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Michael Berger

Publications and source records attributed to Michael Berger.

18 recordsLinked to original sources
PubMed2026

The Genomic Landscape of MYC-, MYCL-, and MYCN-Amplified Solid Tumors.

PURPOSE: MYC, MYCN, and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESIGN: We analyzed copy-number alterations of MYC family genes and their features in more than 68,000 tumor-normal paired samples from pediatric and adult patients sequenced with MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) and annotated with FACETS (Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing). The relationship between amplification features and MYC mRNA expression levels were evaluated in more than 10,000 samples from The Cancer Genome Atlas (TCGA). RESULTS: Across MSK Cancer Center samples, MYC amplifications were most common, found in 2,949 samples compared with 310 in MYCL and 217 in MYCN. Although MYCN and MYCL amplifications were predominantly focal (<10 Mb, 79% and 93%, respectively), MYC amplifications were frequently broader (>10 Mb, 62%). Although most tumor types showed similar features between broad and focal amplifications of MYC, in select cancer types, we identified differing co-occurrence and mutual exclusivity patterns with other disease-specific drivers. Furthermore, although MYC-amplified TCGA samples showed higher mRNA expression than wild-type ones, the focality of MYC amplification was seen to have limited influence on expression levels. CONCLUSIONS: Our results suggest that MYC dependency likely depends on many factors, including, but not limited to, total copy number of the detected amplification, lineage-specific factors, concomitant presence or absence of additional oncogenic alterations, and in some cases amplification focality.

Humans↗
PubMed2006

The algT gene of Pseudomonas syringae pv. glycinea and new insights into the transcriptional organization of the algT-muc gene cluster.

The phytopathogenic bacterium Pseudomonas syringae pv. glycinea infects soybean plants and causes bacterial blight. In addition to P. syringae, the human pathogen Pseudomonas aeruginosa and the soil bacterium Azotobacter vinelandii produce the exopolysaccharide alginate, a copolymer of d-mannuronic and l-guluronic acids. Alginate production in P. syringae has been associated with increased fitness and virulence in planta. Alginate biosynthesis is tightly controlled by proteins encoded by the algT-muc regulatory gene cluster in P. aeruginosa and A. vinelandii. These genes encode the alternative sigma factor AlgT (sigma(22)), its anti-sigma factors MucA and MucB, MucC, a protein with a controversial function that is absent in P. syringae, and MucD, a periplasmic serine protease and homolog of HtrA in Escherichia coli. We compared an alginate-deficient algT mutant of P. syringae pv. glycinea with an alginate-producing derivative in which algT is intact. The alginate-producing derivative grew significantly slower in vitro growth but showed increased epiphytic fitness and better symptom development in planta. Evaluation of expression levels for algT, mucA, mucB, mucD, and algD, which encodes an alginate biosynthesis gene, showed that mucD transcription is not dependent on AlgT in P. syringae in vitro. Promoter mapping using primer extension experiments confirmed this finding. Results of reverse transcription-PCR demonstrated that algT, mucA, and mucB are cotranscribed as an operon in P. syringae. Northern blot analysis revealed that mucD was expressed as a 1.75-kb monocistronic mRNA in P. syringae.

Alginates↗
PubMed2006

Causes of death in obesity: relevant increase in cardiovascular but not in all-cancer mortality.

BACKGROUND AND OBJECTIVE: To assess the relation between body mass index (BMI) and the risk of death from various causes in a prospective cohort study. METHODS: In 6,192 obese patients (BMI > or =25 kg/m(2)) with mean BMI 36.6 kg/m(2) (SD 6.1) and mean age 40.4 years (SD 12.9) who had been referred to the obesity clinic of the Heinrich-Heine-University Düsseldorf, Germany, between 1961 and 1994, there were 1,058 deaths from all causes during a median follow-up time of 14.8 years. We calculated standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) for death from predefined groups of diseases by using Germany as reference population. RESULTS: In both sexes, risk of death from cardiovascular diseases (men: SMR = 2.2, CI 1.9-2.5; women: SMR = 1.6, CI 1.5-1.8), from diabetes (men: SMR = 5.4, CI 3.2-8.7; women: SMR = 3.5, CI 2.6-4.8), and in men from digestive diseases (SMR = 1.6, CI 1.01-2.3) was significantly increased. In contrast to other studies, an association between obesity and all-cancer mortality could not be found. Only in morbidly obese women (BMI > or =40 kg/m(2)), all-cancer mortality was significantly increased (SMR = 1.5, CI 1.1-1.9). CONCLUSION: Obesity is associated with increased risk of death from cardiovascular diseases and diabetes in both sexes, and from diseases of the digestive system in men.

