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PubMed2005

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement.

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Adolescent↗

PubMed2005

New antibodies recognizing p73: comparison with commercial antibodies.

p73, unlike p53, is expressed as a number of isomeric forms. Alternative splicing at the 3' end of p73 transcript, together with the usage of a second promoter downstream of exon 3, can generate up to 24 p73 isoforms. Variants lacking the TA domain (DeltaN isoforms) are induced by TAp73 and by p53, and inhibit their transcriptional activity. However, understanding the complex biology of p73 has been handicapped by the lack of high affinity specific antibodies for the different isoforms. Here, we report the characterization, by Western blotting and immunoprecipitation, of three new polyclonal antisera recognizing all p73 isoforms, only DeltaN isoforms or only p73alpha, and which have advantages of affinity and specificity over previously available antibodies.

Antibodies↗

PubMed2005

p73 induces apoptosis by different mechanisms.

p73, like its homologue, the tumor suppressor p53, is able to induce apoptosis in several cell types. This property is important for the involvement of p73 in cancer development and therapy. However, in contrast with p53, the TAp73 gene has two distinct promoters coding for two protein isoforms with opposite effects: while the transactivation proficient TAp73 shows pro-apoptotic effects, the amino-terminal-deleted DeltaNp73 has an anti-apoptotic function. Indeed, the relative expression of these two proteins is related to the prognosis of several cancers. Here we discuss recent developments in the control of p73-induced apoptosis. First, TAp73 induces ER stress via the direct transactivation of Scotin. Second, TAp73 induces the mitochondrial pathway by directly transactivating both Bax and the BH3 only protein PUMA promoters. While the first transactivation is weak, and not sufficient to trigger apoptosis (at least in the in vitro cellular models so far evaluated), the induction of PUMA is strong and lethal. Third, the promoter of the death receptor CD95 contains a p53 responsive element and preliminary experiments suggest that TAp73 also activates the death receptor pathway. In addition, TAp73 is able to transactivate its own second promoter, thus inducing the expression of the anti-apoptotic DeltaNp73 isoform. Therefore, the balance between TAp73 and DeltaNp73 finely regulates cellular sensitivity to death.

Animals↗

PubMed2005

p63 protein is essential for the embryonic development of vibrissae and teeth.

Development of skin appendages strongly depends on epithelial-mesenchymal interactions. One of the genes involved in this process is p63, a member of the p53 family of transcription factors, essential for ectodermal development, as elucidated by the phenotype of p63 knock-out mice. Surprisingly, no information on p63 expression in tooth and hair is yet available. Here, we show p63 expression during teeth and vibrissae morphogenesis in mouse embryos and we also show a correlation with the expression patterns of the epithelial marker keratin 5 and the proliferation marker Ki67. Our results show that p63 colocalizes with both K5 and Ki67 in the epithelium of developing vibrissae, while in teeth p63 is expressed, together with K5, in the undifferentiated ectoderm (enamel organ), and in ameloblasts, a subpopulation of differentiated ectodermal cells. Moreover, p63 expression in tooth seems not to be fully colocalized with nuclear Ki67 expression.

Animals↗

PubMed2006

p63 and p73, members of the p53 gene family, transactivate PKCdelta.

The p53 family comprises three genes that encode for p53, p63 and p73. These genes have a significant degree of sequence homology, especially in the central sequence-specific DNA-binding domain. The high homology among the three DNA-binding domains indicates that these transcription factors have identical residues interacting with DNA, and thus potentially can recognize the same transcriptional targets. In this study, we demonstrate that PKCdelta is induced by p63 and p73 in Saos2 cells. The putative human PKCdelta promoter harbours three p53-like binding sites (RE I, RE II, RE III). In order to confirm the transactivation of PKCdelta by p53 family members, we performed transcription assays using the entire or selected regions of the promoter upstream of a luciferase reporter gene. The results obtained demonstrated that, at least in vitro, the p53 family members tested (TAp63alpha, TAp73alpha, DeltaNp63alpha, but not DeltaNp73alpha) were able to drive transcription from the PKCdelta promoter.

Cell Line, Tumor↗

PubMed2005

Subjective and physiological reactivity to chocolate images in high and low chocolate cravers.

