RESUMO
BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). PATIENTS AND METHODS: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. CONCLUSIONS: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.
Assuntos
Adenocarcinoma , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Endothelial cells in blood vessels are known to be important during the later stages of organ development in the embryo. However, their involvement at the induction stage of organ formation has not been previously documented. As Bahary and Zon explain in their Perspective, new work demonstrates that endothelial cells secrete factors early in development that induce embryonic endoderm to become liver or pancreas (Matsumoto et al., Lammert et al.).
Assuntos
Indução Embrionária , Endoderma/fisiologia , Endotélio Vascular/fisiologia , Ilhotas Pancreáticas/embriologia , Fígado/embriologia , Pâncreas/embriologia , Animais , Aorta/embriologia , Aorta/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Técnicas de Cultura , Fatores de Crescimento Endotelial/genética , Endotélio Vascular/citologia , Endotélio Vascular/embriologia , Proteínas do Olho , Regulação da Expressão Gênica no Desenvolvimento , Fator de Crescimento de Hepatócito/fisiologia , Hepatócitos/citologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Insulina/biossíntese , Insulina/genética , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/citologia , Rim/embriologia , Fígado/citologia , Linfocinas/genética , Camundongos , Camundongos Transgênicos , Mitógenos/genética , Mitógenos/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Pâncreas/irrigação sanguínea , Pâncreas/citologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/fisiologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Repressoras , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fator de Crescimento do Endotélio Vascular Derivado de Glândula Endócrina , Fatores de Crescimento do Endotélio Vascular , XenopusRESUMO
BACKGROUND: Pancreatic panniculitis is a rare cause of subcutaneous fat necrosis secondary to elevated serum levels of pancreatic enzymes. It is most often associated with pancreatic acinar cell carcinoma, but has also been seen in patients with pancreatitis. CASE REPORT: We present a case of a 64 year old Caucasian man without symptoms of pancreatitis who presents with pancreatic panniculitis manifesting in multiple subcutaneous ulcerating nodules of the bilateral lower extremities, discovered to have a previously unreported etiology for this condition. He had no evidence of pancreatitis or malignancy, but instead a pancreatic-portal fistula resulting in panniculitis. CONCLUSION: Peripancreatic vascular lesions must also be considered in the differential diagnosis of pancreatic panniculitis. The diagnosis, pathology, and treatment of pancreatic panniculitis are reviewed herein.
RESUMO
Hematopoiesis in the vertebrate is characterized by the induction of ventral mesoderm to form hematopoietic stem cells and the eventual differentiation of these progenitors to form the peripheral blood lineages. Several genes have been implicated in the differentiation and development of hematopoietic and vascular progenitor cells, yet our understanding of the discrete steps involved in the induction of these cells from the ventral mesoderm is still incomplete. One method of delineating these processes is based on the use of lower vertebrates. The zebrafish (Danio rerio) is an especially robust vertebrate system for both isolating and characterizing genes involved in these processes. Hematopoietic mutants have been generated with defects in many of the steps of both the primitive and definitive hematopoietic programs. Cloning of the genes that underlie these mutations should yield valuable details of hematopoiesis and may have therapeutic implications for bone marrow transplantation and stem cell gene therapy.
Assuntos
Hematopoese , Peixe-Zebra , Animais , Previsões , Hematopoese/genética , Humanos , Mutagênese , Peixe-Zebra/genéticaRESUMO
Hematopoiesis in the vertebrate is characterized by the induction of ventral mesoderm to form hematopoietic stem cells and the eventual differentiation of these progenitors to form the peripheral blood lineages. Several genes have been implicated in the differentiation and development of hematopoietic and vascular progenitor cells, yet our understanding of the discrete steps involved in the induction of these cells from the ventral mesoderm is still incomplete. One method of delineating these processes is based on the use of lower vertebrates. The zebrafish (Danio rerio) is an especially robust vertebrate system for both isolating and characterizing genes involved in these processes. Hematopoietic mutants have been generated with defects in many of the steps of both the primitive and definitive hematopoietic programs. Cloning of the genes that underlie these mutations should yield valuable details of hematopoiesis and may have therapeutic implications for bone marrow transplantation and stem cell gene therapy.
Assuntos
Hematopoese/genética , Células-Tronco/fisiologia , Peixe-Zebra/genética , Animais , Modelos BiológicosRESUMO
Advances in molecular genetics have made it possible to clone mutant genes from mammals. This capability should facilitate efforts to determine the genetic factors that control food intake and body composition. In order to identify these genetic factors, we have been making use of mouse mutations that cause obesity. The basic premise of this approach is to take advantage of the mouse as a genetic system for the analysis of genetically complex disorders and to then apply that information to the study of human disease. This paper reviews: (1) current concepts concerning the control of body weight in man and other mammals; (2) the biologic characteristics of the mouse obesity mutations; (3) our progress in the use of positional cloning techniques to clone the mouse obese (ob) and diabetes (db) genes; (4) an approach to polygenic obesity in mice; and (5) the possible relevance of the mouse obesity mutations to human obesity.
