Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies

Background: Hypoxia is a negative prognostic factor and this study investigated the relationship between hypoxia, hypoxia inducible factor 1 (HIF-1) and AKT signaling in head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC). Results/methodology: pAKT was induced by hypoxia (0.5% O2) in a part of HNSCC (3/4) and squamous (2/3) and adenocarcinoma (1/3) NSCLS lines. AKT-inhibitor MK-2206 reduced hypoxic HIF-1 signaling in most HNSCC cell lines. This reduction did not correlate with hypoxic induction of pAKT or with sensitivity to MK-2206 under hypoxia. Patient biopsies revealed a hypoxia-induced expression pattern of pAKT in HNSCC (n = 16), which was not observed in squamous cell (n = 34) or adenocarcinoma (n = 41) NSCLC. Conclusion: The interaction between hypoxia, HIF-1 and AKT signaling varies between tumor types and histologies, which could significantly affect response to targeted therapies.</p

Expression of CD3-ζ on T-cells in primary cervical carcinoma and in metastasis-positive and -negative pelvic lymph nodes

Lymphocytic infiltrate is often present in cervical cancer lesions, possibly reflecting an ongoing, but ineffective, immune response to the tumour. Recently, evidence has accumulated for systemically impaired T-cell functions in cancer patients, associated with decreased expression of signal-transducing zeta (ζ) chain dimer molecules on circulating T-cells and NK-cells. Here, we report on the intralesional down-regulation of ζ chain expression on T-cells in cervical carcinoma. Paraffin-embedded or snap-frozen sections from 24 different cervical cancer specimens were studied. Paraffin-embedded tumour-positive (n = 7) and tumour-negative (n = 15) pelvic lymph nodes were also included in the study. Immunostaining was performed on consecutive sections with antibodies specific for CD3-ɛ or the CD3-associated ζ chain dimer. Antigen retrieval by sodium citrate/microwave treatment was essential for ζ staining of paraffin sections. The amount of ζ positive cells was quantitated and related to the number of CD3-ɛ+ cells in corresponding tumour areas. Of the 24 cervical cancer specimens studied, ζ chain dimer expression was reduced in seven cases and strongly reduced in the other 17 samples. In tonsil control sections, CD3-ɛ and CD3-ζ were always co-expressed in almost equal numbers. Also, both tumour-negative and -positive lymph nodes showed ζ chain expression which equalled that of CD3-ɛ expression. These data indicate that a decreased expression of signal-transducing ζ molecules on tumour-infiltrating T-cells is frequent in cervical cancer. The apparently unimpaired ζ chain expression within draining lymph nodes suggests that local tumour-derived factors at the primary site are instrumental in ζ chain down-regulation. © 1999 Cancer Research Campaig

Necrosis related HIF-1α expression predicts prognosis in patients with endometrioid endometrial carcinoma

<p>Abstract</p> <p>Background</p> <p>Hypoxia inducible factor 1α (HIF-1α) plays an essential role in the adaptive response of cells to hypoxia and is associated with aggressive tumour behaviour. We have shown p27^kip1, which is generally reduced in endometrial cancer, to be re-expressed in hypoxic regions. This possibly contributes to survival of cancer cells. The aim of this study was to evaluate the prognostic value of HIF-1α and p27^kipexpression in patients with endometrioid endometrial cancer.</p> <p>Methods</p> <p>Expression levels of HIF-1α, CAIX, Glut-1, and p27^kip1were analyzed by immunohistochemistry. Percentage of positive cells, staining pattern (perinecrotic, diffuse, or mixed) and presence of necrosis were noted.</p> <p>Results</p> <p>Necrosis was correlated with shortened disease free survival (DFS) (p <it>= </it>0.008) and overall survival (OS) (p <it>= </it>0.045). For DFS, perinecrotic HIF-1α expression was also prognostic (p <it>= </it>0.044). Moreover, high p27^kip1expression was an additional prognostic factor for these patients with perinecrotic HIF-1α expression. In multivariate Cox regression, perinecrotic HIF-expression emerged as an independent prognostic factor. Perinecrotic HIF-1α expression was significantly associated with CAIX and Glut-1 expression, pointing towards functional HIF-1.</p> <p>Conclusions</p> <p>In patients with endometrioid endometrial cancer, necrosis and necrosis-related expression of HIF-1α are important prognostic factors. More aggressive adjuvant treatment might be necessary to improve the outcome of patients with these characteristics.</p

Are anthropogenic factors affecting nesting habitat of sea turtles? The case of Kanzul beach, Riviera Maya-Tulum (Mexico)

