RESUMO
Aims To investigate whether pathological fractures impact on osteosarcoma patient prognosis in Ireland. Methods This was a retrospective study over 22 years in a National Orthopaedic Oncology Centre. There were 117 nonfracture cases and 15 fracture cases. Outcome measures included 5 and 10 year event-free (EFS) and overall survival (OS). Kaplan-Meier curves assessed length of survival and time to death. Results Pathological fracture has no significant effect on 10 year EFS or 10 year OS. 3 factors strongly associate with 10 year OS rates: American Joint Committee on Cancer (AJCC) classification (p<0.001), Metastases site (p<0.001) and Distant recurrence (p<0.001). Fractures had poorer post-chemotherapeutic necrosis rates (p=0.005). Conclusion Pathological fractures have no significant effect on survival rates or length of survival in an Irish population. The effect of pathological fractures on necrosis rates must be explored in future research.
Assuntos
Neoplasias Ósseas/complicações , Neoplasias Ósseas/mortalidade , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/mortalidade , Osteossarcoma/complicações , Osteossarcoma/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Criança , Estudos de Coortes , Feminino , Humanos , Irlanda/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/epidemiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
A 10-year-old neutered female domestic longhair cat was presented to a tertiary care veterinary hospital for evaluation of a right renal mass that was identified incidentally on abdominal radiographs and classified further as a sarcoma based on fine needle aspiration cytology. Further diagnostic workup, including ultrasound and cytology, identified a sarcoma in the left kidney. After approximately 1 month of conservative medical management, the clinical condition deteriorated and the cat was humanely destroyed. Post-mortem examination confirmed bilateral renal masses with multifocal infarction and extensive necrosis, and further identified a large mass at the apex of the heart as well as multiple pulmonary nodules. Microscopical examination of the masses identified a population of poorly-differentiated neoplastic spindle cells, consistent with sarcoma. Immunohistochemically, the neoplastic cells expressed smooth muscle actin and muscle-specific actin, but were negative for myoglobin and factor VIII. Phosphotungstic acid-haematoxylin staining was unable to identify cross-striations in the neoplastic cells. Based on these results and the pattern of lesion distribution, the cat was diagnosed with cardiac leiomyosarcoma with pulmonary and bilateral renal metastasis.
Assuntos
Doenças do Gato/patologia , Neoplasias Cardíacas/veterinária , Neoplasias Renais/veterinária , Leiomiossarcoma/veterinária , Animais , Gatos , FemininoRESUMO
Limitations associated with demineralised bone matrix and other grafting materials have motivated the development of alternative strategies to enhance the repair of large bone defects. The growth plate (GP) of developing limbs contain a plethora of growth factors and matrix cues which contribute to long bone growth, suggesting that biomaterials derived from its extracellular matrix (ECM) may be uniquely suited to promoting bone regeneration. The goal of this study was to generate porous scaffolds from decellularised GP ECM and to evaluate their ability to enhance host mediated bone regeneration following their implantation into critically-sized rat cranial defects. The scaffolds were first assessed by culturing with primary human macrophages, which demonstrated that decellularisation resulted in reduced IL-1ß and IL-8 production. In vitro, GP derived scaffolds were found capable of supporting osteogenesis of mesenchymal stem cells via either an intramembranous or an endochondral pathway, demonstrating the intrinsic osteoinductivity of the biomaterial. Furthermore, upon implantation into cranial defects, GP derived scaffolds were observed to accelerate vessel in-growth, mineralisation and de novo bone formation. These results support the use of decellularised GP ECM as a scaffold for large bone defect regeneration.
