RESUMEN
To test the traditional model of tumor progression, Darwinian-type evolution, against the more recent Big Bang model, we selected 6 microsatellite-stable colorectal standard-type adenocarcinomas and their synchronous lymph node and liver metastases. Somatic genomic variants were identified by whole-exome sequencing (WES) of large tumor fragments from the primaries and 1 liver metastasis each, and used to design targeted resequencing next-generation sequencing (NGS) panels, 1 per case. Targeted deep resequencing (mean coverage, 2725; median, 2222) was performed with DNA from punch samples (1-mm tissue microarrayer needles) obtained from different regions of the primaries and their metastases. In total, 255 genomic variants were interrogated in 108 punch samples. Clonal heterogeneity was infrequent: a pattern of clonal heterogeneity consistent with a role in metastasis formation was observed only in 1 case in a single gene (p. Asp604Tyr of the PTPRT gene). However, when comparing variant allele frequencies (VAFs) of genomic variants in adjacent positions on chromosomes ("matched genomic variant loci") across punch samples, differences that exceeded 2 SD of the NGS assay variations (ad hoc dubbed VAF dysbalance) were observed in 7.1% of the punch samples (2.6%-12.0% per case), which indicates an intricate intermixing of mutated and nonmutated tumor cells ("intrinsic heterogeneity"). Additional OncoScan array analyses on a subset of the punch samples (31 in total) showed gross genomic aberrations as a possible explanation in only some (39.2%) of the matched genomic variant loci with VAF dysbalance. Our study provides a fairly direct (statistical model-free) view of the genomic states of microsatellite-stable colorectal carcinomas and their metastases, and suggests that Darwinian-type tumor evolution is not the key pathway of the metastasizing disease; instead, we recorded an "intrinsic" genomic heterogeneity, which may echo an initial Big Bang-like event.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Repeticiones de Microsatélite/genética , MutaciónRESUMEN
Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the NPC1 leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-Npc1m1N/-J Jackson Npc1 mice in female and male Npc1+/+ and Npc1-/- mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 Npc1+/+, 175 Npc1-/-) were dissected at P65. In both sexes, the body weights of None and Sham Npc1-/- mice were lower than those of respective Npc1+/+ mice. The influence of the Npc1 mutation and/or sex on the weights of various organs, however, differed considerably. In males, Npc1+/+ and Npc1-/- mice had comparable absolute weights of lungs, spleen, and adrenal glands. In Npc1-/- mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female Npc1-/- mice, ovaries, and uteri were significantly smaller. In Npc1-/- mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies.
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1-Desoxinojirimicina , Ciclodextrinas , Tamaño de los Órganos , Pregnanolona , Animales , Femenino , Masculino , Ratones , 1-Desoxinojirimicina/farmacología , Peso Corporal , Ciclodextrinas/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética , Pregnanolona/farmacología , Ratones NoqueadosRESUMEN
Background. For neurodegenerative diseases such as Huntington's disease (HD), early diagnosis is essential to treat patients and delay symptoms. Impaired olfaction, as observed as an early symptom in Parkinson´s disease, may also constitute a key symptom in HD. However, there are few reports on olfactory deficits in HD. Therefore, we aimed to investigate, in a transgenic rat model of HD: (1) whether general olfactory impairment exists and (2) whether there are disease-specific dynamics of olfactory dysfunction when the vomeronasal (VNE) and main olfactory epithelium (MOE) are compared. Methods. We used male rats of transgenic line 22 (TG22) of the bacterial artificial chromosome Huntington disease model (BACHD), aged 3 days or 6 months. Cell proliferation, apoptosis and macrophage activity were examined with immunohistochemistry in the VNE and MOE. Results. No differences were observed in cellular parameters in the VNE between the groups. However, the MOE of the 6-month-old HD animals showed a significantly increased number of mature olfactory receptor neurons. Other cellular parameters were not affected. Conclusions. The results obtained in the TG22 line suggest a relative stability in the VNE, whereas the MOE seems at least temporarily affected.
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Enfermedad de Huntington , Trastornos del Olfato , Neuronas Receptoras Olfatorias , Animales , Cromosomas Artificiales Bacterianos , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Masculino , Trastornos del Olfato/metabolismo , Mucosa Olfatoria/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Ratas , Ratas TransgénicasRESUMEN
In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1-/- mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1-/- and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1-/- mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1-/- mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1-/- mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1-/- mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1-/- mice was almost completely reduced only in the female groups.