Marine coast modification and human pressure affects many species, including sea turtles. In order to study nine anthropogenic impacts that might affect nesting selection of females, incubation and hatching survival of loggerhead (Caretta caretta) and green turtle (Chelonia mydas), building structures were identified along a 5.2 km beach in Kanzul (Mexico). A high number of hotels and houses (88; 818 rooms), with an average density of 16.6 buildings per kilometer were found. These buildings form a barrier which prevents reaching the beach from inland, resulting in habitat fragmentation. Main pressures were detected during nesting selection (14.19% of turtle nesting attempts interrupted), and low impact were found during incubation (0.77%) and hatching (4.7%). There were three impacts defined as high: beach furniture that blocks out the movement of hatchlings or females, direct pressure by tourists, and artificial beachfront lighting that can potentially mislead hatchlings or females. High impacted areas showed lowest values in nesting selection and hatching success. Based on our results, we suggest management strategies to need to be implemented to reduce human pressure and to avoid nesting habitat loss of loggerhead and green turtle in Kanzul, Mexico

Nuclear Scaffold Attachment Sites within ENCODE Regions Associate with Actively Transcribed Genes

The human genome must be packaged and organized in a functional manner for the regulation of DNA replication and transcription. The nuclear scaffold/matrix, consisting of structural and functional nuclear proteins, remains after extraction of nuclei and anchors loops of DNA. In the search for cis-elements functioning as chromatin domain boundaries, we identified 453 nuclear scaffold attachment sites purified by lithium-3,5-iodosalicylate extraction of HeLa nuclei across 30 Mb of the human genome studied by the ENCODE pilot project. The scaffold attachment sites mapped predominately near expressed genes and localized near transcription start sites and the ends of genes but not to boundary elements. In addition, these regions were enriched for RNA polymerase II and transcription factor binding sites and were located in early replicating regions of the genome. We believe these sites correspond to genome-interactions mediated by transcription factors and transcriptional machinery immobilized on a nuclear substructure

Lymphatic mapping and sentinel node biopsy in gynecological cancers: a critical review of the literature

Although it does not have a long history of sentinel node evaluation (SLN) in female genital system cancers, there is a growing number of promising study results, despite the presence of some aspects that need to be considered and developed. It has been most commonly used in vulvar and uterine cervivcal cancer in gynecological oncology. According to these studies, almost all of which are prospective, particularly in cases where Technetium-labeled nanocolloid is used, sentinel node detection rate sensitivity and specificity has been reported to be 100%, except for a few cases. In the studies on cervical cancer, sentinel node detection rates have been reported around 80–86%, a little lower than those in vulva cancer, and negative predictive value has been reported about 99%. It is relatively new in endometrial cancer, where its detection rate varies between 50 and 80%. Studies about vulvar melanoma and vaginal cancers are generally case reports. Although it has not been supported with multicenter randomized and controlled studies including larger case series, study results reported by various centers around the world are harmonious and mutually supportive particularly in vulva cancer, and cervix cancer. Even though it does not seem possible to replace the traditional approaches in these two cancers, it is still a serious alternative for the future. We believe that it is important to increase and support the studies that will strengthen the weaknesses of the method, among which there are detection of micrometastases and increasing detection rates, and render it usable in routine clinical practice

Reforming healthcare in the Netherlands: practical population health management and the Plot model: A questionnaire survey and focus group study to assess the willingness and readiness of six regions in the Netherlands

Objective: As in many other countries, the Netherlands is facing challenges in the provision of healthcare to its population. To ensure the population remains in good health in coming decades, an integrative approach to the many factors that influence health and health outcomes is needed. Population health management is gaining interest as a strategic framework for systems change in healthcare organisations. Based on population health management, the Dutch HealthKIC has developed the ‘Plot model’, which takes a regional perspective. The aim of this study was to detail the extent to which six prospective regions in the Netherlands were ready and willing to implement population health management using the Plot model, guided by the Five Lenses Model. Methods: Using an exploratory focus group reporting study, we involved stakeholders from six regions in the Netherlands. Thematic analysis followed the five predesigned dimensions of a validated cooperation model. Results: The study uncovered the potential for realisation of model aims, as assessed by an expert team, regarding shared ambition, mutual gains, relationship dynamics, organisational dynamics and process management. The exploratory questionnaire suggested that organisational dynamics is the least integrated topic in all areas, followed by process management, a finding confirmed in focus groups. Conclusion: The building themes of the Five Lenses Model all represent preconditions for the success of integration in the prospective regions. The present study showed that while some themes were reasonably represented in prospective regions, no region was satisfactory for all themes