Showing papers by "University of Medicine and Dentistry of New Jersey published in 2007"
TL;DR: Evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.
Abstract: Autophagy is a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles. The recycling of these intracellular constituents also serves as an alternative energy source during periods of metabolic stress to maintain homeostasis and viability. In tumour cells with defects in apoptosis, autophagy allows prolonged survival. Paradoxically, autophagy defects are associated with increased tumorigenesis, but the mechanism behind this has not been determined. Recent evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.
2,016 citations
TL;DR: This Review focuses on pharmacological strategies to attenuate the toxic effects of peroxynitrite, which include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
Abstract: Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases
1,804 citations
TL;DR: The results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemIA/reperfusion stimulates autophile through a Beclin 1–dependent but AM PK-independent mechanism.
Abstract: Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-beta-d-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1(+/-) mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.
1,385 citations
TL;DR: The hypervariable sequence-specific dendrograms and the "MEGALIGN" files provided online will be highly useful tools for designing specific probes and primers for molecular assays to detect pathogenic bacteria, including select agents.
1,014 citations
TL;DR: The results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt 1.
Abstract: Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.
987 citations
TL;DR: The need for clinicians to increase efforts to detect and treat depression in physically abused and neglected children is supported, as child abuse and neglect were associated with an increased risk for current MDD.
Abstract: Context Few prospective longitudinal studies have examined the relationship between abuse or neglect in childhood and depression in adulthood. Objective To determine whether abused and neglected children were at elevated risk of major depressive disorder (MDD) and psychiatric comorbidity, compared with matched control subjects, when followed up into young adulthood. Design Prospective cohort design study. Setting Midwestern metropolitan county area. Participants Children with substantiated cases of physical and sexual abuse and neglect (before the age of 11 years) from January 1, 1967, to December 31, 1971 (n = 676) were matched based on age, race, sex, and approximate family social class with a group of nonabused and nonneglected children (n = 520) and followed up into young adulthood (mean age, 28.7 years). Main Outcomes Measures Between October 20, 1989, and December 22, 1995, 2-hour in-person interviews were conducted, using the National Institute of Mental Health Diagnostic Interview Schedule, Version III Revised, to determine DSM-III-R MDD and other psychiatric diagnoses. Results Child abuse and neglect were associated with an increased risk for current MDD (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.06-2.14; P ≤.05) in young adulthood. Children who were physically abused (OR, 1.59; 95% CI, 1.00-2.52; P ≤.05) or experienced multiple types of abuse (OR, 1.75; 95% CI, 1.01-3.02; P ≤.05) were at increased risk of lifetime MDD, whereas neglect increased risk for current MDD (OR, 1.59; 95% CI, 1.10-2.29; P df = 1; P =.04) showed earlier onset of MDD for abused and neglected children compared with controls. Among those with MDD, comorbidity was higher for abused and neglected individuals than for controls. Conclusion These results support the need for clinicians to increase efforts to detect and treat depression in physically abused and neglected children.
944 citations
TL;DR: This article showed that compromised autophagy promoted chromosome instability and increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis, providing an explanation for how the loss of a survival pathway leads to tumor progression.
Abstract: Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.
881 citations
TL;DR: Teenage pregnancy increases the risk of adverse birth outcomes that is independent of important known confounders, and challenges the accepted opinion that adverse birth outcome associated with teenage pregnancy is attributable to low socioeconomic status, inadequate prenatal care and inadequate weight gain during pregnancy.
Abstract: Results All teenage groups were associated with increased risks for pre-term delivery, low birth weight and neonatal mortality Infants born to teenage mothers aged 17 or younger had a higher risk for low Apgar score at 5min Further adjustment for weight gain during pregnancy did not change the observed association Restricting the analysis to white married mothers with ageappropriate education level, adequate prenatal care, without smoking and alcohol use during pregnancy yielded similar results Conclusions Teenage pregnancy increases the risk of adverse birth outcomes that is independent of important known confounders This finding challenges the accepted opinion that adverse birth outcome associated with teenage pregnancy is attributable to low socioeconomic status, inadequate prenatal care and inadequate weight gain during pregnancy
864 citations
TL;DR: This work shows that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini and proposed that autophagic limits metabolic stress to protect the genome.
Abstract: Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.
800 citations
TL;DR: It is proposed that microRNAs play an essential regulatory role in the development of cardiac hypertrophy, wherein downregulation of miR-1 is necessary for the relief of growth-related target genes from its repressive influence and induction ofhypertrophy.
