Increasing chromosome 1 copy number parallels histological progression in breast carcinogenesis

Chromosome 1 copy number in the benign breast lesions hyperplasia and atypical duct hyperplasia (ADH) was investigated using fluorescence in situ hybridization on paraffin sections. Progression of chromosome 1 changes occurring in parallel with histological progression from normal through hyperplasia and ADH to ductal carcinoma in situ (DCIS) and invasive carcinoma was also assessed, both overall and within individual patients. The mean signal number for normal cells was 1.14, while that for hyperplasia was 1.56 and ADH was 1.5, while values for DCIS of 1.95 and invasive duct carcinoma of 1.79, were higher (P< 0.001). Six of the seven cases also showed a significant trend towards an increasing proportion of cells with greater than 2 signals per nucleus occurring with histological progression (P< 0.001). These results support the concept that benign proliferative breast disease is a biological precursor of in-situ and invasive ductal carcinoma, the early histological changes possibly indicating a field effect with further genetic changes required for the development of a malignant phenotype. © 2000 Cancer Research Campaig

In situ quantification of HER2–protein tyrosine kinase 6 (PTK6) protein–protein complexes in paraffin sections from breast cancer tissues

BACKGROUND: Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2. METHOD AND RESULTS: In this study, we used the proximity ligation assay (PLA) technique on formalin-fixed paraffin sections from eighty invasive breast carcinoma tissue specimens to locate PTK6-HER2 protein-protein complexes. Proximity ligation assay signals from protein complexes were assessed quantitatively, and expression levels showed a statistically significant association with tumour size (P=0.015) and course of the cancer disease (P=0.012). CONCLUSION: Protein tyrosine kinase 6 forms protein complexes with HER2 in primary breast cancer tissues, which can be visualised by use of the PLA technique. Human epidermal growth factor receptor 2-PTK6 complexes are of prognostic relevance

In Your Face: Our Experience With Proactive Chat Reference

Reference at our academic library, following an interval of protracted decline, recently went through a renaissance period following the evolution of our chat reference service. This change was brought about by a desire to more actively capture today’s digitally native students. Academic libraries have previously sought to increase usage of their reference services by a variety of methods, including physically roving through the library or offering satellite locations. In an attempt to mirror that approach in an online environment, we implemented a proactive chat widget that allowed us to “e-rove” to students throughout our library’s website and catalog. Our previous chat implementation was passive in nature, requiring students to seek out help, often prior to searching. This meant that students would need to seek out the chat button in order to use the service. The redesign of chat reference included a proactive widget that popped-up, getting the users attention and encouraging them to chat with a librarian. The transition to a proactive approach resulted in a staggering increase in the number of chats that occured. This dramatic increase resulted in both positive and negative effects for students and librarians alike. The philosophy of reference at our academic library calls upon librarians to treat each reference interaction as an instructional opportunity. A hallmark of outstanding customer service is the anticipation of patron needs, and actively offering assistance. The increase in chat volume often called into question our ability to provide adequate patron instruction and quality service. Our presentation will discuss the successes and challenges brought on by this change from a passive chat service to a proactive one. We will discuss topics such as: the quality (READ Scale) of chat reference questions that occured during this evolution, how the volume increase impacted librarian responsibilities and how the library reacted to each of these events. In an age where many academic libraries are seeing a decline in reference services, chat reference brings this service to the 21st century at lightning speed. By fine tuning their own chat references services, libraries can make research even more relevant for today’s student

A paleomagnetic study of Permian and Triassic rocks from the Toulon-Cuers Basin, SE France: Evidence for intra-Pangea block rotations in the Permian

The identification of a massive shear zone separating Gondwana from Laurasia during late Palaeozoic times is one of the prerequisites for the controversial Pangea B to A transition. Here we present new paleomagnetic data from Permian and Triassic sediments and volcanic rocks from the Toulon-Cuers basin, SE France, likely to be situated within this intra-Pangea shear zone. A total of 150 samples from 14 sites were collected in the field; 108 samples yielded reliable paleomagnetic component directions based on stepwise thermal demagnetization up to maximum temperatures of 690C. After removal of an initial viscous magnetic component from room temperature up to 200C, a second component of reverse polarity, oriented to the south-and-up, was identified in almost all samples of Permian age. The Triassic samples behave similarly, with the notable difference that here, two polarities of magnetization are present. Positive field tests suggest the primary character of this characteristic magnetization. The latitudes of the resulting Early to Mid Permian paleopoles agree well with the corresponding segment of the apparent polar wander path (APWP) for Europe, whereas the longitudes are strung out along a small circle segment, indicating relative rotations between the sampled regions and stable Europe. The Triassic poles, instead, plot close to the Triassic segment of the European APWP and provide an upper time limit for the observed rotations. These results suggest a wrench faulting event associated with intra-Pangea crustal instability and transformation during the Permian

The Predictive Value of PITX2 DNA Methylation for High-Risk Breast Cancer Therapy: Current Guidelines, Medical Needs, and Challenges

High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and the HER2 receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of the PITX2 (paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application of PITX2 as a predictive biomarker to personalize breast cancer management