Cue-reactivity to chocolate images was assessed using self-report and physiological measures. From a pre-screening sample of 454, young women were selected and assigned to high and low chocolate craving groups (N = 36/group). The experimental procedure consisted in the elicitation and measurement of the cardiac defense and startle reflexes while viewing chocolate and standard affective images selected from the International Affective Picture System. In response to chocolate images, high cravers reported more pleasure and arousal but less control than low cravers. In high cravers, viewing chocolate images inhibited the cardiac defense but potentiated the startle reflex, as compared to low cravers. The results confirmed at the physiological level that the motivational state that underlies the experience of chocolate craving include both appetitive (inhibition of the defense reflex) and aversive (potentiation of the startle response) components. The findings supported a motivational conflict theory of chocolate craving.

Adult↗

PubMed2006

Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.

Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.

Administration, Oral↗

PubMed2006

Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors.

A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.

Administration, Oral↗

PubMed2006

PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.

TGFbeta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFbeta responses are generally mediated through transcriptional functions of Smads. A key step in TGFbeta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFbeta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFbeta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Calpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFbeta-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFbeta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling.

Active Transport, Cell Nucleus↗

PubMed2005

Separation and analysis of glycyrrhizin, 18beta-glycyrrhetic acid and 18alpha-glycyrrhetic acid in liquorice roots by means of capillary zone electrophoresis.

Glycyrrhizin is the main active compound of Glycyrrhiza glabra root extracts; according to recent studies, glycyrrhizin and its aglycon, glycyrrhetic acid, have interesting therapeutic properties. A new capillary electrophoretic method has been developed for the separation and quantification of glycyrrhizin, beta-glycyrrhetic acid and its isomer a-glycyrrhetic acid. Separation of the analytes was achieved in less than 3 min on a fused silica capillary, by injecting the samples at the short end of the capillary (effective length: 8.5 cm). The background electrolyte was composed of pH 10.0 carbonate buffer, methanol and ethylene glycol (80/10/10) and contained 0.4% beta-cyclodextrin; indomethacin was used as the internal standard. Diode array detection was used, with quantitative assays carried out at 254 nm. Linearity was found over the 5-200 and 2.5-100 microg mL(-1) concentration ranges for glycyrrhizin and glycyrrhetic acid, respectively. This method has been applied to the determination of the analytes in different matrices (liquorice roots and commercial confectionery products), and to the purity control of beta-glycyrrhetic acid obtained from the hydrolysis of glycyrrhizin. When analysing beta-glycyrrhetic acid and its epimer in roots, the samples were purified by means of a suitable solid-phase extraction (SPE) procedure with Oasis HLB cartridges, which granted good selectivity, eliminating matrix interference.

Candy↗

PubMed2006

Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.

AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission in the brain. Diversity in excitatory signalling arises, in part, from functional differences among AMPAR subtypes. Although the rapid insertion or deletion of AMPARs is recognised as important for the expression of conventional forms of long-term synaptic plasticity--triggered, for example, by Ca2+ entry through NMDA-type glutamate receptors--only recently has attention focused on novel forms of plasticity that are regulated by, or alter the expression of, Ca2+-permeable AMPARs. The dynamic regulation of these receptors is important for normal synaptic function and in disease states.

Animals↗

PubMed2004

Treatment of cancer-related anemia with epoetin alfa: a review.

Erythropoietin (EPO) is a hematopoietic growth hormone that regulates survival, proliferation, and differentiation of erythroid progenitor cells. A reduction in tissue oxygenation stimulates EPO production, through a complex feedback mechanism. Patients with cancer-related anemia have an inadequate EPO response that is further impaired by cancer treatments such as chemotherapy. Cancer-related anemia substantially impairs patient functioning and may contribute to poor treatment outcomes. A significant number of studies demonstrates that treatment of anemia in cancer patients using recombinant human EPO (rHuEPO, epoetin alfa) significantly increases haemoglobin (Hb) levels, reduces transfusion requirements, and improves quality of life, particularly by relieving fatigue. Recent data also show that epoetin alfa therapy may improve cognitive function in patients receiving chemotherapy. In addition, the correction of anemia may prolong survival by enhancing tumor oxygenation, thus increasing tumor sensitivity to chemotherapy or radiation. The indicated dose of epoetin alfa is 150-300 IU/kg three times per week, but it is commonly dosed at 40,000-60,000 IU once weekly based on trial data and extensive clinical use. Determining the timing of initiation of epoetin alfa is a clinical judgement; however, data suggest that patient functioning declines and the risk of transfusion increases when the Hb level falls under 12 g/dL.

