Showing papers by "Johns Hopkins University School of Medicine published in 2003"
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.
6,024 citations
TL;DR: Obesity appears to lessen life expectancy markedly, especially among younger adults, and Marked race and sex differences were observed in estimated YLL.
Abstract: ContextPublic health officials and organizations have disseminated health messages
regarding the dangers of obesity, but these have not produced the desired
effect.ObjectiveTo estimate the expected number of years of life lost (YLL) due to overweight
and obesity across the life span of an adult.Design, Setting, and SubjectsData from the (1) US Life Tables (1999); (2) Third National Health and
Nutrition Examination Survey (NHANES III; 1988-1994); and (3) First National
Health and Nutrition Epidemiologic Follow-up Study (NHANES I and II; 1971-1992)
and NHANES II Mortality Study (1976-1992) were used to derive YLL estimates
for adults aged 18 to 85 years. Body mass index (BMI) integer-defined categories
were used (ie, <17; 17 to <18; 18 to <19; 20 to <21; 21 to 45;
or ≥45). A BMI of 24 was used as the reference category.Main Outcome MeasureThe difference between the number of years of life expected if an individual
were obese vs not obese, which was designated YLL.ResultsMarked race and sex differences were observed in estimated YLL. Among
whites, a J- or U-shaped association was found between overweight or obesity
and YLL. The optimal BMI (associated with the least YLL or greatest longevity)
is approximately 23 to 25 for whites and 23 to 30 for blacks. For any given
degree of overweight, younger adults generally had greater YLL than did older
adults. The maximum YLL for white men aged 20 to 30 years with a severe level
of obesity (BMI >45) is 13 and is 8 for white women. For men, this could represent
a 22% reduction in expected remaining life span. Among black men and black
women older than 60 years, overweight and moderate obesity were generally
not associated with an increased YLL and only severe obesity resulted in YLL.
However, blacks at younger ages with severe levels of obesity had a maximum
YLL of 20 for men and 5 for women.ConclusionObesity appears to lessen life expectancy markedly, especially among
younger adults.
2,416 citations
TL;DR: Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Abstract: Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause α-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of α-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
1,606 citations
TL;DR: Crystal structures of the entire extracellular regions of rat and human HER2 reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding.
Abstract: HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.
1,558 citations
TL;DR: It is shown that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP, and it is proposed that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check.
1,542 citations
TL;DR: It is shown that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly that eradication is unlikely.
Abstract: Latent HIV-1 persists in resting memory CD4+ T cells, even in patients receiving highly active antiretroviral therapy (HAART). It has been unclear how stable this latent reservoir is and whether its persistence reflects replenishment by low-level viremia. Here we show that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly (t(1/2) = 44 months) that eradication is unlikely.
1,528 citations
TL;DR: Aminotransferase elevation was common in the United States, and the majority could not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis, and thus may represent nonalcoholic fatty liver disease.
1,300 citations
TL;DR: It is shown that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung, and that perturbation of this function can contribute to the pathogenesis of disease.
Abstract: Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1‐3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome 4 . Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-β attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.
1,283 citations
TL;DR: It is hypothesized that race concordance is associated with higher levels of communication behaviors that are considered patient centered, higher patient ratings of physicians' participatory decision making, and higher ratings of patient satisfaction.
Abstract: When patients and physicians are of the same race, patients are more satisfied with care in the office setting. The authors found that having the same race did not affect patient-centered communica...
1,198 citations
University of Pennsylvania1, New York University2, National Institutes of Health3, National Institute for Health and Welfare4, Cardiff University5, University of Bonn6, Johns Hopkins University School of Medicine7, Harvard University8, University of Medicine and Dentistry of New Jersey9, Rutgers University10, Columbia University11, University of Louisville12, University College London13, Uppsala University14, University of Utah15, University of California, Irvine16, Queen's University Belfast17, Virginia Commonwealth University18, University of Helsinki19, University of California, Los Angeles20, University of Geneva21, University of Queensland22, Icahn School of Medicine at Mount Sinai23, University of Iowa24, Washington University in St. Louis25, University of Toronto26
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
1,176 citations
TL;DR: The rod–cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions such as pupillary light reflex and circadian photo-entrainment.
Abstract: In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
TL;DR: It is proposed that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation, and a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway is identified.
Abstract: Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.
Johns Hopkins University School of Medicine1, Harvard University2, University of Alberta3, University of Basel4, University of California, Los Angeles5, Catholic University of Leuven6, University of Pittsburgh7, Vanderbilt University8, University of Leicester9, University of Helsinki10, University of Iowa11, Yale University12, University of Texas Health Science Center at Houston13, Nagoya City University14, University of North Carolina at Chapel Hill15, University of Vienna16, University of Barcelona17, Cornell University18, Rockyview General Hospital19
TL;DR: This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001, to be revisited as additional data accumulate in this important area of renal transplantation.
TL;DR: P pH effects were noninvasively imaged in ischemic rat brain to show the potential of amide proton transfer (APT) contrast for detecting acute stroke, and opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, in clinical imaging.
Abstract: In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.