Assuntos
Regeneração Óssea , Osso e Ossos/patologia , Matriz Extracelular/metabolismo , Lâmina de Crescimento/metabolismo , Alicerces Teciduais/química , Cicatrização , Animais , Osso e Ossos/diagnóstico por imagem , Condrogênese , Citocinas/biossíntese , Glicosaminoglicanos/metabolismo , Lâmina de Crescimento/ultraestrutura , Humanos , Macrófagos/citologia , Masculino , Osteogênese , Fenótipo , Porosidade , Ratos Endogâmicos F344 , Crânio/diagnóstico por imagem , Crânio/patologia , Sus scrofa , Microtomografia por Raio-XRESUMO
INTRODUCTION: Various techniques are used for spinal cord untethering. The purpose of this study was to compare patient characteristics, postoperative course, and early complications after laminotomy vs. laminoplasty for transection of the filum terminale for tethered cord release. METHODS: Retrospective analysis of clinical and magnetic resonance imaging data was undertaken for all patients (<18 years) who underwent tethered cord release by transection of the filum terminale at Oregon Health & Science University, Doernbecher Children's Hospital, from 2000 to 2011. RESULTS: Data from two hundred and forty-eight patients were analyzed. Mean age was 5.2 years (range 0.3 to 16.8 years). Access to the thecal space during surgery was achieved using laminotomy or laminoplasty in 82 (33.1 %) and 166 (66.9 %) patients, respectively. Laminoplasty patients were significantly younger than laminotomy patients (3.2 vs. 9.3 years, p<0.0001); other clinical and radiographic characteristics were similar between the groups. Nine patients (3.6 %) experienced early complications, including cerebrospinal fluid leak (n=2), suprafascial infection requiring surgical management and intravenous (IV) antibiotics (n=3) or IV antibiotics alone (n=1), a small area of peri-incisional cutaneous necrosis (n=1), perioperative seizures (n=1), and mild, transient malignant hyperthermia (n=1). There was no difference in the number of early complications between the two groups. Univariate and multivariate analyses revealed no significant risk factor for postoperative complication associated with technique. As judged by caregivers, independent of surgical technique, 97 % of patients improved after surgery. CONCLUSION: There was no difference in complication risk when performing transection of the filum terminale for tethered cord release using laminotomy or laminoplasty.
Assuntos
Cauda Equina/cirurgia , Laminectomia/métodos , Laminoplastia/métodos , Doenças do Sistema Nervoso Periférico/cirurgia , Complicações Pós-Operatórias/fisiopatologia , Adolescente , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Pigmentation is one of the most variable traits within and between Drosophila species. Much of this diversity appears to be adaptive, with environmental factors often invoked as selective forces. Here, we describe the geographic structure of pigmentation in Drosophila americana and evaluate the hypothesis that it is a locally adapted trait. Body pigmentation was quantified using digital images and spectrometry in up to 10 flies from each of 93 isofemale lines collected from 17 locations across the United States and found to correlate most strongly with longitude. Sequence variation at putatively neutral loci showed no evidence of population structure and was inconsistent with an isolation-by-distance model, suggesting that the pigmentation cline exists despite extensive gene flow throughout the species range, and is most likely the product of natural selection. In all other Drosophila species examined to date, dark pigmentation is associated with arid habitats; however, in D. americana, the darkest flies were collected from the most humid regions. To investigate this relationship further, we examined desiccation resistance attributable to an allele that darkens pigmentation in D. americana. We found no significant effect of pigmentation on desiccation resistance in this experiment, suggesting that pigmentation and desiccation resistance are not unequivocally linked in all Drosophila species.
Assuntos
Drosophila/fisiologia , Adaptação Fisiológica , Animais , Drosophila/genética , Feminino , Fluxo Gênico , Variação Genética , Masculino , Pigmentação , Seleção GenéticaRESUMO
OBJECTIVE: This study seeks to identify factors associated with post-traumatic stress disorder (PTSD) following Hurricane Ivan among a cohort of tertiary-level students in Jamaica. METHODS: A 22-item, self-administered questionnaire was administered to a non-random sample. Using parametric and non-parametric analyses, the relationship between PTSD symptoms and several variables was examined. RESULTS: Feeling anxious, worried or fearful and/or experiencing loss and injury during the hurricane were significant (p < 0.01) predictors for PTSD symptoms. CONCLUSIONS: Factors predicting the development of PTSD symptoms were feeling anxious, worried or fearful during the hurricane and experiencing loss of property and/or death or injury of a family member during the hurricane.
Assuntos
Tempestades Ciclônicas , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adolescente , Adulto , Ansiedade/epidemiologia , Medo , Feminino , Humanos , Masculino , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
We report the novel HLA-Cw allele HLA-Cw*0751. The allele was identified during routine sequence-based typing in our laboratory. The novel allele is identical to Cw*07020101 except for a single nucleotide change in codon 90.2 in position 268. HLA-Cw*0751 allele possesses an adenine at position 268 in exon 2, while HLA-Cw*07020101 has a cytosine at this position. Although this substitution does not change serologic reactivity of HLA-Cw7 molecule, it changes the amino acid at codon 90 from an aspartic acid to an alanine. Aspartic acid is polar and acidic, while alanine is non-polar and neutral.