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1-Desoxinojirimicina/análogos & derivados , 2-Hidroxipropil-beta-Ciclodextrina/farmacología , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 1-Desoxinojirimicina/farmacología , Animales , Ciclodextrinas/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Pregnanolona/farmacologíaRESUMEN
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann-Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.
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Enfermedad de Niemann-Pick Tipo C/etiología , Enfermedad de Niemann-Pick Tipo C/metabolismo , Animales , Transporte Biológico , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Humanos , Metabolismo de los Lípidos , Ratones , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/terapia , Especificidad de ÓrganosRESUMEN
Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsonian (hemi-PD) rats. The initiation time (IT) is considered the most sensitive parameter in the stepping test procedure. Here we propose a novel, reliable, and simple method for the measurement of IT of both forelimbs in both forehand and backhand directions in rats. Evaluating the same videos taken for quantifying adjusting steps, IT measurements were done without additional experiments. This is in contrast to the classical approach introduced by Olsson et al. (1995), in which separate experiments are necessary. We successfully applied our approach to hemi-PD rats intrastriatally treated with botulinum neurotoxin-A (BoNT-A). In naïve rats, an IT of about 0.62 s was found, and in right-sided hemi-PD rats the IT of the left forepaw increased to about 3.62 s. These hemi-PD rats showed, however, reduced ITs of the impaired left forepaws 1 month and the second time 7 months after induction of hemi-PD via the injection of 1 ng BoNT-A into the ipsilateral striatum, depending on post BoNT-A survival time. The method described offers the possibility of a precise and animal-friendly evaluation of IT in rats, including the beneficial effect of BoNT-A treatment in hemi-PD rats.
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Toxinas Botulínicas Tipo A/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Miembro Anterior/inervación , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/terapia , Animales , Toxinas Botulínicas Tipo A/farmacología , Modelos Animales de Enfermedad , Inyecciones , Masculino , Ratas , Ratas WistarRESUMEN
Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1-/- mutant mice compared with healthy controls (NPC1+/+). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1-/- mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and allopregnanolone or a monotherapy with HPßCD, we recorded a remarkable reduction of morphological damages in NPC1-/- mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.
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Mutación , Enfermedad de Niemann-Pick Tipo C/genética , Mucosa Olfatoria/patología , Proteínas/genética , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacología , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/patología , Mucosa Olfatoria/efectos de los fármacos , Pregnanolona/administración & dosificación , Pregnanolona/farmacología , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/farmacologíaRESUMEN
Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1-/- mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1-/- animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.
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1-Desoxinojirimicina/análogos & derivados , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Ciclodextrinas/farmacología , Hipolipemiantes/farmacología , Pregnanolona/farmacología , 1-Desoxinojirimicina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Modelos Animales de Enfermedad , Esquema de Medicación , Combinación de Medicamentos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/fisiopatología , Tamaño de los Órganos/efectos de los fármacosRESUMEN
BACKGROUND: In this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). METHODS: We analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group. RESULTS: We found significant effects of diagnosis (Pcorrected < .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P < .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects. CONCLUSIONS: The results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Encéfalo/patología , Sustancia Blanca/patología , Anciano , Anciano de 80 o más Años , Anisotropía , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Background: Niemann-Pick disease type C1 (NPC1, MIM 257220) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of Npc1-/- displays a rapidly progressing form of Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage. Npc1-/- mice receiving a combined therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPßCD) showed prevention of Purkinje cell loss, improved motor function and reduced intracellular lipid storage. Although therapy of Npc1-/- mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced. Methods: In order to evaluate alterations of different brain areas caused by pharmacotherapy, fresh volumes (volumes calculated from the volumes determined from paraffin embedded brain slices) of various brain structures in sham- and drug-treated wild type and mutant mice were measured using stereological methods. Results: In the wild type mice, the volumes of investigated brain areas were not significantly altered by either therapy. Compared with the respective wild types, fresh volumes of specific brain areas, which were significantly reduced in sham-treated Npc1-/- mice, partly increased after the pharmacotherapies in all treatment strategies; most pronounced differences were found in the CA1 area of the hippocampus and in olfactory structures. Discussion: Volumes of brain areas of Npc1-/- mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in Npc1-/- mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model.