Abstract: MicroRNAs are naturally existing, small, noncoding RNA molecules that downregulate posttranscriptional gene expression. Their expression pattern and function in the heart remain unknown. Here we report an array of microRNAs that are differentially and temporally regulated during cardiac hypertrophy. Significantly, the muscle-specific microRNA-1 (miR-1) was singularly downregulated as early as day 1 (0.56+/-0.036), persisting through day 7 (0.29+/-0.14), after aortic constriction-induced hypertrophy in a mouse model. Overexpression experiments showed that miR-1 inhibited its in silico-predicted, growth-related targets, including Ras GTPase-activating protein (RasGAP), cyclin-dependent kinase 9 (Cdk9), fibronectin, and Ras homolog enriched in brain (Rheb), in addition to protein synthesis and cell size. Thus, we propose that microRNAs play an essential regulatory role in the development of cardiac hypertrophy, wherein downregulation of miR-1 is necessary for the relief of growth-related target genes from its repressive influence and induction of hypertrophy.
761 citations
TL;DR: This work systematically mapped ACC functional connectivity during rest and demonstrates the presence of negatively predicted relationships between distinct ACC functional networks, which support the commonly observed rostral/caudal distinction but also suggest the existence of a dorsal/ventral functional distinction.
TL;DR: It is indicated that pollution levels in households using solid fuel generally exceed China’s indoor air quality standards, and intervention technologies ranging from simply adding a chimney to the more complex modernized bioenergy program are available.
Abstract: Although some areas of China are becoming more urban, more than 60% of the population is still rural, most of which still uses biomass (mainly wood and crop residues) and coal fuels that produce substantial pollution in simple stoves. In 2003 approximately 80% of the energy consumed by rural households was in the form of biomass and almost 10% as coal. Furthermore, although most Chinese cities have plans to eliminate coal for households, many urban communities continue to rely on coal. The combustion of biomass and coal (collectively called “solid fuels”) is the dominant source of indoor air pollution (IAP) in the country and contributes significantly to the total burden of ill health.
In the most recent global analysis of the health effects of major risk factors, the World Health Organization (WHO) estimated that solid fuels used in Chinese households cause approximately 420,000 premature deaths annually; this is 40% more than the approximately 300,000 premature deaths attributed to outdoor air pollution in Chinese cities with populations of more than 100,000 (Cohen et al. 2004; Smith et al. 2004). Household use of solid fuels is thus estimated to be the largest single environmental risk factor and ranks sixth among all risk factors examined for ill-health (Figure 1; Smith et al. 2005). These risk estimates, however, were based primarily on studies in other countries because, as discussed in this review, few epidemiologic studies have been conducted in China on biomass smoke compared with those conducted on coal smoke.
Figure 1
Rough estimates of the burden of disease in China: the top 10 risk factors plus other selected risk factors [adapted from Smith et al. (2005)]. Note: Indoor smoke from solid fuels does not include smoke from other fuels or tobacco. Burden of disease is ...
In the 1980s China conducted more IAP measurements focused on household combustion than all other developing countries combined. Indeed, by the early 1990s, the results of more than 100 published studies were combined into a WHO database (Sinton et al. 1996). In contrast, the Chinese environmental health community conducted few IAP measurements in the 1990s (Saksena et al. 2003), but epidemiologic studies of coal smoke, mainly on cancer end points, continued and have resulted in a large body of evidence. In particular, over 25 years a wide-ranging set of studies has been conducted on coal smoke exposures, toxicology, and health effects in one rural area—Xuanwei in Yunnan Province—with severe impacts.
In this review we address the following questions in order to put Chinese household IAP from solid fuel use into perspective, nationally and internationally, and highlight research gaps: a) What toxic constituents have been found in the emissions of solid fuel combustion? b) What are the reported human exposure characteristics? c) What health effects have been documented? and d) What technologies exist or are possible for reducing this IAP exposure?
TL;DR: It is shown that increased TGF-β activity leads to failed muscle regeneration in fibrillin-1–deficient mice and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.
Abstract: Skeletal muscle has the ability to achieve rapid repair in response to injury or disease Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs 2,3) TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy
Columbia University1, California Pacific Medical Center2, Washington University in St. Louis3, Mayo Clinic4, University of California, San Francisco5, University of Colorado Hospital6, University of California, Irvine7, University of Medicine and Dentistry of New Jersey8, Virginia Mason Medical Center9, Duke University10, University of California, Los Angeles11, University of Pennsylvania12, University of Kansas13, University of Vermont14
TL;DR: The finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocyCline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in Patients with ALS.