TL;DR: It was decided that all of the information dealing with the initial empiric treatment regimens should be in tabular format with footnotes, and the topics selected for updating have been organized according to the headings used in the August 2000 CAP guidelines.
Abstract: The Infectious Diseases Society of America (IDSA) produced guidelines for community-acquired pneumonia (CAP) in immunocompetent adults in 1998 and again in 2000 [1, 2]. Because of evolving resistance to antimicrobials and other advances, it was felt that an update should be provided every few years so that important developments could be highlighted and pressing questions answered. We addressed those issues that the committee believed were important to the practicing physician, including suggestions for initial empiric therapy for CAP. In some cases, only a few paragraphs were needed, whereas, in others, a somewhat more in-depth discussion was provided. Because many physicians focus on the tables rather than on the text of guidelines, it was decided that all of the information dealing with the initial empiric treatment regimens should be in tabular format with footnotes (tables 1–3). The topics selected for updating have been organized according to the headings used in the August 2000 CAP guidelines pub-
TL;DR: A mechanistic view of ErbB receptor homo- and heterodimerization is outlined, which suggests new approaches for interfering with these processes when they are implicated in human cancers.
TL;DR: The first evidence, to the knowledge, is reported that ART is associated with a human overgrowth syndrome-namely, Beckwith-Wiedemann syndrome (BWS), similar to the large offspring syndrome reported in ruminants.
Abstract: Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth syndrome—namely, Beckwith-Wiedemann syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART—five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS—four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring syndrome reported in ruminants.
TL;DR: The data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.
Abstract: The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)-->adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.
TL;DR: It is found that PKA phosphorylation of the AMPA receptor subunits GluR4 and GLUR1 directly controlled the synaptic incorporation of AMPA receptors in organotypic slices from rat hippocampus.
Abstract: The regulated incorporation of AMPA receptors into synapses is important for synaptic plasticity. Here we examine the role of protein kinase A (PKA) in this process. We found that PKA phosphorylation of the AMPA receptor subunits GluR4 and GluR1 directly controlled the synaptic incorporation of AMPA receptors in organotypic slices from rat hippocampus. Activity-driven PKA phosphorylation of GluR4 was necessary and sufficient to relieve a retention interaction and drive receptors into synapses. In contrast, PKA phosphorylation of GluR1 and the activity of calcium/calmodulin-dependent kinase II (CaMKII) were both necessary for receptor incorporation. Thus, PKA phosphorylation of AMPA receptor subunits contributes to diverse mechanisms underlying synaptic plasticity.
TL;DR: Chronic graft versus host disease (GvHD) continues to be a significant problem in the allogeneic stem cell transplant setting and, as the authors continue to use alternative stem cell sources and attempt to modulate the immune system to increase an anti-tumour effect, they will probably see rising numbers of patients with this complication.
TL;DR: The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low- grade and high-grade ovarian serous carcinomas develop through independent pathways.
Abstract: Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.
TL;DR: In this paper, the authors analyzed responses to a cross-sectional telephone survey to assess the independent relationship of self-reported race (non-Hispanic black or non-Hispanic white) with trust in physicians, hospitals, and health insurance plans.
Abstract: Objective. A legacy of racial discrimination in medical research and the health care system has been linked to a low level of trust in medical research and medical care among African Americans. While racial differences in trust in physicians have been demonstrated, little is known about racial variation in trust of health insurance plans and hospitals. For the present study, the authors analyzed responses to a cross sectional telephone survey to assess the independent relationship of self-reported race (non-Hispanic black or non-Hispanic white) with trust in physicians, hospitals, and health insurance plans. Methods. Respondents ages 18–75 years were asked to rate their level of trust in physicians, health insurance plans, and hospitals. Items from the Medical Mistrust Index were used to assess fear and suspicion of hospitals. Results. Responses were analyzed for 49 (42%) non-Hispanic black and 69 (58%) non-Hispanic white respondents (N=118; 94% of total survey population). A majority of respondents trusted physicians (71%) and hospitals (70%), but fewer trusted their health insurance plans (28%). After adjustment for potential confounders, non-Hispanic black respondents were less likely to trust their physicians than non-Hispanic white respondents (adjusted absolute difference 37%; p=0.01) and more likely to trust their health insurance plans (adjusted absolute difference 28%; p=0.04). The difference in trust of hospitals (adjusted absolute difference 13%) was not statistically significant. Non-Hispanic black respondents were more likely than non-Hispanic white respondents to be concerned about personal privacy and the potential for harmful experimentation in hospitals. Conclusions. Patterns of trust in components of our health care system differ by race. Differences in trust may reflect divergent cultural experiences of blacks and whites as well as differences in expectations for care. Improved understanding of these factors is needed if efforts to enhance patient access to and satisfaction with care are to be effective.
TL;DR: The evidence for persistent changes in intrinsic neuronal excitability — what the authors will call intrinsic plasticity — that is produced by training in behaving animals and by artificial patterns of activation in brain slices and neuronal cultures is considered.