Adolescent↗
PubMed2005

Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage.

Tumor suppression by the p53 protein largely depends on the elimination of damaged cells by apoptosis. Mutations in the polyproline region (PPR) of p53 impair its apoptotic function. Deletion of the PPR renders p53 more sensitive to inhibition by Mdm2 via an unknown mechanism. We have explored the mechanism by which the PPR modulates the p53/Mdm2 loop. Proline 82 of p53 was identified to be essential for its interaction with the checkpoint kinase 2 (Chk2) and consequent phosphorylation of p53 on serine 20, following DNA damage. These physical and functional interactions are regulated by Pin1 through cis-trans isomerization of proline 82. Our study unravels the pathway by which Pin1 activates p53 in response to DNA damage and explains how Pin1 protects p53 from Mdm2. Further, we propose a role for Pin1-dependent induction of p53 conformational change as a mechanism responsible for the enhanced interaction between p53 and Chk2 following DNA damage. Importantly, our findings elucidate the selection for mutations in the Pin1 target Thr81/Pro82 motif within the PPR of p53 in human cancer.

Animals↗
PubMed2005

Intravenous chlorpromazine for the emergency treatment of uncontrolled symptomatic hypertension in the pre-hospital setting: data from 500 consecutive cases.

BACKGROUND: Chlorpromazine is a dopamine-receptor antagonist antipsychotic agent. Because of its strong alpha-blocking and sedative actions, it has also been used as emergency therapy for extreme arterial hypertension. Published reports to date have included very small numbers of patients (i.e., 5-30). OBJECTIVES: To analyze data on almost 500 patients who received intravenous chlorpromazine for the emergency treatment of uncontrolled symptomatic hypertension in the pre-hospital setting. METHODS: We reviewed data from 496 consecutive patients who received intravenous chlorpromazine as emergency therapy for uncontrolled symptomatic hypertension. Chlorpromazine was injected intravenously. The dose was 1 mg every 2-5 minutes until the systolic pressure was < or =140 mmHg and the diastolic pressure < or =100 mmHg with alleviation of symptoms. RESULTS: The mean dose of chlorpromazine administered was 4.5 +/- 5 mg (range 1-50 mg). Only 33 patients (7%) required >10 mg. Chlorpromazine reduced systolic BP from 222.82 +/- 26.31 to 164.93 +/- 22.66 mmHg (P< 0.001) and diastolic BP from 113.5 +/-16.63 to 85.83 +/- 11.61 mmHg (P< 0.001). The sinus rate decreased from 97.9 +/- 23.5 to 92.2 +/- 19.7 beats per minute (P< 0.001). These results were achieved within the first 37 +/- 11 minutes. CONCLUSIONS: Intravenous chlorpromazine is safe and effective when used as emergency treatment for uncontrolled symptomatic hypertension.

Aged↗
PubMed2004

Zinc reduces intimal hyperplasia in the rat carotid injury model.

BACKGROUND: The response to arterial injury following balloon dilatation is known to involve proliferative and inflammatory processes. The current widespread use of stents to maintain arterial patency not only does not eliminate but possibly exaggerates the proliferative and inflammatory phenotype and although drug-eluting stents are available, their long-term safety is yet to be determined. Zinc is a trace element that serves as a cofactor of many enzymes. Interestingly, it has been shown to have anti-inflammatory and anti-proliferative properties. We thus sought to investigate its effect on smooth muscle cell proliferation and intimal thickening in the rat carotid artery injury model. METHODS AND RESULTS: Smooth muscle cells (SMC) were cultured from carotid arteries of rats and proliferation was assessed by thymidine incorporation after exposure to different concentrations of zinc. Next, carotid artery injury was induced in rats by balloon dilatation and they were either treated with I.P injections of zinc or PBS for 2 weeks until sacrifice for assessment of neointimal formation and lumen area. Zinc inhibited in vitro SMC proliferation in a dose-dependent manner. In vivo, zinc treatment resulted in a 50% reduction in neointimal area and a significant decrease in neointimal/media ratio with no significant change in lumen area. CONCLUSION: Thus, zinc appears to reduce neointimal growth and should be tested by local delivery systems including stent coatings.