Abstract: Summary Background Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). Methods We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. Findings ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (−1·30 vs −1·04 units/month, 95% CI for difference −0·44 to −0·08; p=0·005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (−3·48 vs −3·01, −1·03 to 0·11; p=0·11) and MMT score (−0·30 vs −0·26, −0·08 to 0·01; p=0·11), and greater mortality during the 9-month treatment phase (hazard ratio=1·32, 95% CI 0·83 to 2·10; p=0·23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. Interpretation Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.
TL;DR: This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress.
Abstract: The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.
TL;DR: Recent advances that support the design of more specific receptor‐selective nicotinic agonists that have anti‐inflammatory effects while eluding its collateral toxicity are reviewed.
Abstract: The physiological regulation of the immune system encompasses comprehensive anti-inflammatory mechanisms that can be harnessed for the treatment of infectious and inflammatory disorders. Recent studies indicate that the vagal nerve, involved in control of heart rate, hormone secretion and gastrointestinal motility, is also an immunomodulator. In experimental models of inflammatory diseases, vagal nerve stimulation attenuates the production of proinflammatory cytokines and inhibits the inflammatory process. Acetylcholine, the principal neurotransmitter of the vagal nerve, controls immune cell functions via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). From a pharmacological perspective, nicotinic agonists are more efficient than acetylcholine at inhibiting the inflammatory signaling and the production of proinflammatory cytokines. This 'nicotinic anti-inflammatory pathway' may have clinical implications as treatment with nicotinic agonists can modulate the production of proinflammatory cytokines from immune cells. Nicotine has been tested in clinical trials as a treatment for inflammatory diseases such as ulcerative colitis, but the therapeutic potential of this mechanism is limited by the collateral toxicity of nicotine. Here, we review the recent advances that support the design of more specific receptor-selective nicotinic agonists that have anti-inflammatory effects while eluding its collateral toxicity.
TL;DR: Early microcirculatory perfusion indices in severe sepsis and septic shock are more markedly impaired in nonsurvivors compared with survivors and with increasing severity of global cardiovascular dysfunction.
University of California, Davis1, University of Utah2, Wake Forest University3, Loyola University Chicago4, University of Texas Southwestern Medical Center5, Harvard University6, University of Texas Medical Branch7, University of Florida8, University of Medicine and Dentistry of New Jersey9, MedStar Washington Hospital Center10, Regions Hospital11, University of Cincinnati12, University of Texas Health Science Center at San Antonio13, University of Southern California14, Case Western Reserve University15, University of Iowa16
TL;DR: The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population, which will improve the capability of performing more meaningful multicenter trials among burn centers.
Abstract: Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.
TL;DR: Results indicated that an earlier onset of maltreatment, measured dichotomously and developmentally, predicted more symptoms of anxiety and depression in adulthood, while controlling for gender, race, current age, and other abuse reports.
Abstract: The authors tested the hypothesis that children who are maltreated earlier in life are at greater risk for poor psychological functioning in adulthood than those maltreated later in life. Age of onset of maltreatment was assessed with 3 classifications: (a) continuous (ages 0-11 years); (b) dichotomous (early [ages 0-5 years] vs. later [ages 6-11 years]); and (c) developmental (infancy [ages 0-2 years], preschool [ages 3-5 years], early school age [ages 6-8 years], and school age [ages 9-11 years]). Individuals with documented cases of physical and sexual abuse and neglect prior to age 12 (N=496) were followed up and assessed in adulthood. Results indicated that an earlier onset of maltreatment, measured dichotomously and developmentally, predicted more symptoms of anxiety and depression in adulthood, while controlling for gender, race, current age, and other abuse reports. Later onset of maltreatment, measured continuously or developmentally, was predictive of more behavioral problems in adulthood. Implications for the assessment of maltreated children, the prevention of adult psychopathology, and the classification of age of maltreatment onset are discussed.
TL;DR: Two potentially complementary meanings of recovery were identified and the first meaning of recovery in derives from the Mental Health Consumer/Survivor Movement and refers instead to a person's rights to self-determination and inclusion in community life despite continuing to suffer from mental illness.
Abstract: Background: There is an increasing global commitment to recovery as the expectation for people with mental illness. There remains, however, little consensus on what recovery means in relation to me...
TL;DR: It is shown that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes, and this results suggest that dex Razoxane antagonizesDoxorubsicin-induced DNA damage through its interference with Top2beta, which could implicate Top2 beta indoxorUBicin cardiotoxicity.
Abstract: Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks.
TL;DR: PE is a highly prevalent sexual problem, with significant sexual and psychological comorbidities, and most men with PE do not seek assistance from their physician, and those who do are not satisfied with the results.
TL;DR: It is concluded that the PSPRS is a practical measure that is sensitive to disease progression and could be useful as a dependent variable in observational or interventional trials and as an indicator of prognosis in clinical practice.
