer

Background: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. Results: We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Conclusions: Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0675-4) contains supplementary material, which is available to authorized users

Extensive rewiring of epithelial-stromal co-expression networks in breast cancer

Abstract Background Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. Results We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Conclusions Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer

Code: Analysis in R

This code used computed features as input and generate analysis figures as output that described the framework performance