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Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson's disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB.
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Toxinas Botulínicas Tipo A/administración & dosificación , Bulbo Olfatorio/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D2/metabolismo , Anfetamina , Animales , Apomorfina , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Inyecciones , Masculino , Bulbo Olfatorio/metabolismo , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Ratas WistarRESUMEN
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time.
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Modelos Animales de Enfermedad , Enfermedad de Machado-Joseph/patología , Ratones , Animales , Ataxina-3 , Femenino , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/terapia , Masculino , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Parkinson's patients often suffer from depression and anxiety, for which there are no optimal treatments. Hemiparkinsonian (hemi-PD) rats were used to test whether intrastriatal Botulinum neurotoxin-A (BoNT-A) application could also have antidepressant-like properties in addition to the known improvement of motor performance. To quantify depression- and anxiety-like behavior, the forced swim test, tail suspension test, open field test, and elevated plus maze test were applied to hemi-PD rats injected with BoNT-A or vehicle. Furthermore, we correlated the results in the forced swim test, open field test, and elevated plus maze test with the rotational behavior induced by apomorphine and amphetamine. Hemi-PD rats did not show significant anxiety-like behavior as compared with Sham 6-OHDA- + Sham BoNT-A-injected as well as with non-injected rats. However, hemi-PD rats demonstrated increased depression-like behaviors compared with Sham- or non-injected rats; this was seen by increased struggling frequency and increased immobility frequency. Hemi-PD rats intrastriatally injected with BoNT-A exhibited reduced depression-like behavior compared with the respective vehicle-receiving hemi-PD animals. The significant effects of intrastriatally applied BoNT-A seen in the forced swim test are reminiscent of those found after various antidepressant drug therapies. Our data correspond with the efficacy of BoNT-A treatment of glabellar frown lines in treating patients with major depression and suggest that also intrastriatal injected BoNT-A may have some antidepressant-like effect on hemi-PD.
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Antidepresivos/uso terapéutico , Toxinas Botulínicas Tipo A/uso terapéutico , Anfetamina , Animales , Apomorfina , Conducta Animal , Toxinas Botulínicas Tipo A/administración & dosificación , Cuerpo Estriado , Modelos Animales de Enfermedad , Inyecciones , Masculino , Actividad Motora , Oxidopamina , Enfermedad de Parkinson , Trastornos Parkinsonianos , Ratas , Ratas WistarRESUMEN
Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is caused by the expansion of a polyglutamine repeat in the ataxin-3 protein. We generated a mouse model of SCA3 expressing ataxin-3 with 148 CAG repeats under the control of the huntingtin promoter, resulting in ubiquitous expression throughout the whole brain. The model resembles many features of the disease in humans, including a late onset of symptoms and CAG repeat instability in transmission to offspring. We observed a biphasic progression of the disease, with hyperactivity during the first months and decline of motor coordination after about 1 year of age; however, intranuclear aggregates were not visible at this age. Few and small intranuclear aggregates appeared first at the age of 18 months, further supporting the claim that neuronal dysfunction precedes the formation of intranuclear aggregates.
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Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Repeticiones de Trinucleótidos/genética , Edad de Inicio , Animales , Ataxina-3 , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Inestabilidad Cromosómica/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/metabolismo , Cuerpos de Inclusión Intranucleares/patología , Enfermedad de Machado-Joseph/fisiopatología , Ratones , Ratones Transgénicos , Trastornos del Movimiento/genética , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/fisiopatología , Mutación/genética , Proteínas Nucleares/genética , Ratas , Caracteres Sexuales , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Periductal stromal tumors of the breast are exceedingly rare biphasic breast tumors with close morphological relationship to phyllodes tumors. So far, results of genetic analyses on these tumors have not been reported. CASE PRESENTATION: A 50 year old female patient was admitted to the hospital because of a palpable lump in her right breast with a diameter of approximately 5-6 cm which was surgically removed by lumpectomy. Histologic examination revealed a biphasic breast tumor classified as periductal stromal tumor. Array analysis showed a pseudotetraploid tumor with a copy number of 4 for most of the chromosomes. In addition, further changes of chromosomes 1, 5, and 6 were noted but there were no mutations of MED12 as those frequently seen in fibroadenomas or phyllodes tumors. CONCLUSIONS: The genetic alterations observed indicate karyotypic evolution leading to marked heterogeneity which fits with the tumor´s histologic and cytologic appearance as well as with its malignant behavior. Because of the absence of genetic similarities with phyllodes tumors, the case does not offer evidence for a common entity but rather suggests the existence of two independent entities.