Assuntos
Antígenos HLA-C/genética , Adenina/química , Alelos , Substituição de Aminoácidos , Citosina/química , Antígenos HLA-C/química , HumanosRESUMO
This study was undertaken to document the phenotype of Kabuki (Niikawa-Kuroki) syndrome in patients from Australia and New Zealand, with particular emphasis on growth patterns, behavior, and relationship between head circumference and intellectual level. Data on 27 children and adults with Kabuki (Niikawa-Kuroki) syndrome from Australia and New Zealand were collected by questionnaire and clinical assessment. The patients ranged in age from 7 months to 36 years with a mean age of 7 years and 2 months. The mean age at diagnosis was 3(5/6) years, but in most cases, the facial phenotype was evident from infancy. The minimum birth prevalence was calculated at 1 in 86,000. Three of our patients died. Parents reported a behavior phenotype characterized by an excellent long-term memory and avoidance of eye contact. No correlation was found between head circumference and severity of intellectual disability. Eight of 14 patients over the age of 5 years were overweight or obese. Six of these eight patients had failure to thrive in infancy. One patient developed insulin-dependent diabetes mellitus in adolescence. Some individuals with Kabuki (Niikawa-Kuroki) syndrome show a characteristic growth profile with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence. A behavior phenotype was noted which requires further investigation. Head size is not a predictor of degree of intellectual disability.
Assuntos
Anormalidades Múltiplas/patologia , Crescimento/fisiologia , Deficiência Intelectual/patologia , Fenótipo , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Austrália , Sintomas Comportamentais/patologia , Peso ao Nascer , Criança , Pré-Escolar , Face/patologia , Feminino , Cabeça/patologia , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Nova Zelândia , SíndromeRESUMO
Toxic epidermal necrolysis (TEN) is a rare severe reaction of the skin resulting in full thickness damage to the epidermis. The condition has significant morbidity as a result of dehydration, protein loss, thermoregulatory difficulties, and renal, lung, liver and heart failure. The mortality rate approaches 30%, most commonly from bacterial sepsis. Management of this condition is cessation of the suspected causative agent and supportive care on a burns or intensive care unit. There have been recent reports of treatment using intravenous immunoglobulin (IVIG) therapy, though its efficacy is yet to be established. It has been proposed that IVIG inhibits the Fas-FasL mediated apoptosis of keratinocytes affected by TEN. We describe a case of extensive drug-induced TEN in a 33-year-old woman who showed rapid improvement with IVIG therapy at a dose of 0.75 g/kg/day given for four consecutive days.
Assuntos
Antidepressivos de Segunda Geração/efeitos adversos , Antimaníacos/efeitos adversos , Carbamazepina/efeitos adversos , Cicloexanóis/efeitos adversos , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Stevens-Johnson/tratamento farmacológico , Adulto , Depressão Pós-Parto/tratamento farmacológico , Feminino , Humanos , Síndrome de Stevens-Johnson/etiologia , Cloridrato de VenlafaxinaRESUMO
PEHO syndrome is a rare progressive infantile encephalopathy with onset within the first few months of life. Few patients fulfilling the diagnostic criteria for PEHO syndrome have been reported outside Finland. Affected infants have facial dysmorphism and suffer from severe hypotonia, profound mental retardation, convulsions (often with a hypsarrhythmic EEG pattern), transient or persistent peripheral oedema, and optic atrophy. Cerebellar and brainstem atrophy are usually present on neuroimaging. A PEHO-like syndrome has been described, in which the affected individuals have neither optic atrophy nor the typical neuroradiological findings. We report five Australian patients, the first with classical features of PEHO syndrome, and four who have a PEHO-like disorder. We compare their features with other published cases. We suggest that PEHO or a PEHO-like syndrome may affect more patients than are currently identified, based on the original diagnostic criteria for this disorder.