Animals↗
PubMed2003

Apoptosis - the p53 network.

Exposure to cellular stress can trigger the p53 tumor suppressor, a sequence-specific transcription factor, to induce cell growth arrest or apoptosis. The choice between these cellular responses is influenced by many factors, including the type of cell and stress, and the action of p53 co-activators. p53 stimulates a wide network of signals that act through two major apoptotic pathways. The extrinsic, death receptor pathway triggers the activation of a caspase cascade, and the intrinsic, mitochondrial pathway shifts the balance in the Bcl-2 family towards the pro-apoptotic members, promoting the formation of the apoptosome, and consequently caspase-mediated apoptosis. The impact of these two apoptotic pathways may be enhanced when they converge through Bid, which is a p53 target. The majority of these apoptotic effects are mediated through the induction of specific apoptotic target genes. However, p53 can also promote apoptosis by a transcription-independent mechanism under certain conditions. Thus, a multitude of mechanisms are employed by p53 to ensure efficient induction of apoptosis in a stage-, tissue- and stress-signal-specific manner. Manipulation of the apoptotic functions of p53 constitutes an attractive target for cancer therapy.

Animals↗
PubMed2003

Incidence of blindness in southern Germany due to glaucoma and degenerative conditions.

PURPOSE: To estimate population-based incidence rates of registered blindness separately, to determine its main causes. METHODS: The files of all newly registered blindness-allowance recipients in Württemberg-Hohenzollern, Germany (population: approximately 5 million), between 1994 and 1998 were reviewed. From ophthalmological reports on file the fulfillment of the German criteria for blindness (visual acuity of 1/50 or less or equivalent reduction of visual function) was ascertained, and the causes of blindness were obtained. Incidence rates of blindness due to macular degeneration, glaucoma, cataract, optic atrophy, and diabetic retinopathy were estimated. RESULTS: There were 3531 newly registered blindness-allowance recipients (67.1% female; mean age, 72.8 +/- 21.0 years). Standardized incidence rates in the general population (per 100,000 person-years; 95% confidence interval): All causes 12.27 (11.87-12.68), macular degeneration 5.29 (5.02-5.55), cataract 3.32 (3.11-3.52), optic atrophy 2.86 (2.66-3.05), glaucoma 2.43 (2.25-2.61), diabetic retinopathy 2.13 (1.96-2.30), other or unknown causes 5.17 (4.91-5.43). In many cases, blindness was attributable to more than one cause. Assuming that incidence rates are the same in other parts of the country, 9,939 (9,608-10,270) new cases of blindness were estimated to occur in Germany per year. CONCLUSIONS: The most common single cause of blindness was macular degeneration. Incidence rates of blindness due to such treatable conditions as glaucoma were also high. This finding suggests that the taking of measures for secondary prevention (e.g., early detection and optimal treatment of patients with glaucoma and diabetic retinopathy) should be intensified.

Adolescent↗
PubMed2003

Flow cytometric analysis of p53-induced apoptosis.

The p53 protein is a key player in the cellular response to stress conditions. Activation of p53 induces growth inhibition in the form of cell growth arrest or apoptosis. The latter plays an important role in the tumor suppression function of p53. It is therefore of great interest to understand in detail the mechanisms by which p53 induces apoptosis. In this chapter, we describe a flow cytometric assay for the measurement of p53 apoptotic activity. This assay is applicable for exogenously expressed p53 by transfection as well as for endogenous p53. The p53 protein is detected by intra-cellular fluorescent staining of p53 or by tagging p53 with GFP. The extent of apoptosis in cells expressing p53 is determined by cell cycle distribution using flow cytometry. The protocol described here can be employed to study the regulation of p53-mediated apoptosis and can be broadly applied to other apoptotic proteins.

Animals↗
PubMed2002

Body weight, blood pressure, and mortality in a cohort of obese patients.