Abstract: Modern theories of memory storage have largely focused on persistent, experience-dependent changes in synaptic function such as long-term potentiation and depression But in addition to these synaptic changes, certain learning tasks produce enduring changes in the intrinsic excitability of neurons by changing the function of voltage-gated ion channels, a change that can produce broader, even neuron-wide changes in synaptic throughput We will consider the evidence for persistent changes in intrinsic neuronal excitability — what we will call intrinsic plasticity — that is produced by training in behaving animals and by artificial patterns of activation in brain slices and neuronal cultures These intrinsic changes might function as part of the engram itself, or as a related phenomenon such as a trigger for the consolidation or adaptive generalization of memories
TL;DR: The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions, which contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.
TL;DR: This review summarizes the current understanding of the major families of axon guidance cues and their receptors, with a particular emphasis on receptor signaling mechanisms.
Abstract: The guidance of axons during the establishment of the nervous system is mediated by a variety of extracellular cues that govern cytoskeletal dynamics in axonal growth cones. A large number of these guidance cues and their cell-surface receptors have now been identified, and the intracellular signaling pathways by which these cues induce cytoskeletal rearrangements are becoming defined. This review summarizes our current understanding of the major families of axon guidance cues and their receptors, with a particular emphasis on receptor signaling mechanisms. We also discuss recent advances in understanding receptor cross talk and how the activities of guidance cues and their receptors are modulated during neural development.
TL;DR: To elude immune surveillance, tumors must develop mechanisms that block the elaboration and sensing of proinflammatory danger signals, thereby shifting the balance from activation to tolerance induction.
Abstract: Given the vast number of genetic and epigenetic changes associated with carcinogenesis, it is clear that tumors express many neoantigens. A central question in cancer immunology is whether recognition of tumor antigens by the immune system leads to activation (i.e., surveillance) or tolerance. Paradoxically, while strong evidence exists that specific immune surveillance systems operate at early stages of tumorigenesis, established tumors primarily induce immune tolerance. A unifying hypothesis posits that the fundamental processes of cancer progression, namely tissue invasion and metastasis, are inherently proinflammatory and thus activating for innate and adaptive antitumor immunity. To elude immune surveillance, tumors must develop mechanisms that block the elaboration and sensing of proinflammatory danger signals, thereby shifting the balance from activation to tolerance induction. Elucidation of these mechanisms provides new strategies for cancer immunotherapy.
TL;DR: Results show that MCE is a prerequisite for differentiation of 3T3-L1 preadipocytes into adipocytes, and the more potent and specific MEK inhibitor UO126 and the cyclin-dependent kinase inhibitor roscovitine block MCE, expression of cell cycle and adipocyte markers, as well as adipogenesis.
Abstract: When induced to differentiate, growth-arrested 3T3-L1 preadipocytes synchronously reenter the cell cycle and undergo mitotic clonal expansion (MCE) followed by expression of genes that produce the adipocyte phenotype. The preadipocytes traverse the G1/S checkpoint synchronously as evidenced by the expression/activation of cdk2-cyclin-E/A, turnover of p27/kip1, hyperphosphorylation of Rb, translocation of cyclin D1 from nuclei to cytoplasm and GSK-3β from cytoplasm to nuclei, and incorporation of [3H]thymidine into DNA. As the cells cross the G1/S checkpoint, C/EBPβ acquires DNA-binding activity, initiating a cascade of transcriptional activation that culminates in the expression of adipocyte proteins. The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059 delays, but does not block, MCE and differentiation, the extent of the delay causing a comparable delay in the expression of cell-cycle markers, MCE, and adipogenesis. The more potent and specific MEK inhibitor UO126 and the cyclin-dependent kinase inhibitor roscovitine, which inhibit the cell cycle at different points, block MCE, expression of cell cycle and adipocyte markers, as well as adipogenesis. These results show that MCE is a prerequisite for differentiation of 3T3-L1 preadipocytes into adipocytes.
TL;DR: Loss of imprinting can be assayed with a DNA-based blood test, and it may be a valuable predictive marker of an individual's risk for CRC.
Abstract: Loss of imprinting (LOI), an epigenetic alteration affecting the insulin-like growth factor II gene (IGF2), is found in normal colonic mucosa of about 30% of colorectal cancer (CRC) patients, but it is found in only 10% of healthy individuals. In a pilot study to investigate the utility of LOI as a marker of CRC risk, we evaluated 172 patients at a colonoscopy clinic. The adjusted odds ratio for LOI in lymphocytes was 5.15 for patients with a positive family history [95% confidence interval (95% CI), 1.70 to 16.96; probability P = 0.002], 3.46 for patients with adenomas (95% CI, 1.14 to 11.37; P = 0.026), and 21.7 for patients with CRC (95% CI, 3.48 to 153.6; P = 0.0005). LOI can be assayed with a DNA-based blood test, and it may be a valuable predictive marker of an individual's risk for CRC.
TL;DR: In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, expressing the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment as discussed by the authors.
Abstract: In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.
TL;DR: MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of M SCs in MI.
Abstract: Background— We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. Methods and Results— Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16×107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. Conclusion— MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.