Observation of the geology and geomorphology of the 1999 Marsokhod test site

The Marsokhod rover returned data from six stations that were used to decipher the geomorphology and geology of a region not previously visited by members of the geomorphology field team. Satellite images and simulated descent images provided information about the regional setting. The landing zone was on an alluvial apron flanking a mountain block to the west and a playa surface to the east. Rover color images, infrared spectra analysis of the mountains, and the apron surface provided insight into the rock composition of the nearby mountains. From the return data the geomorphology team interpreted the region to consist of compressionally deformed, ancient marine sediments and igneous rocks exposed by more recent extensional tectonics. Unconsolidated alluvial materials blanket the lower flanks of the mountains. Bn ancient shoreline cut into alluvial material marks a high stand of water during a past, wetter climate period. Playa sediments floor a present-day, seasonally, dry lake. Observations made by the rover using panoramic and close-up (hand specimens-scale) image data and color scene data confirmed the presence of boulders, cobbles, and fines of various provinces. Rover traverses to sites identified as geologically distinct, such as fan, channel, shoreline, and playa, provided useful clues to the geologic interpretations. Analysis of local rocks was given concert only through comparison with distant geologic features. These results demonstrated the importance of a multifaceted approach to site interpretation through comparison of interpretations derived by differing geologic techniques

PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (P⩽0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan–Meier analysis. In multivariate analysis for metastases-free survival of >240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status

Observations of the geology and geomorphology of the 1999 Marsokhod test site

The Marsokhod rover returned data from six stations that were used to decipher the geomorphology and geology of a region not previously visited by members of the geomorphology field team. Satellite images and simulated descent images provided information about the regional setting. The landing zone was on an alluvial apron flanking a mountain block to the west and playa surface to the east. Rover color images, infrared spectra analysis of the mountains, and the apron surface provided insight into the rock composition of the nearby mountains. From the return data the geomorphology team interpreted the region to consist of compressionally deformed, ancient marine sediments and igneous rocks exposed by more recent extensional tectonics. Unconsolidated alluvial materials blanket the lower flanks of the mountains. An ancient shoreline cut into alluvial material marks a high stand of water during a past, wetter climate period. Playa sediments floor a present-day, seasonally, dry lake. Observations made by the rover using panoramic and close-up (hand specimens—scale) image data and color scene data confirmed the presence of boulders, cobbles, and fines of various provinces. Rover traverses to sites identified as geologically distinct, such as a fan, channel, shoreline, and playa, provided useful clues to the geologic interpretations. Analysis of local rocks was given context only through comparison with distant geologic features. These results demonstrated the importance of a multifaceted approach to site interpretation through comparison of interpretations derived by differing geologic techniques

Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients

The cytoplasmic tyrosine kinase PTK6 (BRK) shows elevated expression in approximately two-thirds of primary breast tumours, and is implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. Using immunohistochemistry, we performed a retrospective study on 426 archival breast cancer samples from patients with long-term follow-up and compared the protein expression levels of PTK6, the HER receptors, Sam68 (a substrate of PTK6), and signalling proteins including MAP kinase (MAPK), phosphorylated MAPK (P-MAPK), and PTEN. We show that PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of ⩾240 months was directly associated with the protein expression level of PTK6 (P⩽0.001), but was also inversely associated with nodal status (P⩽0.001) and tumour size (P⩽0.01). PTK6 expression in tumour tissue significantly correlated (P⩽0.05) with the expression of PTEN, MAPK, P-MAPK, and Sam68. To investigate whether these correlations may be due to molecular interactions between PTK6 and these proteins, we used protein extracts from the T47D cell line for immunoprecipitation and western blot analysis. By this, interactions could be demonstrated between PTK6 and MAPK, P-MAPK, HER2/neu, HER3, HER4, PTEN, and Sam68. On the basis of these results, we suggest that PTK6 may serve as a future target for the development of novel treatments in breast cancer

Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York

High-resolution array comparative genomic hybridisation (aCGH) analysis of DNA copy number aberrations (CNAs) was performed on breast carcinomas in premenopausal women from Western New York (WNY) and from Gomel, Belarus, an area exposed to fallout from the 1986 Chernobyl nuclear accident. Genomic DNA was isolated from 47 frozen tumour specimens from 42 patients and hybridised to arrays spotted with more than 3000 BAC clones. In all, 20 samples were from WNY and 27 were from Belarus. In total, 34 samples were primary tumours and 13 were lymph node metastases, including five matched pairs from Gomel. The average number of total CNAs per sample was 76 (range 35–134). We identified 152 CNAs (92 gains and 60 losses) occurring in more than 10% of the samples. The most common amplifications included gains at 8q13.2 (49%), at 1p21.1 (36%), and at 8q24.21 (36%). The most common deletions were at 1p36.22 (26%), at 17p13.2 (26%), and at 8p23.3 (23%). Belarussian tumours had more amplifications and fewer deletions than WNY breast cancers. HER2/neu negativity and younger age were also associated with a higher number of gains and fewer losses. In the five paired samples, we observed more discordant than concordant DNA changes. Unsupervised hierarchical cluster analysis revealed two distinct groups of tumours: one comprised predominantly of Belarussian carcinomas and the other largely consisting of WNY cases. In total, 50 CNAs occurred significantly more commonly in one cohort vs the other, and these included some candidate signature amplifications in the breast cancers in women exposed to significant radiation. In conclusion, our high-density aCGH study has revealed a large number of genetic aberrations in individual premenopausal breast cancer specimens, some of which had not been reported before. We identified a distinct CNA profile for carcinomas from a nuclear fallout area, suggesting a possible molecular fingerprint of radiation-associated breast cancer