Assuntos
Encefalopatias Metabólicas Congênitas/fisiopatologia , Edema/fisiopatologia , Atrofia Óptica/fisiopatologia , Espasmos Infantis/fisiopatologia , Encefalopatias Metabólicas Congênitas/genética , Pré-Escolar , Edema/genética , Feminino , Humanos , Lactente , Masculino , Atrofia Óptica/genética , Espasmos Infantis/genéticaAssuntos
Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Aconselhamento Genético , Mutação/genética , Proteínas Repressoras , Síndrome de Rett/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett/diagnósticoRESUMO
Dermatobia hominis causes furuncular myiasis and is endemic to South America. This report describes a case in a young woman who had recently visited Belize, highlighting the importance of clinical history (including travel history) and close liaison between pathologist and surgeon.
Assuntos
Cisto Epidérmico/diagnóstico , Miíase/diagnóstico , Dermatoses do Couro Cabeludo/diagnóstico , Adulto , Animais , Belize , Dípteros , Cisto Epidérmico/parasitologia , Feminino , Humanos , Dermatoses do Couro Cabeludo/parasitologia , ViagemAssuntos
Genoma , Urocordados/genética , Animais , Cromossomos Artificiais Bacterianos , Ciona intestinalis/genética , Clonagem Molecular , DNA Complementar , DNA Intergênico , Etiquetas de Sequências Expressas , Genes , Íntrons , Masculino , Sequências Repetitivas de Ácido Nucleico , Análise de Sequência de DNA , Espermatozoides/química , Urocordados/anatomia & histologia , Urocordados/crescimento & desenvolvimentoRESUMO
To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Permeabilidade do Canal Arterial/genética , Mutação/genética , Fatores de Transcrição/genética , Células 3T3 , Anormalidades Múltiplas/fisiopatologia , Motivos de Aminoácidos , Animais , Criança , Reagentes de Ligações Cruzadas/metabolismo , DNA/genética , DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Dedos/anormalidades , Genótipo , Humanos , Masculino , Camundongos , Fenótipo , Ligação Proteica , Estrutura Terciária de Proteína , Síndrome , Fator de Transcrição AP-2 , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ativação Transcricional , TransfecçãoRESUMO
BACKGROUND: We observed IgM deposits in the macula densa of the distal convoluted tubule in some renal biopsies with mesangial IgM deposits and did a systematic study to investigate the frequency of this phenomenon. We compared the findings with those in IgA disease. METHODS: A total of 30 renal biopsies with either isolated predominantly mesangial IgM, or mesangial IgA (+/-IgM) deposition, were retrieved from the files and reviewed independently by both authors. RESULTS: Eight showed strong macula densa IgM deposits and another three showed weak deposits in the macula densa on immunoperoxidase staining. A total of 14 biopsies also showed mesangial IgA deposition but IgA was not seen in the macula densa. CONCLUSIONS: These results confirm the association of IgM deposits in the macula densa with mesangial IgM, and suggest that mesangial IgM deposits may be a reflection of non-specific macromolecule transport rather than an immune reactant.
Assuntos
Mesângio Glomerular/metabolismo , Imunoglobulina M/metabolismo , Sistema Justaglomerular/metabolismo , Transporte Biológico , Mesângio Glomerular/imunologia , Humanos , Técnicas Imunoenzimáticas , Substâncias MacromolecularesRESUMO
Retroviral envelope glycoprotein gp70 is present in the sera of immunologically normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and these have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB x (C57BL/10 x BXSB)F(1))- and (C57BL/10 x (C57BL/10 x BXSB)F(1))-backcrossed male mice. Production of gp70 mapped to a single major locus located on chromosome 13 (Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 x 10(-38)). The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 levels were greater than a threshold value of approximately 4.0 microg/ml. The subdivision of the (BXSB x (C57BL/10 x BXSB)F(1))-backcrossed mice into those homozygous or heterozygous for Bxs6 enabled a remarkable association to be observed between high levels of gp70IC and severe nephritis in the Bxs6 homozygote population. A further mapping study in these two subgroups identified a previously unrecognized interval associated with the production of autoantibodies.