Anemia, Hypochromic↗

PubMed2005

Injection systems for two luteinising hormone-releasing hormone agonists: a comparative assessment of administration times and nurses' perceptions.

The aim of this study was to compare the speed of administration (preparation and delivery) and nurses' perceived ease of use and relative safety of two injection systems used to administer luteinising hormone-releasing hormone agonists: a depot system used to administer goserelin acetate ('Zoladex', AstraZeneca) and a vial system used to administer leuprorelin acetate ('Prostap', Wyeth). This was a randomised, crossover study with 82 volunteer nurses (50 pre-registration and 32 post-registration). All nurses were timed in the administration of both systems and all were required to assess the two systems by completing a questionnaire. Results indicate that both pre- and post-registration nurses administered the depot system in less time than the vial system. Overall mean times for administration of the depot system and the vial system were 1.70 and 3.34min, respectively. In questionnaire responses, significantly more nurses thought that the depot system had 'good safety precautions' compared with the vial system (85% versus 40%; P<0.001) and significantly more nurses also expressed a preference for the depot system (58% versus 42%; P=0.036). In conclusion, this study demonstrates that nurses prefer the one-step depot system used to administer goserelin acetate over the vial system used to administer leuprorelin acetate.

Antineoplastic Agents, Hormonal↗

PubMed2005

Methylmercury exposure in Wisconsin: A case study series.

Many popular varieties of commercially sold fish, including tilefish, seabass, shark, and swordfish, contain enough mercury so that eating them once or twice a month can lead to high mercury body burdens. Wisconsin has issued mercury-based sport-fish consumption advice to people of all ages since 1985. Wisconsin's advisory was revised in 2000 to address all inland waters and again in 2004 to integrate information about sport-caught fish with advice for commercially sold fish. Because of the increased popularity of fish as a source of dietary protein, a significant percentage of the US population may be at risk of methylmercury-induced health problems. Although several studies have assessed mercury exposure among children and women of child-bearing age, very little is known about mercury body burdens among men or postmenopausal women. This article describes fish consumption and mercury exposure among 14 people who consumed fish twice a week or more and 1 person who ate no fish. Steady-state blood mercury levels available for 10 adults and 1 child ranged from <5 to 58 microg/L and correlated well with dietary mercury intake estimates. Three of these individuals reported vague, subclinical symptoms such as mental confusion, sleep difficulty, balance problems, or visual disturbances, which improved after their mercury levels returned to normal.

Adult↗

PubMed2006

Genomic and experimental evidence for a potential sexual cycle in the pathogenic thermal dimorphic fungus Penicillium marneffei.

All meiotic genes (except HOP1) and genes encoding putative pheromone processing enzymes, pheromone receptors and pheromone response pathways proteins in Aspergillus fumigatus and Aspergillus nidulans and a putative MAT-1 alpha box mating-type gene were present in the Penicillium marneffei genome. A putative MAT-2 high-mobility group mating-type gene was amplified from a MAT-1 alpha box mating-type gene-negative P. marneffei strain. Among 37 P. marneffei patient strains, MAT-1 alpha box and MAT-2 high-mobility group mating-type genes were present in 23 and 14 isolates, respectively. We speculate that P. marneffei can potentially be a heterothallic fungus that does not switch mating type.

Amino Acid Sequence↗

PubMed2005

Laparoscopic Nissen fundoplication decreases gastroesophageal junction distensibility in patients with gastroesophageal reflux disease.

