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Recent advances in molecular genetics of breast cancer.

Breast cancer is among the most common tumors affecting women. It is characterized by a number of genetic aberrations. Some 5-10% of cases are thought to be inherited. The hereditary breast and ovarian cancer syndrome includes genetic alterations of various susceptibility genes, particularly BRCA1 and BRCA2. Breast tumors of patients with germ-line mutations in the BRCA1 and BRCA2 genes have more genetic defects than sporadic breast tumors. Here we review new findings in the function of BRCA1 gene function. Accumulation of somatic genetic changes during tumor progression map follows a specific and more aggressive pathway of chromosome damage in these individuals. A major BRCA1 downstream target gene is the DNA damage-responsive gene GADD45. Induction of BRCA1 triggers apoptosis by activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). BRCA1 interacts with SWI/SNF, a chromatin remodeling complex important in gene expression. Recent advances in genomics and bioinformatics, particularly in DNA-sequencing approaches and DNA-chip technology are expected to improve identification of small molecules, which might be drugable targets. New knowledge about the genetic portrait of breast tumor is coming from differential gene expression profiling using microarrays. Human genome studies, as well as development of "DNA chips," provide a window for observing patterns of gene activity in cells, which will contribute to more accurate cancer classification. However, substantial work connected with analytical and statistical tools must still be carried out to confirm the function of differentially expressed genes. Knowledge of the molecular characteristics of breast tumor has already started to make possible the identification of breast cancer patients who could benefit from therapies that target those features. Progress in basic research into signaling provides the opportunity to attack at least some signal-transduction targets involved in proliferation, survival, invasion, angiogenesis, metastasis, and resistance. Exciting knowledge in breast cancer biology is rapidly accumulating in parallel with recent developments in rational selection and validation of relevant targets that provide unique opportunities for development of "intelligent" therapeutics.

BRCA1 Protein↗

Specific accumulation and elimination kinetics of tris(4-chlorophenyl)methane, tris(4-chlorophenyl)methanol, and other persistent organochlorines in humans from Japan.

We examined human adipose tissue, liver, and bile from humans in Japan to understand the contamination status, specific accumulation, and elimination of two newly identified environmental contaminants, tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and other persistent organochlorines such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs). TCPMe and TCPMOH concentrations in Japanese human adipose tissue were slightly higher than those reported previously, indicating widespread exposure to these compounds in humans. Elevated residues of PCBs and DDTs are found in adipose tissue and liver. Concentrations in bile strongly correlated with concentrations in adipose fat and liver, which may suggest an equilibration in adipose fat/bile and liver/bile and possible biliary excretion of persistent organochlorines in humans. Composition of the organochlorines accumulated further indicates a metabolic capacity in humans higher than that of marine mammals. We observed age-dependent accumulation for TCPMe, TCPMOH, and other organochlorines, but there were no significant gender differences. p,p'-DDE and TCPMe were estimated to have low biliary excretion rate. Elimination potential of persistent organochlorines may be related to their octanol-water partition coefficient. The relationship between excretion rate and octanol-water partition coefficient may be used to predict the biliary excretion potential of some other lipophilic organochlorines such as dioxins and dibenzofurans in humans. The presence of organochlorines in bile suggests that the hepatic excretory system plays a major role in the elimination of xenobiotics in humans. To our knowledge, this is the first study of accumulation and elimination of TCPMe and TCPMOH in humans.

Adipose Tissue↗

[99mTc(V)-DMSA accumulation in gynecomastia].

The accumulation of 99mTc(V)-DMSA in bilateral breasts was recognized in a 60-year-old male with drug-induced gynecomastia. There are some reports describing 99mTc(V)-DMSA accumulation in normal female breast, fibrous dysplasia of the breast and metastatic lesions of breast carcinoma, but to my knowledge, there have been no reports describing 99mTc(V)-DMSA accumulation in gynecomastia.

Digoxin↗

The importance of epithelial uptake systems in lung toxicity.