Abstract: We devised a Progressive Supranuclear Palsy (PSP) Rating Scale comprising 28 items in six categories: daily activities (by history), behaviour, bulbar, ocular motor, limb motor and gait/midline. Scores range from 0 to 100, each item graded 0-2 (six items) or 0-4 (22 items). Inter-rater reliability is good, with intra-class correlation coefficient for the overall scale of 0.86 (95% CI 0.65-0.98). A single examiner applied the PSPRS at every visit for 162 patients. Mean rate of progression was 11.3 (+/-11.0) points per year. Neither onset age nor gender correlated well with rate of progression. Median actuarially corrected survival was 7.3 years. The PSPRS score was a good independent predictor of subsequent survival (P < 0.0001). For example, for patients with scores from 40 to 49, 3-year survival was 41.9% (95% CI 31.0-56.6) but 4-year survival was only 17.9% (95% CI 10.2-31.5). For those patients, likelihood or retaining some gait function was 51.7% (40.0-66.9) at 1 year but only 6.5% (1.8-23.5) at 3 years. We conclude that the PSPRS is a practical measure that is sensitive to disease progression and could be useful as a dependent variable in observational or interventional trials and as an indicator of prognosis in clinical practice.
Royal Free Hospital1, Boston University2, University of California, Los Angeles3, University of Leeds4, University of Medicine and Dentistry of New Jersey5, Genzyme6, Lund University7, Coventry Health Care8, University of Salford9, University of Texas Health Science Center at Houston10, St. Vincent's Health System11, University of Michigan12
TL;DR: The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed, and the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug CAT-192 was reported.
Abstract: Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta 1 (TGF beta 1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). Methods. Patients with SSc duration of < 18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mglkg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGF beta 1 and TGF beta 2. Results. Forty-five patients were enrolled. There was significant morbidity and mortality, including I death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). Conclusion. We report the first evaluation of a systemically administered and repeatedly dosed anti-TGF beta 1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. (Less)
TL;DR: SNP-829C→T, a naturally occurring SNP, near the miR-24 binding site in the 3′ UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with mi R-24 function, resulting in DHFR overexpression and methotrexate resistance.
Abstract: MicroRNAs are predicted to regulate ≈30% of all human genes by targeting sequences in their 3′ UTR Polymorphisms in 3′ UTR of several genes have been reported to affect gene expression, but the mechanism is not fully understood Here, we demonstrate that 829C→T, a naturally occurring SNP, near the miR-24 binding site in the 3′ UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance miR-24 has a conserved binding site in DHFR 3′ UTR DHFR with WT and 3′ UTR containing the 829C→T mutation were expressed in DG44 cells that lack DHFR Overexpression of miR-24 in cells with WT DHFR resulted in down-regulation of DHFR protein, whereas no effect on DHFR protein expression was observed in the mutant 3′ UTR-expressing cells Inhibition of endogenous miR-24 with a specific inhibitor led to up-regulation of DHFR in WT and not in mutant cells Cells with the mutant 3′ UTR had a 2-fold increase in DHFR mRNA half-life, expressed higher DHFR mRNA and DHFR protein, and were 4-fold more resistant to methotrexate as compared with WT cells SNP-829C→T, therefore, leads to a decrease in microRNA binding leading to overexpression of its target and results in resistance to methotrexate We demonstrate that a naturally occurring miRSNP (a SNP located at or near a microRNA binding site in 3′ UTR of the target gene or in a microRNA) is associated with enzyme overproduction and drug resistance
TL;DR: Despite serious immunological and non-immunological complications, RBC transfusion holds a therapeutic index that exceeds that of many common medications.
TL;DR: A function for p53 in maternal reproduction through the regulation of LIF is demonstrated, in a gender-specific manner, and evidence is accumulating that p53 may have a similar function in humans.
Abstract: The transcription factor p53 has been studied extensively as a tumour suppressor, but little is known about its normal physiological role. A study in mice now links normal p53 function to reproduction and fertility. A p53 deficiency results in poor implantation of embryos in female mice, low pregnancy rates and small litter sizes. In this role p53 acts by regulating LIF (leukaemia inhibitory factor), a cytokine involved in blastocyst implantation. This work raises the possibility that the normal function of p53 is important for the success of implantation particularly in women undergoing in vitro fertilization or embryo transfer, and suggests a potential strategy to improve implantation efficiency in women with recurrent implantation failure. The p53 gene has been extensively studied for its role in tumour prevention but little is known about its normal physiological function. A crucial role of this factor in fecundity and reproduction is now reported. Extensive studies have shown that p53 is important in tumour prevention1. However, little is known about its normal physiological function. Here we show that p53 is important in reproduction, in a gender-specific manner. Significant decreases in embryonic implantation, pregnancy rate and litter size were observed in matings with p53-/- female mice but not with p53-/- male mice. The gene encoding leukaemia inhibitory factor (LIF), a cytokine critical for implantation2, was identified as a p53-regulated gene that functions as the downstream mediator of this effect. p53 can regulate both basal and inducible transcription of LIF. Loss of p53 decreased both the level and function of LIF in uteri. Lower LIF levels were observed in the uteri of p53-/- mice than in those of p53+/+ mice, particularly at day 4 of pregnancy, when transiently induced high levels of LIF were crucial for embryonic implantation. This observation probably accounts for the impaired implantation of embryos in p53-/- female mice. Administration of LIF to pregnant p53-/- mice restored maternal reproduction by improving implantation. These results demonstrate a function for p53 in maternal reproduction through the regulation of LIF. Evidence is accumulating that p53 may have a similar function in humans.
TL;DR: HRV biofeedback appears to be a useful adjunctive treatment for the treatment of MDD, associated with large acute increases in HRV and some chronic increases, suggesting increased cardiovagal activity.
Abstract: Major depressive disorder (MDD) is a common mood disorder that can result in significant discomfort as well as interpersonal and functional disability. A growing body of research indicates that autonomic function is altered in depression, as evidenced by impaired baroreflex sensitivity, changes in heart rate, and reduced heart rate variability (HRV). Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in participants with MDD, and baroreflex gain is decreased. Study objectives: To assess the feasibility of using HRV biofeedback to treat major depression. Design: This was an open-label study in which all eleven participants received the treatment condition. Participants attended 10 weekly sessions. Questionnaires and physiological data were collected in an orientation (baseline) session and Treatment Sessions 1, 4, 7 and 10. Measurements and results: Significant improvements were noted in the Hamilton Depression Scale (HAM-D) and the Beck Depression Inventory (BDI-II) by Session 4, with concurrent increases in SDNN, standard deviation of normal cardiac interbeat intervals) an electrocardiographic estimate of overall measure of adaptability. SDNN decreased to baseline levels at the end of treatment and at follow-up, but clinically and statistically significant improvement in depression persisted. Main effects for task and session occurred for low frequency range (LF) and SDNN. Increases in these variables also occurred during breathing at one’s resonant frequency, which targets baroreflex function and vagus nerve activity, showing that subjects performed the task correctly Conclusions: HRV biofeedback appears to be a useful adjunctive treatment for the treatment of MDD, associated with large acute increases in HRV and some chronic increases, suggesting increased cardiovagal activity. It is possible that regular exercise of homeostatic reflexes helps depression even when changes in baseline HRV are smaller. A randomized controlled trial is warranted.
TL;DR: A functional link is demonstrated between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1, and these activities independently contribute to elevated levels of SUV39h1 activity resulting in increased levels of the H3K9me3 modification.
Abstract: In contrast to stably repressive, constitutive heterochromatin and stably active, euchromatin, facultative heterochromatin has the capacity to alternate between repressive and activated states of transcription. As such, it is an instructive source to understand the molecular basis for changes in chromatin structure that correlate with transcriptional status. Sirtuin 1 (SIRT1) and suppressor of variegation 3-9 homologue 1 (SUV39H1) are amongst the enzymes responsible for chromatin modulations associated with facultative heterochromatin formation. SUV39H1 is the principal enzyme responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in regions of heterochromatin. SIRT1 is an NAD+-dependent deacetylase that targets histone H4 at lysine 16 (refs 3 and 4), and through an unknown mechanism facilitates increased levels of H3K9me3 (ref. 3). Here we show that the mammalian histone methyltransferase SUV39H1 is itself targeted by the histone deacetylase SIRT1 and that SUV39H1 activity is regulated by acetylation at lysine residue 266 in its catalytic SET domain. SIRT1 interacts directly with, recruits and deacetylates SUV39H1, and these activities independently contribute to elevated levels of SUV39H1 activity resulting in increased levels of the H3K9me3 modification. Loss of SIRT1 greatly affects SUV39H1-dependent H3K9me3 and impairs localization of heterochromatin protein 1. These findings demonstrate a functional link between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1.
TL;DR: A 3- and 8-fold higher rate of elevated blood pressure strata was observed in acute stroke than the existing rates of stages 1 and 2 hypertension in the US population.
Abstract: Purpose
To estimate the prevalence of elevated blood pressure in adult patients with acute stroke in the United States (U.S.).