Assuntos
Autoanticorpos/biossíntese , Autoantígenos/biossíntese , Autoantígenos/genética , Glicoproteínas/biossíntese , Glicoproteínas/genética , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Animais , Complexo Antígeno-Anticorpo/biossíntese , Complexo Antígeno-Anticorpo/sangue , Cruzamentos Genéticos , Ligação Genética/imunologia , Marcadores Genéticos/imunologia , Predisposição Genética para Doença , Glicoproteínas/sangue , Nefrite Lúpica/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Característica Quantitativa HerdávelRESUMO
Appendicularia are protochordates that rely on a complex mucous secretion, the house, to filter food particles from seawater. A monolayer of cells covering the trunk of the animal, the oikoplastic epithelium, secretes the house. This epithelium contains a fixed number of cells arranged in characteristic patterns with distinct sizes and nuclear morphologies. Certain house structures appear to be spatially related to defined, underlying groups of cells in the epithelium. We show that the house is composed of at least 20 polypeptides, a number of which are highly glycosylated, with glycosidase treatments resulting in molecular mass shifts exceeding 100 kDa. Nanoelectrospray tandem mass spectrometric microsequencing of house polypeptides was used to design oligonucleotides to screen an adult Oikopleura dioica cDNA library. This resulted in the isolation of cDNAs coding for three different proteins, oikosin 1, oikosin 2, and oikosin 3. The latter two are novel proteins unrelated to any known data base entries. Oikosin 1 has 13 repeats of a Cys domain, previously identified as a subunit of repeating sequences in some vertebrate mucins. We also find one repeat of this Cys domain in human cartilage intermediate layer protein but find no evidence of this domain in any invertebrate species, including those for which entire genomes have been sequenced. The three oikosins show distinct and complementary expression patterns restricted to the oikoplastic epithelium. This easily accessible epithelium, with differential gene expression patterns in readily identifiable groups of cells with distinctive nuclear morphologies, is a highly attractive model system for molecular studies of pattern formation.
Assuntos
Glicoproteínas/genética , Urocordados/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , DNA Complementar , Eletroforese em Gel de Poliacrilamida , Epitélio/metabolismo , Glicoproteínas/química , Glicoproteínas/metabolismo , Dados de Sequência Molecular , Sequências Repetitivas de Aminoácidos , Homologia de Sequência de AminoácidosRESUMO
Expression of iNOS in glioma and other tumors has been extensively documented but the effects of NO derived from iNOS on tumor-killing mechanisms of chemotherapy drugs remain to be fully defined. We note that increased NO synthesis by cytokine exposure or iNOS overexpression neutralized the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but not cisplatin, in rat C6 glioma cells. Suppression of BCNU cytotoxicity associated with iNOS overexpression could be abolished by pharmacological inhibition of NOS or coexpression of an antisense RNA against iNOS. Both BCNU and CCNU are chloroethylnitrosoureas that kill tumor cells via carbamoylating and alkylating actions. Further studies using compounds that each carry these different activities indicate that iNOS neutralized carbamoylating, but not alkylating, action of chloroethylnitrosoureas. Temozolomide, a novel chemotherapy drug recently available for treating brain tumors, carries only alkylating, but not carbamoylating, action. Overexpression of iNOS in C6 cells failed to neutralize temozolomide cytotoxicity. Results from the present study demonstrate the ability of iNOS-derived NO to confer chemoresistance against the carbamoylating potential of chloroethylnitrosoureas in vitro. Further investigation is needed to test whether iNOS expression, frequently noted in malignant brain tumors, also enhances chemoresistance against chloroethylnitrosoureas in vivo.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Carmustina/farmacologia , Glioma/tratamento farmacológico , Óxido Nítrico Sintase/fisiologia , Animais , Elementos Antissenso (Genética)/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glioma/metabolismo , Glioma/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo II , Ratos , Células Tumorais CultivadasRESUMO
The filter-feeding house secreted by urochordate Appendicularians is among the most complex extracellular structures constructed by any organism. This structure allows the Appendicularia to exploit a wide range of food particle sizes, including nanoplankton and submicrometer colloids, establishing them as an important and abundant component of marine zooplankton communities throughout the world. The oikoplastic epithelium, a monolayer of cells covering the trunk of the animal, is responsible for secretion of the house. The epithelium has a fixed number of cells, organized in distinct fields, characterized by defined cell shapes and nuclear morphologies. Certain structures in the house appear to be spatially linked to these different fields of cells. Using cDNA representation difference analysis (cDNA RDA) on whole animals at two different developmental stages separated by the metamorphic tailshift event, we isolated four families of genes (oikosins) that are expressed only from specific subregions of the oikoplastic epithelium. The molecular patterns defined by oikosin gene expression establish the epithelium as an ideal and easily accessible monolayer cellular template for exploring coordinate regulation of gene expression, cell-cell interactions involved in pattern formation, gene/genome amplification, and the role of temporal changes in nuclear architecture in regulating gene expression.