The discovery that the herbicide paraquat was selectively accumulated by the lung, both in vivo and in vitro, in comparison with other tissues, provided an explanation for its selective toxicity to the lung. This uptake process is energy dependent and obeys saturation kinetics. A characterization of the process led to the identification of endogenous chemicals that are the natural substrates for the system. Among these are a series of diamines and polyamines, as well as the diaminodisulfide cystamine. It appears that paraquat, because of specific structural similarities to these endogenous polyamines, is mistakenly accumulated by the lung. This uptake process is specifically located in the alveolar Type II cell, the Clara cell, and probably the alveolar Type I cell. With the development of knowledge of the structural requirements of chemicals to be accumulated by this system, it is possible to predict which chemicals will be accumulated by the lung or design molecules that are targeted to the alveolar epithelial and Clara cells. In the wider perspective, this polyamine uptake system has been found on a number of cancerous cells or tissues. With the knowledge of the uptake system in the lung, it should be possible to design drugs that will be specifically concentrated in cells that possess this system.

Animals↗

Accumulation of heavy metals by intestinal helminths in fish: an overview and perspective.

Intestinal helminths of fish are of increasing interest as potential bioindicators for heavy metal contamination in aquatic habitats. Among these parasites cestodes and acanthocephalans in particular have an enormous heavy metal accumulation capacity exceeding that of established free living sentinels. Metal concentrations several thousand times higher in acanthocephalans than in host tissues were described from field and laboratory studies. Whereas larval stages inside their intermediate hosts are not able to take up high quantities of metals, young worms begin to take up metals immediately after infection of the final host. After four to five weeks of exposure, the parasites reach a steady-state concentration orders of magnitude higher than the ambient water level. Thus, acanthocephalans are not only very effective in taking up metals, but they can also respond very rapidly to changes in environmental exposure. The mechanism which enable acanthocephalans to take up metals from the intestinal lumen of the host appears to be based on the presence of bile acids, which form organo-metallic complexes that are easily absorbed by the worms due to their lipophilicity. Investigations of the environmental conditions affecting metal uptake have shown that the parasites are more consistent and reliable indicators for metal pollution than the host tissues as metal levels of the latter are much more dependent on the water chemistry. Thus, after some years of research on the uptake of metals by acanthocephalans and on the factors affecting metal accumulation in intestinal parasites it should be asked if acanthocephalans meet the criteria commonly accepted for sentinels. If parasites can be considered as promising sentinels, we need reasons for the establishment of 'new' indicators. Therefore, this review summarises the present knowledge about parasites as bioindicators and compares the accumulation properties of parasites and established free living indicators. Finally, this review presents possible answers to the question why it could be advantageous to have new and even more sensitive indicators for environmental monitoring purposes.

Acanthocephala↗

In situ hybridization as a tool to study the role of microRNAs in plant development.

MicroRNAs (miRNAs) have a vital role in the generation of plant forms through post-transcriptional regulation of the accumulation of developmental regulators. Analysis of their roles requires detailed knowledge of their expression patterns. We describe an in situ hybridization technique we have used to study the patterns of miRNA accumulation in Arabidopsis and in maize.

Gene Expression Regulation, Plant↗

Neuroanatomy of penile erection: its relevance to iatrogenic impotence.

The neuroanatomy of erection in men is not well defined. Recently, we isolated successfully the cavernous nerves for acute and chronic neurostimulation to induce penile erection in dogs and monkeys. We then investigated the anatomy of these nerves in humans by cadaveric dissection and serial histologic sectioning. Our experience in tracing the spinal nuclei responsible for vesical and urethral function by transportation of horseradish peroxidase enabled us to explore the location and organization of the spinal center for erection. Thus, systemic knowledge of the neuroanatomy of erection was accumulated. The spinal nuclei for control of erection are located in the intermediolateral gray matter at the S1 to S3 and T12 to L3 levels in dogs, and the S2 to S4 and T10 to L2 levels in humans. From these sacral nuclei axons issue ventrally and join the axons of the nuclei for the bladder and rectum to form the sacral visceral efferent fibers. These fibers emerge from the anterior root of S2 to S4, and join the sympathetic fibers to form the pelvic plexus, which then branches out to innervate the bladder, rectum and penis. The fibers innervating the penis (cavernous nerves) travel along the posterolateral aspect of the seminal vesicle and prostate, and then accompany the membranous urethra through the genitourinary diaphragm. These fibers are located on the lateral aspect of the membranous urethra and ascend gradually to the 1 and 11 o'clock positions in the proximal bulbous urethra. Some of the fibers penetrate the tunica albuginea of the corpus spongiosum, while others spread to the trifurcation of the terminal internal pudendal artery and innervate the dorsal, deep and urethral arteries. Shortly before the 2 corpora cavernosa merge the cavernous nerves penetrate the tunica albuginea along with the deep artery and cavernous vein. The terminal branches of these nerves innervate the helicine arteries and the erectile tissue within the corpora cavernosa. Because of the intimate relationship of the cavernous nerves to the rectum, prostate and urethra, they can be damaged easily during urological and pelvic procedures. This systemic knowledge of the human cavernous nerves from the spinal center to the erectile tissue should permit a better understanding of erection and impotence. Furthermore, with the aid of intraoperative neurostimulation, the cavernous nerves may be identified and preserved, thereby preventing iatrogenic impotence.

Animals↗

Convergence of philosophy and science: the third international congress on vegetarian nutrition.

Populations of vegetarians living in affluent countries appear to enjoy unusually good health, characterized by low rates of cancer, cardiovascular disease, and total mortality. These important observations have fueled much research and have raised 3 general questions about vegetarians in relation to nonvegetarians: Are these observations the result of better nondietary lifestyle factors, such as lower prevalences of smoking and higher levels of physical activity?; Are they the result of lower intakes of harmful dietary components, in particular meat?; and Are they the result of higher intakes of beneficial dietary components that tend to replace meat in the diet? Current evidence suggests that the answer to all 3 questions is "Yes." Low smoking rates contribute importantly to the low rates of cardiovascular disease and many cancers, probably including colon cancer, in Seventh-day Adventists and other vegetarian populations. Also, avoidance of red meat is likely to account in part for low rates of cardiovascular disease and colon cancer, but this does not appear to be the primary reason for general good health in these populations. Evidence accumulated in the past decade emphasizes the importance of adequate consumption of beneficial dietary factors-rather than just the avoidance of harmful factors-including an abundance of fruit, vegetables, and whole grains and regular consumption of vegetable oils, including those from nuts. Although current knowledge already provides general guidance toward healthy diets, accumulated evidence now strongly indicates that diet has a powerful yet complex effect on health and that further investigation is needed.

Congresses as Topic↗

A memory learning framework for effective image retrieval.

Most current content-based image retrieval systems are still incapable of providing users with their desired results. The major difficulty lies in the gap between low-level image features and high-level image semantics. To address the problem, this study reports a framework for effective image retrieval by employing a novel idea of memory learning. It forms a knowledge memory model to store the semantic information by simply accumulating user-provided interactions. A learning strategy is then applied to predict the semantic relationships among images according to the memorized knowledge. Image queries are finally performed based on a seamless combination of low-level features and learned semantics. One important advantage of our framework is its ability to efficiently annotate images and also propagate the keyword annotation from the labeled images to unlabeled images. The presented algorithm has been integrated into a practical image retrieval system. Experiments on a collection of 10,000 general-purpose images demonstrate the effectiveness of the proposed framework.

Algorithms↗

Past and future contributions to traditional medicine in the health care system of the Middle-East.

Due to the rich cultural heritage and relatively rich flora, a wealth of knowledge on traditional and folk medicine has been accumulated in the Middle-East. However, except Turkey, the number of ethnobotanical field studies is few and mainly focused on Unani medicine, which is practised widespread in the southern communities. Urgent scientific field surveys should be conducted among the native people in order to document the wealth of knowledge on folk medicine, other than Unani medicine, before it will be lost by the erosive effects of modernization.

History, 20th Century↗

Deleterious mitochondrial DNA mutations accumulate in aging human tissues.

This paper reviews the current state of knowledge of the contribution of mitochondrial DNA (mtDNA) mutations to the phenotype of aging. Its major focus is on the discovery of deletions of mtDNA which previously were thought to occur only in individuals with neuromuscular disease. One particular deletion (mtDNA4977) accumulates with age primarily in non-dividing cells such as muscle and brain of normal individuals. The level of the deletion rises with age by more than 1000 fold in heart and brain and to a lesser extent in other tissues. In the brain, different regions have substantially different levels of the deletion. High levels of accumulation of the deletion in tissues are correlated with high oxygen consumption. We speculate that oxidative damage to mtDNA may be 'catastrophic'; mutations affecting mitochondrially encoded polypeptides involved in electron transport could increase free radical generation leading to more mtDNA damage.

Aging↗

Definition of a "functional R domain" of the cystic fibrosis transmembrane conductance regulator.

The R domain of the cystic fibrosis transmembrane conductance regulator (CFTR) was originally defined as 241 amino acids, encoded by exon 13. Such exon/intron boundaries provide a convenient way to define the R domain, but do not necessarily reflect the corresponding functional domain within CFTR. A two-domain model was later proposed based on a comparison of the R-domain sequences from 10 species. While RD1, the N-terminal third of the R domain is highly conserved, RD2, the large central region of the R domain has less rigid structural requirements. Although this two-domain model was given strong support by recent functional analysis data, the simple observation that two of the four main phosphorylation sites are excluded from RD2 clearly indicates that RD2 still does not satisfy the requirements of a "functional R domain." Nevertheless, knowledge of the CFTR structure and function accumulated over the past decade and reevaluated in the context of a comprehensive sequence comparison of 15 CFTR homologues made it possible to define such a "functional R domain," i.e., amino acids C647 to D836. This definition is validated primarily because it contains all of the important potential consensus phosphorylation sequences. In addition, it includes the highly charged motif from E822 to D836. Finally, it includes all of the deletions/insertions in this region. This definition also aids in understanding the effects of missense mutations occurring within this domain.

Amino Acid Sequence↗

The impact of molecular biology in the diagnosis and management of viral hepatitis.

In recent years molecular biology techniques allowed an extraordinary progress in knowledge of hepatitis viruses. New informations have accumulated on the mechanisms of virus replication and on the pathogenesis of liver damage. In the clinical setting, simple noninvasive methods that use the same technological approach provide a useful diagnostic tool for infections of hepatitis B virus (HBV) and hepatitis delta virus (HDV). Using these tests we may define whether a carrier of hepatitis B surface antigen has a liver damage due to HBV or HDV or to other, non-virological causes. Detection of HBV-DNA and HDV-RNA in serum and liver can also be used as a guide for prognosis and therapy.

Animals↗

Accumulation of 67Ga citrate in early pregnancy.

A 26-year-old pregnant woman complained of chest pain and dyspnea and was diagnosed with malignant lymphoma of the mediastinum. To determine the stage of malignant lymphoma, tumor scintigraphy with 67Ga citrate was performed. 67Ga scintigraphy revealed an abnormal accumulation in the center of the pelvic cavity. An artificial abortion was performed, and the early pregnancy obtained from the abortion showed a prominent uptake of 67Ga citrate ex vivo. 67Ga citrate re-examination, which was performed immediately after the abortion, showed no abnormal accumulation in the pelvic cavity. To our knowledge, this is the first medical report on an aborted tissue investigated ex vivo to determine whether it demonstrated increased uptake of 67Ga citrate.

Abortion, Induced↗

Clinicopathological features and outcome of hepatic resection for intrahepatic cholangiocarcinoma in Japan.

As a result of an increasing number of studies on the surgical treatment of intrahepatic cholangiocarcinoma (ICC), knowledge of its biological characteristics has been accumulating. We analyzed the clinicopathological features and outcome of 36 of 48 surgical patients with histologically proven ICC (75.0%) who underwent hepatic resection between March 1979 and July 1998. According to tumor location, 12 patients had the central type and 24, the peripheral type. The incidence of portal vein tumor thrombus and lymph node metastasis was higher in the central type than in the peripheral type. All 12 patients with the central type had stage IV disease, and none of them underwent complete resection, whereas 12 of the 24 patients with peripheral type tumors had stage IV disease; complete resection was achieved in 12 of the 24 patients with peripheral type tumors (50%). Outcome after resection was significantly poorer in the patients with the central type. The macroscopic type of lesion in the resected specimens was the mass-forming type in 15 patients (41.7%), the mass-forming + periductal-infiltrating type in 15 patients (41.7%), the periductal-infiltrating type in 3 patients (8.3%) and the intraductal growth type in 3 patients (8.3%). The macroscopic tumor type was associated with mode of tumor spread and outcome. All 3 patients with the intraductal growth type are alive without tumor recurrence 26-138 months after surgery. The survival rate was much higher in the patients with the mass-forming type than in those with the mass-forming + periductal-infiltrating type. Importantly, the outcome in the 17 patients who underwent resection for stage IV-B disease and who accounted for 47.2% of patients with resection in the present series was very poor, almost the same as that in the 12 patients who did not undergo resection. By selecting patients based on the biological characteristics of the tumor and taking into account patients' quality of life, complete surgical resection can be performed safely and is associated with long-term survival.

Aged↗

Estimation and mapping of wet and dry mercury deposition across northeastern North America.

Whereas many ecosystem characteristics and processes influence mercury accumulation in higher trophic-level organisms, the mercury flux from the atmosphere to a lake and its watershed is a likely factor in potential risk to biota. Atmospheric deposition clearly affects mercury accumulation in soils and lake sediments. Thus, knowledge of spatial patterns in atmospheric deposition may provide information for assessing the relative risk for ecosystems to exhibit excessive biotic mercury contamination. Atmospheric mercury concentrations in aerosol, vapor, and liquid phases from four observation networks were used to estimate regional surface concentration fields. Statistical models were developed to relate sparsely measured mercury vapor and aerosol concentrations to the more commonly measured mercury concentration in precipitation. High spatial resolution deposition velocities for different phases (precipitation, cloud droplets, aerosols, and reactive gaseous mercury (RGM)) were computed using inferential models. An empirical model was developed to estimate gaseous elemental mercury (GEM) deposition. Spatial patterns of estimated total mercury deposition were complex. Generally, deposition was higher in the southwest and lower in the northeast. Elevation, land cover, and proximity to urban areas modified the general pattern. The estimated net GEM and RGM fluxes were each greater than or equal to wet deposition in many areas. Mercury assimilation by plant foliage may provide a substantial input of methyl-mercury (MeHg) to ecosystems.

Air Pollutants↗

Epigenetic developmental mechanisms in plants: molecules and targets of plant epigenetic regulation.

Genetic approaches to understanding the role of epigenetic regulation of gene expression in plants and its mechanisms have revealed several new components. Rapidly accumulating information from other eukaryotes provides complementary knowledge with important implications for plant research. Comparison of epigenetic events across species is proving critical for defining the mechanisms and functions of epigenetic modification, including those specific to plants.

Chromatin↗

Information literacy as the foundation for evidence-based practice in graduate nursing education: a curriculum-integrated approach.

As part of a system-wide initiative to advance evidence-based practice among clinicians, graduate students, and educators, the New York University Division of Nursing embarked on a curricular initiative to integrate components of information literacy in all core courses of the master's program. Increasing competency in information literacy is the foundation for evidence-based practice and provides nursing professionals with the skills to be literate consumers of information in an electronic environment. Competency in information literacy includes an understanding of the architecture of information and the scholarly process; the ability to navigate among a variety of print and electronic tools to effectively access, search, and critically evaluate appropriate resources; synthesize accumulated information into an existing body of knowledge; communicate research results clearly and effectively; and appreciate the social issues and ethical concerns related to the provision, dissemination, and sharing of information. In collaboration with the New York University Division of Libraries' Health Sciences Librarian, instructional modules in information literacy relevant to each of the 5 core nursing master's courses were developed, complemented by a Web-based tutorial: http://library.nyu.edu/research/health/tutorial. The Web site is multifaceted, with fundamentals for the beginner, as well as more complex content for the advanced user. Course assignments were designed to promote specific competencies in information literacy and strategies for evaluating the strength of the evidence found. A survey of information literacy competencies, which assessed students' knowledge, misconceptions, and use of electronic information resources, was administered when students entered the program and at 1-year intervals thereafter.

Computer Literacy↗