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Our insights into the molecular pathogenesis of uterine smooth muscle tumors have improved significantly. Accordingly, in the present review, we advocate a more refined risk assessment for patients considering surgical removal of fibroids or hysterectomy, respectively, requiring morcellation. For this procedure, the risk estimates given for the iatrogenic spread of a previously unexpected malignancy considerably vary among different studies. Nearly all previous studies conducted retrospectively refer to the risk of a patient having an unexpected malignancy at the time of surgery. We feel that, more appropriately, risk should refer to the number of tumors because, as a rule, every single nodule arises independently and, thus, carries an independent risk of being malignant or not. Furthermore, whether so-called parasitic fibroids carry an underestimated risk of stepwise malignant transformation is discussed.
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Leiomioma/patología , Útero/patología , Femenino , Humanos , Leiomioma/cirugía , Morcelación/métodos , Estudios Retrospectivos , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugía , Útero/cirugíaRESUMEN
In Parkinson's disease, dopamine depletion leads to hyperactivity of cholinergic interneurons in the caudate-putamen (CPu). Botulinum neurotoxin-A (BoNT-A) inhibits the release of acetylcholine in the peripheral nervous system and is also thought to act as a local anticholinergic drug when injected intrastriatally. In hemiparkinsonian (hemi-PD) rats, a unilateral intrastriatal injection of 1 ng BoNT-A significantly diminished apomorphine-induced rotation behavior for at least 3 months, the effect fading thereafter. A second intrastriatal BoNT-A application, 6 months after the first one, led to a stronger and longer-lasting, beneficial behavioral reaction. As a single BoNT-A injection was not cytotoxic in the rat striatum and resembled BoNT-A treatment in clinical practice, here, we investigated the structural outcome of repeated intrastriatal BoNT-A injections with respect to striatal volume, the number of choline acetyltransferase-immunoreactive (ChAT-ir) interneurons and of the length of their dendritic arbors, and the numeric density of ChAT-ir BoNT-A-induced varicosities (BiVs). Repeated unilateral intrastriatal BoNT-A application decreased the volume of the injected CPu, but did not significantly change the number of striatal ChAT-ir interneurons. Also, the total dendrite length of ChAT-ir interneurons after repeated BoNT-A application resembled the values in double vehicle-injected hemi-PD rats. In repeatedly BoNT-A-injected hemi-PD rats, the numeric density of ChAT-ir BiVs in the CPu was increased compared with rats only intrastriatally injected once with BoNT-A. Even repeated BoNT-A injections in rat striata did not cause substantial morphological changes in ChAT-ir neuron, except for the increased numeric density of ChAT-ir BiVs.
Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Interneuronas/metabolismo , Enfermedad de Parkinson/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Toxinas Botulínicas/administración & dosificación , Toxinas Botulínicas/farmacología , Toxinas Botulínicas Tipo A/administración & dosificación , Toxinas Botulínicas Tipo A/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Colina O-Acetiltransferasa/metabolismo , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Interneuronas/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas WistarRESUMEN
Niemann-Pick disease Type C (NPC) is a rare progressive neurodegenerative disorder with an incidence of 1:120,000 caused by mutations in the NPC1 or NPC2 gene leading to a massive cholesterol accumulation. Here, we describe the generation of induced pluripotent stem cells (iPSCs) of an affected female adult individual carrying the NPC1 mutation p.Val1023Serfs*15/p.Gly992Arg and an iPSC line from an unrelated healthy female adult control individual. Human iPSCs were derived from fibroblasts using retroviruses carrying the four reprogramming factors OCT4, SOX2, KLF4 and C-MYC. These lines provide a valuable resource for studying the pathophysiology of NPC and for pharmacological intervention.
RESUMEN
Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.