Laparoscopic Nissen fundoplication (LNF) is the surgical treatment of choice for gastroesophageal reflux disease (GERD). Post-LNF complications, such as gas bloat syndrome, inability to belch and vomit, and dysphagia, remain too common and prevent LNF from being more highly recommended. It remains controversial as to whether preoperative assessment can predict the development of post-LNF complications. Some authors have shown a correlation between pre-LNF manometry characteristics and post-LNF dysphagia, and others have not. We hypothesize that many post-LNF complications are caused by a decrease in the distensibility of the GEJ and that standard manometry is at best an indirect measure of this. The aim of this study is to directly measure the effect of LNF on gastroesophageal junction (GEJ) distensibility (GEJD). The lower esophageal sphincter (LES) of 15 patients undergoing LNF was characterized using standard manometry. The GEJD before and after a standardized LNF was measured using a specialized catheter, containing an infinitely compliant bag, placed within the LES. GEJD was measured, as dV/dP over volumes 5 to 25 mL distended at a rate of 20 mL/min. Mean dP +/- standard error of the mean for each volume was calculated, and distensibility curves were generated and compared. Measurements were also taken after abolishing LES tone by mid-esophageal balloon distension. Patient symptoms were recorded before and after surgery. Statistical analysis was performed by two-way repeated-measures analysis of variance, paired t test, and the Tukey test. Laparoscopic Nissen fundoplication led to a statistically significant increase in Delta pressure over each volume tested and therefore a significant decrease in the distensibility of the GEJ. Abolition of LES tone had no statistical effect on GEJD after fundoplication. There were no complications, and none of the patients developed the symptom of dysphagia postoperatively. These are the first direct measurements to show that LNF significantly reduces the distensibility of the GEJ. We hypothesize that the magnitude of this reduction may be the vital variable in the development of post-LNF complications and specifically post-LNF dysphagia. The intraoperative measurement of LES distensibility may provide a means for avoiding this feared and other post-LNF complications in the future.

Adult↗

PubMed2024

RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures.

PURPOSE: RORA encodes the RAR-related orphan receptor-α, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder. METHODS: Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration. RESULTS: The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (n = 21), chromosomal microarray analysis (n = 7), or gene panels (n = 4), included frameshift (n = 18/33), missense (n = 9/33), and stop codon (n = 6/33). Developmental disability (n = 32/37), intellectual disability (n = 22/32), and cerebellar signs (n = 25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset, and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (n = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (n = 18/38), with prominent myoclonic seizure types (n = 11/18), was classified in (1) genetic generalized epilepsy (n = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (n = 5/6) and epilepsy with myoclonic absence (n = 1/6); (2) developmental and epileptic encephalopathy (n = 5/18); and (3) unclassified (n = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported. CONCLUSION: Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The RORA-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.

Humans↗

PubMed2006

Service implications from a comparison of the evidence on the effectiveness and a survey of provision in England and Wales of COPD specialist nurse services in the community.

STUDY BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of mortality worldwide and is a burden on healthcare resources. Therefore, implementing the right care model(s) for patients with COPD is a priority. Nurses, particularly those with specialist roles, are often the principal health professionals involved in new service models. NEW SERVICES: for patients in the community with COPD are increasing in many countries. Two main types of initiatives have been evaluated; those designed to transfer acute care out of hospital and into the community, and those offering chronic disease management. The extent and nature of such specialist services in the UK and internationally are unknown. OBJECTIVES: To present the results of the first survey of specialist nurse service provision for patients in the community with COPD in England and Wales. To combine the survey findings with systematic review evidence to explore to what extent provision is supported by evidence of effectiveness. METHODS: A postal survey of respiratory healthcare professionals undertaken concurrently with a review of the evidence of the effectiveness of nurse COPD services (review findings are reported fully elsewhere). RESULTS: Two hundred and thirty four specialist nurse services were identified; 71% involved chronic disease management, of which 47% also provided acute care. Seventeen per cent of services involved acute care only. The review identified evidence to support the provision of acute services but data on chronic disease management services are sparse and there is currently little evidence to support these services. Those interventions that have been evaluated to date differed from many of the services provided. CONCLUSIONS: This study identifies a considerable mismatch between existing evidence around effectiveness and services provision for patients with COPD. It clearly highlights the need for greater interaction between what happens in practice and research. This is an issue that has relevance across all healthcare practice, both nationally and internationally.

Acute Disease↗