Membranous expression of Her3 is associated with a decreased survival in head and neck squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Head and neck squamous cell carcinoma (HNSCC) still remains a lethal malignancy benefiting from the identification of the new target for early detection and/or development of new therapeutic regimens based on a better understanding of the biological mechanism for treatment. The overexpression of Her2 and Her3 receptors have been identified in various solid tumors, but its prognostic relevance in HNSCC remains controversial.</p> <p>Methods</p> <p>Three hundred eighty-seven primary HNSCCs, 20 matching metasis and 17 recurrent HNSCCs were arrayed into tissue microarrays. The relationships between Her2 and Her3 protein expression and clinicopathological parameters/survival of HNSCC patients were analyzed with immunohistochemistry.</p> <p>Results</p> <p>Her3 is detected as either a cytoplasmic or a membranous dominant expression pattern whereas Her2 expression showed uniform membranous form. In primary tumor tissues, high membranous Her2 expression level was found in 104 (26.9%) cases while positive membranous and cytoplasmic Her3 expression was observed in 34 (8.8%) and 300 (77.5%) samples, respectively. Membranous Her2 expression was significantly associated with histological grade (<it>P </it>= 0.021), as grade 2 tumors showed the highest positive expression. Membranous Her3 over-expression was significantly prevalent in metastatic tissues compared to primary tumors (<it>P </it>= 0.003). Survival analysis indicates that membranous Her3 expression is significantly associated with worse overall survival (<it>P </it>= 0.027) and is an independent prognostic factor in multivariate analysis (hazard ratio, 1.51; 95% confidence interval, 1.01-2.23; <it>P </it>= 0.040).</p> <p>Conclusions</p> <p>These results suggest that membranous Her3 expression is strongly associated with poor prognosis of patients with HNSCC and is a potential candidate molecule for targeted therapy.</p

Cell-Cycle Protein Expression in a Population-Based Study of Ovarian and Endometrial Cancers

Aberrant expression of cyclin-dependent kinase (CDK) inhibitors is implicated in the carcinogenesis of many cancers, including ovarian and endometrial cancers. We examined associations between CDK inhibitor expression, cancer risk factors, tumor characteristics, and survival outcomes among ovarian and endometrial cancer patients enrolled in a population-based case control study. Expression (negative vs. positive) of three CDK inhibitors (p16, p21, p27) and ki67 was examined with immunohistochemical staining of tissue microarrays. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarkers, risk factors, and tumor characteristics. Survival outcomes were available for ovarian cancer patients and examined using Kaplan-Meier plots and Cox proportional hazards regression. Among ovarian cancer patients (n=175), positive p21 expression was associated with endometrioid tumors (OR=12.22, 95% CI=1.45-102.78) and higher overall survival (log-rank p=0.002). In Cox models adjusted for stage, grade, and histology, the association between p21 expression and overall survival was borderline significant (hazard ratio=0.65, 95% CI=0.42-1.05). Among endometrial cancer patients (n=289), positive p21 expression was inversely associated with age (OR ≥ 65 years of age=0.25, 95% CI=0.07-0.84) and current smoking status (OR: 0.33, 95% CI 0.15, 0.72) compared to negative expression. Our study showed heterogeneity in expression of cell-cycle proteins associated with risk factors and tumor characteristics of gynecologic cancers. Future studies to assess these markers of etiological classification and behavior may be warranted

Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited <it>ex vivo </it>studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets.</p> <p>Results</p> <p>As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels.</p> <p>Conclusions</p> <p>These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type.</p

Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in α-cells or an insulin promoter in β-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated α-cells or β-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases

Tumor Biology and Immune Infiltration Define Primary Liver Cancer Subsets Linked to Overall Survival After Immunotherapy

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors

On the relevance of diapycnal mixing for the stability of frontal meanders

This work examines the possible importance of shear-induced diapycnal mixing in controlling the evolution and stability of meanders in oceanic frontal jets. We first review the conditions necessary for vortex stability and investigate how these may be modified in the presence of diapycnal mixing. The procedure used is rather crude but provides a measure of the relative importance of diapycnal mixing. It consists in constructing a simplified equation for the radial velocity that retains the density tendency and examining under what circumstances this velocity may grow in time. Next, we use a simple two-dimensional isopycnic model to examine the intensity of diapycnal mixing in meanders. In the model the along-front velocity is in geostrophic balance and the ageostrophic contributions are an oscillating deformation field and diapycnal mass exchange. The horizontal deformation field increases the slope of the isopycnals in temporal scales typical of Gulf Stream meanders, causing a reduction of the gradient Richardson number, Ri. The diapycnal flux is calculated as the divergence of the density Reynolds flux, which is parameterized in terms of Ri. The results of the model show that diapycnal mixing increases during the frontogenetical stages, reaching density tendency values of the order of 10-4 kg m-3s-1 and convergence/divergence values of the order of 10-3 s-1. It turns out that diapycnal mixing in meanders may be intense enough to control the separation and slope of the isopycnals and to condition the possibility of barotropic instabilityThis work was supported by the Spanish government trhough projects FRENTES (CICYT grant AMB95-0731) and TALUD (CICYT MAR96-1893) and the European Union through project CANIGO (MAST-CT96-0060)Peer reviewe

Factors Influencing the Degradation of Archival Formalin-Fixed Paraffin-Embedded Tissue Sections

The loss of antigenicity in archival formalin-fixed paraffin-embedded (FFPE) tissue sections negatively affects both diagnostic histopathology and advanced molecular studies. The mechanisms underlying antigenicity loss in FFPE tissues remain unclear. The authors hypothesize that water is a crucial contributor to protein degradation and decrement of immunoreactivity in FFPE tissues. To test their hypothesis, they examined fixation time, processing time, and humidity of storage environment on protein integrity and antigenicity by immunohistochemistry, Western blotting, and protein extraction. This study revealed that inadequate tissue processing, resulting in retention of endogenous water in tissue sections, results in antigen degradation. Exposure to high humidity during storage results in significant protein degradation and reduced immunoreactivity, and the effects of storage humidity are temperature dependent. Slides stored under vacuum with desiccant do not protect against the effects of residual water from inadequate tissue processing. These results support that the presence of water, both endogenously and exogenously, plays a central role in antigenicity loss. Optimal tissue processing is essential. The parameters of optimal storage of unstained slides remain to be defined, as they are directly affected by preanalytic variables. Nevertheless, minimization of exposure to water is required for antigen preservation in FFPE tissue sections. This article contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials