Showing papers by "University of California, San Francisco published in 2002"
TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
12,395 citations
TL;DR: It is shown that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer.
Abstract: Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?
5,860 citations
TL;DR: The causes of variation are determined, there is no evidence for differences in incidence in different countries or times, and the incidences of individual major forms of CHD were determined from 44 studies.
5,016 citations
TL;DR: Self-management education complements traditional patient education in supporting patients to live the best possible quality of life with their chronic condition, and may soon become an integral part of high-quality primary care.
Abstract: Patients with chronic conditions make day-to-day decisions about—selfmanage—their illnesses. This reality introduces a new chronic disease paradigm: the patient-professional partnership, involving collaborative care and self-management education. Self-management education complements traditional patient education in supporting patients to live the best possible quality of life with their chronic condition. Whereas traditional patient education offers information and technical skills, self-management education teaches problem-solving skills. A central concept in self-management is selfefficacy—confidence to carry out a behavior necessary to reach a desired goal. Self-efficacy is enhanced when patients succeed in solving patientidentified problems. Evidence from controlled clinical trials suggests that (1) programs teaching self-management skills are more effective than informationonly patient education in improving clinical outcomes; (2) in some circumstances, self-management education improves outcomes and can reduce costs for arthritis and probably for adult asthma patients; and (3) in initial studies, a self-management education program bringing together patients with a variety of chronic conditions may improve outcomes and reduce costs. Selfmanagement education for chronic illness may soon become an integral part of high-quality primary care.
3,277 citations
TL;DR: In this paper, epidemiological research was done and used to identify individuals at high risk of disabling fractures, thereby allowing careful allocation of expensive treatments to individuals most in need, which could potentially be as expensive as medical treatment of fractures.
3,103 citations
TL;DR: The chronic care model is a guide to higher-quality chronic illness management within primary care and predicts that improvement in its 6 interrelated components can produce system reform in which informed, activated patients interact with prepared, proactive practice teams.
Abstract: The chronic care model is a guide to higher-quality chronic illness management within primary care. The model predicts that improvement in its 6 interrelated components—self-management support, clinical information systems, delivery system redesign, decision support, health care organization, and community resources—can produce system reform in which informed, activated patients interact with prepared, proactive practice teams. Case studies are provided describing how components of the chronic care model have been implemented in the primary care practices of 4 health care organizations.
2,909 citations
TL;DR: Different discrimination methods for the classification of tumors based on gene expression data include nearest-neighbor classifiers, linear discriminant analysis, and classification trees, which are applied to datasets from three recently published cancer gene expression studies.
Abstract: A reliable and precise classification of tumors is essential for successful diagnosis and treatment of cancer. cDNA microarrays and high-density oligonucleotide chips are novel biotechnologies increasingly used in cancer research. By allowing the monitoring of expression levels in cells for thousands of genes simultaneously, microarray experiments may lead to a more complete understanding of the molecular variations among tumors and hence to a finer and more informative classification. The ability to successfully distinguish between tumor classes (already known or yet to be discovered) using gene expression data is an important aspect of this novel approach to cancer classification. This article compares the performance of different discrimination methods for the classification of tumors based on gene expression data. The methods include nearest-neighbor classifiers, linear discriminant analysis, and classification trees. Recent machine learning approaches, such as bagging and boosting, are also considere...
2,810 citations
TL;DR: The studies that brought MPIs into clinical testing are reviewed and the design and outcome of the trials are discussed in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression.
Abstract: For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique ability to degrade all components of the extracellular matrix. Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic metalloproteinase inhibitors (MPIs) were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Here we review the studies that brought MPIs into clinical testing and discuss the design and outcome of the trials in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression. The important lessons learned from the MPI experience may be of great value for future studies of MPIs and for cancer drug development in general.
2,668 citations
TL;DR: MethPrimer, based on Primer 3, is a program for designing PCR primers for methylation mapping that takes a DNA sequence as its input and searches the sequence for potential CpG islands, and picks primers around the predicted C pG islands or around regions specified by users.
Abstract: Motivation: DNA methylation is an epigenetic mechanism of gene regulation. Bisulfite- conversion-based PCR methods, such as bisulfite sequencing PCR (BSP) and methylation specific PCR (MSP), remain the most commonly used techniques for methylation mapping. Existing primer design programs developed for standard PCR cannot handle primer design for bisulfite-conversion-based PCRs due to changes in DNA sequence context caused by bisulfite treatment and many special constraints both on the primers and the region to be amplified for such experiments. Therefore, the present study was designed to develop a program for such applications. Results: MethPrimer, based on Primer3, is a program for designing PCR primers for methylation mapping. It first takes a DNA sequence as its input and searches the sequence for potential CpG islands. Primers are then picked around the predicted CpG islands or around regions specified by users. MethPrimer can design primers for BSP and MSP. Results of primer selection are delivered through a web browser in text and in graphic view. Availability: MethPrimer is freely accessible at the following Web address http://itsa.ucsf.edu/∼urolab/methprimer
2,378 citations
TL;DR: These findings, together with the previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
Abstract: The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
2,377 citations
TL;DR: Research evidence shows to what extent the chronic care model can improve the management of chronic conditions and reduce health care costs and obstacles hinder its widespread adoption.
Abstract: This article reviews research evidence showing to what extent the chronic care model can improve the management of chronic conditions (using diabetes as an example) and reduce health care costs. Thirty-two of 39 studies found that interventions based on chronic care model components improved at least 1 process or outcome measure for diabetic patients. Regarding whether chronic care model interventions can reduce costs, 18 of 27 studies concerned with 3 examples of chronic conditions (congestive heart failure, asthma, and diabetes) demonstrated reduced health care costs or lower use of health care services. Even though the chronic care model has the potential to improve care and reduce costs, several obstacles hinder its widespread adoption.
University of California, Los Angeles1, University of Washington2, Indiana University3, Duke University4, Kaiser Permanente5, University of Texas Health Science Center at San Antonio6, Group Health Cooperative7, University of California, San Francisco8, Dartmouth College9, John A. Hartford Foundation10
TL;DR: The IMPACT collaborative care model appears to be feasible and significantly more effective than usual care for depression in a wide range of primary care practices.
Abstract: ContextFew depressed older adults receive effective treatment in primary care
settings.ObjectiveTo determine the effectiveness of the Improving Mood–Promoting
Access to Collaborative Treatment (IMPACT) collaborative care management program
for late-life depression.DesignRandomized controlled trial with recruitment from July 1999 to August
2001.SettingEighteen primary care clinics from 8 health care organizations in 5
states.ParticipantsA total of 1801 patients aged 60 years or older with major depression
(17%), dysthymic disorder (30%), or both (53%).InterventionPatients were randomly assigned to the IMPACT intervention (n = 906)
or to usual care (n = 895). Intervention patients had access for up to 12
months to a depression care manager who was supervised by a psychiatrist and
a primary care expert and who offered education, care management, and support
of antidepressant management by the patient's primary care physician or a
brief psychotherapy for depresssion, Problem Solving Treatment in Primary
Care.Main Outcome MeasuresAssessments at baseline and at 3, 6, and 12 months for depression, depression
treatments, satisfaction with care, functional impairment, and quality of
life.ResultsAt 12 months, 45% of intervention patients had a 50% or greater reduction
in depressive symptoms from baseline compared with 19% of usual care participants
(odds ratio [OR], 3.45; 95% confidence interval [CI], 2.71-4.38; P<.001). Intervention patients also experienced greater rates of
depression treatment (OR, 2.98; 95% CI, 2.34-3.79; P<.001),
more satisfaction with depression care (OR, 3.38; 95% CI, 2.66-4.30; P<.001), lower depression severity (range, 0-4; between-group
difference, −0.4; 95% CI, −0.46 to −0.33; P<.001), less functional impairment (range, 0-10; between-group
difference, −0.91; 95% CI, −1.19 to −0.64; P<.001), and greater quality of life (range, 0-10; between-group
difference, 0.56; 95% CI, 0.32-0.79; P<.001) than
participants assigned to the usual care group.ConclusionThe IMPACT collaborative care model appears to be feasible and significantly
more effective than usual care for depression in a wide range of primary care
practices.
TL;DR: A unifying hypothesis is proposed whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways plays a key role in causing late complications in type 1 and type 1 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes.
Abstract: In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
University of Texas Southwestern Medical Center1, University of Michigan2, University of Washington3, University of California, San Francisco4, University of California, Los Angeles5, University of Nebraska Omaha6, University of Pittsburgh7, Mayo Clinic8, Baylor University Medical Center9, Northwestern University10, Washington University in St. Louis11, Icahn School of Medicine at Mount Sinai12, Oregon Health & Science University13, University of Miami14, Yale University15, University of Alabama at Birmingham16, Harvard University17
TL;DR: The primary aim was to compare presenting clinical features and liver transplantation in patients with acute liver failure related to acetaminophen hepatotoxicity, other drugs, indeterminate factors, and other causes.
Abstract: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent causes of acute liver failure. The cause of liver failure and coma grade at admission were...
Kaiser Permanente1, University of Colorado Denver2, American Cancer Society3, Rutgers University4, San Diego State University5, National Institutes of Health6, University of California, San Francisco7, Centers for Disease Control and Prevention8, Duke University9, University at Buffalo10, University of Illinois at Chicago11, Harvard University12, Pennsylvania State University13, Tufts University14, University of Arizona15, Fred Hutchinson Cancer Research Center16, University of Utah17, Yeshiva University18, Vanderbilt University19
TL;DR: This committee presents one key recommendation for community action to accompany the four recommendations for individual choices to reduce cancer risk, recognizing that a supportive social environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors.
Abstract: The American Cancer Society (ACS) publishes Nutrition and Physical Activity Guidelines to serve as a foundation for its communication, policy, and community strategies and ultimately, to affect dietary and physical activity patterns among Americans. These Guidelines, published every 5 years, are developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and as such, they represent the most current scientific evidence related to dietary and activity patterns and cancer risk. The ACS Guidelines include recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or interferes with healthy behaviors. Community efforts are essential to create a social environment that promotes healthy food choices and physical activity. Therefore, this committee presents one key recommendation for community action to accompany the four recommendations for individual choices to reduce cancer risk. This recommendation for community action recognizes that a supportive social environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors. The ACS Guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion, as defined by the Department of Health and Human Services' 2005 Dietary Guidelines for Americans.
TL;DR: Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up, and hormone therapy did not reduce risk of cardiovascular events in women with CHD.
Abstract: 1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Conclusions Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.
TL;DR: Reducing SES disparities in health will require policy initiatives addressing the components of socioeconomic status (income, education, and occupation) as well as the pathways by which these affect health.
Abstract: Socioeconomic status (SES) underlies three major determinants of health: health care, environmental exposure, and health behavior. In addition, chronic stress associated with lower SES may also increase morbidity and mortality. Reducing SES disparities in health will require policy initiatives addressing the components of socioeconomic status (income, education, and occupation) as well as the pathways by which these affect health. Lessons for U.S. policy approaches are taken from the Acheson Commission in England, which was charged with reducing health disparities in that country.
TL;DR: In this article, BM ablation induces SDF-1, which upregulates MMP-9 expression, and causes shedding of sKitL and recruitment of c-Kit+ stem/progenitors.
TL;DR: Inadequate health literacy may contribute to the disproportionate burden of diabetes-related problems among disadvantaged populations and efforts should focus on developing and evaluating interventions to improve diabetes outcomes among patients with inadequate health literacy.
Abstract: ContextHealth literacy is a measure of patients' ability to read, comprehend,
and act on medical instructions. Poor health literacy is common among racial
and ethnic minorities, elderly persons, and patients with chronic conditions,
particularly in public-sector settings. Little is known about the extent to
which health literacy affects clinical health outcomes.ObjectivesTo examine the association between health literacy and diabetes outcomes
among patients with type 2 diabetes.Design, Setting, and ParticipantsCross-sectional observational study of 408 English- and Spanish-speaking
patients who were older than 30 years and had type 2 diabetes identified from
the clinical database of 2 primary care clinics of a university-affiliated
public hospital in San Francisco, Calif. Participants were enrolled and completed
questionnaires between June and December 2000. We assessed patients' health
literacy by using the short-form Test of Functional Health Literacy in Adults
(s-TOFHLA) in English or Spanish.Main Outcome MeasuresMost recent hemoglobin A1c (HbA1c) level. Patients
were classified as having tight glycemic control if their HbA1c
was in the lowest quartile and poor control if it was in the highest quartile.
We also measured the presence of self-reported diabetes complications.ResultsAfter adjusting for patients' sociodemographic characteristics, depressive
symptoms, social support, treatment regimen, and years with diabetes, for
each 1-point decrement in s-TOFHLA score, the HbA1c value increased
by 0.02 (P = .02). Patients with inadequate health
literacy were less likely than patients with adequate health literacy to achieve
tight glycemic control (HbA1c ≤7.2%; adjusted odds ratio [OR],
0.57; 95% confidence interval [CI], 0.32-1.00; P
= .05) and were more likely to have poor glycemic control (HbA1c ≥9.5%;
adjusted OR, 2.03; 95% CI, 1.11-3.73; P = .02) and
to report having retinopathy (adjusted OR, 2.33; 95% CI, 1.19-4.57; P = .01).ConclusionsAmong primary care patients with type 2 diabetes, inadequate health
literacy is independently associated with worse glycemic control and higher
rates of retinopathy. Inadequate health literacy may contribute to the disproportionate
burden of diabetes-related problems among disadvantaged populations. Efforts
should focus on developing and evaluating interventions to improve diabetes
outcomes among patients with inadequate health literacy.
TL;DR: Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy, and results in EAE corroborate the microarray studies on MS lesions.
Abstract: Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
TL;DR: Interconnecting signaling pathways controlled by RB and p53 are discussed, attempting to explain their potentially universal involvement in the etiology of cancer.
United States Department of Energy1, Kyoto University2, Marine Biological Laboratory3, University of Queensland4, Stanford University5, University of California, Berkeley6, McGill University7, National Institute of Genetics8, Aix-Marseille University9, Dalhousie University10, University of Tokyo11, Tokyo Metropolitan University12, Tohoku University13, University of South Florida14, Hokkaido University15, Stazione Zoologica Anton Dohrn16, IBM17, University of Maryland, College Park18, University of California, San Francisco19, University of Edinburgh20, Oak Ridge National Laboratory21, Los Alamos National Laboratory22
TL;DR: A draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis, is generated, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development.
Abstract: The first chordates appear in the fossil record at the time of the Cambrian explosion, nearly 550 million years ago. The modern ascidian tadpole represents a plausible approximation to these ancestral chordates. To illuminate the origins of chordate and vertebrates, we generated a draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome contains approximately 16,000 protein-coding genes, similar to the number in other invertebrates, but only half that found in vertebrates. Vertebrate gene families are typically found in simplified form in Ciona, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development. The ascidian genome has also acquired a number of lineage-specific innovations, including a group of genes engaged in cellulose metabolism that are related to those in bacteria and fungi.
TL;DR: It is shown that the PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase messenger RNA and protein.
Abstract: Reactive oxygen species are required for cell proliferation but can also induce apoptosis1. In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis2. By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead transcription factors, the transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans3,4,5,6, and we conclude that this model also extends to mammalian systems.
TL;DR: Compared with calcium-based phosphate binders, sevelamer is less likely to cause hypercalcemia, low levels of PTH, and progressive coronary and aortic calcification in hemodialysis patients.
TL;DR: It is proposed that deregulation of proliferation, together with a reduction in apoptosis, creates a platform that is both necessary and can be sufficient for cancer.
TL;DR: It is shown that a protein produced by glia, tumor necrosis factor α (TNFα), enhances synaptic efficacy by increasing surface expression of AMPA receptors, which may play roles in synaptic plasticity and modulating responses to neural injury.
Abstract: Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.
TL;DR: The primary psychoactive ingredient in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), affects the brain mainly by activating a specific receptor (CB1) and suppressing neurotransmitter release.
Abstract: The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
TL;DR: Mouse cytomegalovirus encodes an MHC-like protein that binds to an inhibitory NK cell receptor in certain MCMV-susceptible mice, and this viral protein engages a related activating receptor and confers host protection.
Abstract: Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I antigens, preventing attack against healthy cells Mouse cytomegalovirus (MCMV) encodes an MHC-like protein (m157) that binds to an inhibitory NK cell receptor in certain MCMV-susceptible mice In MCMV-resistant mice, this viral protein engages a related activating receptor (Ly49H) and confers host protection These activating and inhibitory receptors are highly homologous, suggesting the possibility that one evolved from the other in response to selective pressure imposed by the pathogen
TL;DR: It is shown that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitors in the irradiated hippocampus.
Abstract: In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.