The associations between body weight, raised blood pressure, and mortality remain controversial. The authors examined these relations by considering all degrees of obesity in the Düsseldorf Obesity Mortality Study (1961-1994). Among 6,193 obese German patients aged 18-75 years and having a body mass index (BMI) of > or =25 kg/m(2), 1,059 deaths were observed after a median follow-up of 14.8 years. The entire cohort was grouped into quartiles according to BMI (25-<32, 32-<36, 36-<40, > or =40 kg/m(2)) and systolic blood pressure (SBP) (<140, 140-<160, 160-<180, > or =180 mmHg). Cox proportional hazards analyses were performed to adjust for age. For women, the mortality risk curves for the four BMI groups in relation to SBP were flat without crossing, whereas the risk curve for moderately obese men (BMI 25-<32 kg/m(2)) crossed the risk curves for the higher BMI groups. In the group of patients with very high blood pressure (SBP > or = 180 mmHg), moderately obese subjects (BMI 25-<32 kg/m(2)) had a higher mortality risk for men when compared with the BMI group 32-<36 kg/m(2) (hazard ratio =1.62, 95% confidence interval: 1.0, 2.7) but not for women (hazard ratio = 0.71, 95% confidence interval: 0.4, 1.2). These findings support previous observations that the risk of death is lower for hypertensive men in high compared with low BMI groups.

Adolescent↗
PubMed2002

Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation.

The p53 tumor suppressor is inhibited and destabilized by Mdm2. However, under stress conditions, this downregulation is relieved, allowing the accumulation of biologically active p53. Recently we showed that c-Abl is important for p53 activation under stress conditions. In response to DNA damage, c-Abl protects p53 by neutralizing the inhibitory effects of Mdm2. In this study we ask whether this neutralization involves a direct interplay between c-Abl and Mdm2, and what is the contribution of the c-Abl kinase activity? We demonstrate that the kinase activity of c-Abl is required for maintaining the basal levels of p53 expression and for achieving maximal accumulation of p53 in response to DNA damage. Importantly, c-Abl binds and phosphorylates Mdm2 in vivo and in vitro. We characterize Hdm2 (human Mdm2) phosphorylation at Tyr394. Substitution of Tyr394 by Phe394 enhances the ability of Mdm2 to promote p53 degradation and to inhibit its transcriptional and apoptotic activities. Our results suggest that phosphorylation of Mdm2 by c-Abl impairs the inhibition of p53 by Mdm2, hence defining a novel mechanism by which c-Abl activates p53.

Amino Acid Substitution↗
PubMed2002

Anion-controlled assembly of porphyrin-bicyclic guanidine conjugates.

[reaction: see text] Cationic porphyrins 1-3 bearing one, two, and four bicyclic guanidines form highly ordered chiral assemblies in aqueous solutions. The chirality is controlled by the type of the anionic counterpart and results from a spontaneous process. The chiral assemblies of 1-3 relate structurally to the complexes of achiral porphyrins with helical DNA. However, the presence of a chiral template (DNA, poly L-Glu were tested) is not necessary for formation of these specific chiral porphyrin assemblies.

Anions↗
PubMed2002

Chronically diseased patients and their doctors.

The doctor-patient relationship reflects the role of the physician in society and has thus experienced substantial changes over time. Medical authority can be dissected into three elements, all of which appear essential for any doctor-patient relationship: sapiental authority, i.e. professional competence as called for e.g. by the system of evidence-based medicine; moral authority (paternalism); and charismatic-empathic authority (to treat any patient like a friend). These elements are mirrored by chronically diseased patients who want to be seen as either consumers, clients or patients. The healthcare system needs these three elements to be maintained and further developed and medical school education needs to focus more specifically on these basics of patient care.

Chronic Disease↗
PubMed2002

Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect.

Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the gamma-aminobutyric acid (GABA) binding site of GABA(A) receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors. Patch-clamp studies using human embryonic kidney cells transiently transfected with recombinant GABA(A) receptors composed of alpha 1 beta 2 gamma 2 subunits showed that TAMCA did not activate these receptors but dose dependently blocked GABA-induced chloride ion flux with an IC(50) of 7.1 +/- 3.1 mM. Application of TAMCA to the lumbar spinal cord of rats resulted in dose-dependent hyperexcitability, which was completely blocked by coapplication of the GABA(A) receptor agonist muscimol. These results indicate that TAMCA may induce hyperexcitability by blocking GABA-driven inhibition of the CNS.

Animals↗
PubMedDate not supplied

A model of preverbal social development and its application to social dysfunctions in autism.

Studies of early face perception are used to develop a model of how face expressions might be transduced to initiate consonant internal affect, related outward expressions and other behaviours. Underlying neural mechanisms and processes are identified. The model is generalised to offer an account of aspects of typical preverbal social development. It is then used to develop aetiological hypotheses about the lack of social interest and motivation in autism and to provide a framework for evaluating other theories of autism. Although derived from existing literature, the model offers a distinctive account.

Amygdala↗