Assuntos
Camundongos Obesos/genética , Obesidade/genética , Animais , Peso Corporal/genética , Mapeamento Cromossômico , Ingestão de Alimentos/genética , Humanos , CamundongosRESUMO
Studies of twins, adopted children, and some human populations indicate that body composition is significantly influenced by genetic factors. However, in no specific instance in either man or animals is the precise etiology of obesity known at the molecular level. Attempts to identify the molecular basis of obesity in humans have been hampered by difficulties in measuring food intake and energy expenditure with sufficient accuracy, as well as the apparent polygenic control of body composition in man. These constraints have stimulated interest in inbred animal strains, particularly mice, that have a genetic predisposition to obesity. Using the techniques of positional cloning, molecular markers flanking two autosomal recessive mouse obesity mutants (ob and db), which demonstrate a metabolic/behavioral phenotype similar to that observed in obese humans, have been identified. These markers are being used: (1) as starting points for chromosome walks to identify these genes, (2) as an aid in identifying genetically obese rodents prior to the development of the experimentally confounding obese phenotype, and (3) to investigate the possible contribution of the ob and db gene products to obesity in families segregating an obese phenotype. Additionally, genetic crosses segregating these obesity mutations are being used to identify "polygenes" that influence the severity of obesity and type II diabetes. Such studies may ultimately lead to the characterization of genes that influence the development and severity of obesity and non-insulin-dependent diabetes (NIDDM) in humans.
Assuntos
Obesidade/genética , Animais , Mapeamento Cromossômico , Clonagem Molecular , Humanos , FenótipoRESUMO
Available genetic information places the mouse db gene approximately 5 cM distal to Ifa on mid/distal mouse chromosome 4. These data have indicated that there is a relevant paucity of genetic markers that map to this region of chromosome 4. To increase the density of the genetic map on mid-chromosome 4, we have applied the techniques of microdissection and microcloning of the mid-portion of mouse chromosome 4. A total of 47 RFLPs from the microdissection library were used to type the progeny of three C57BL/6J Mus spretus backcrosses. The resulting composite genetic map positions seven known genes, 41 microclones, and three other anonymous markers to a region of approximately 21 cM on mid-chromosome 4 extending from b to Lck. The density of markers in this region of chromosome 4 should be sufficient to initiate the physical mapping of this subchromosomal segment, facilitating efforts to clone the db gene, as well as other uncloned mutant loci in this region of chromosome 4.
Assuntos
Mapeamento Cromossômico/métodos , Diabetes Mellitus Experimental/genética , Animais , Sequência de Bases , Clonagem Molecular , Cruzamentos Genéticos , DNA/genética , Sondas de DNA , Ligação Genética , Marcadores Genéticos , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Mutantes , Camundongos Obesos , Dados de Sequência Molecular , Mutação , Polimorfismo de Fragmento de Restrição , Translocação GenéticaRESUMO
The gene locus for the alpha 2 chain of type 1 collagen (Cola-2) was previously assigned to chromosome 16. Here we demonstrate, utilising both somatic cell hybrid analysis and genetic linkage analysis, in an interspecific Mus domesticus x Mus spretus cross that Cola-2 fails to cosegregate with mouse chromosome 16, but is linked to the Met proto-oncogene on chromosome 6.
Assuntos
Mapeamento Cromossômico , Colágeno/genética , Proto-Oncogenes , Animais , Cricetinae , Cricetulus , Cruzamentos Genéticos , Feminino , Células Híbridas , Masculino , Camundongos , Hibridização de Ácido NucleicoRESUMO
Diabetes (db) is an autosomal recessive mutation located in the midportion of mouse chromosome 4 that results in profound obesity with hyperphagia, increased metabolic efficiency, and insulin resistance. To clone this gene and generate a molecular map of the region around this mutation, two genetic crosses were established: an intraspecific backcross between C57BL/6J db/db females and C57BL/6J db/db x DBA/2J +/+ F1 (B6D2 db/+ F1) male mice and an interspecific intercross between B6D2 db/+ F1 males and C57BL/6J db/db x Mus spretus F1 (B6spretus db/+ F1) females. The progeny of both crosses were characterized for genotype at the db locus to map a series of restriction fragment length polymorphisms relative to the db locus. Measurements of body weight, body length, and plasma concentrations of glucose and insulin in the animals allowed the assignment of genotype (db/db vs. db/+ or +/+). A total of 132 progeny of the intraspecific cross and 48 db/db progeny of the interspecific cross were typed for individual restriction fragment length polymorphisms to generate a gene order of: centromere-brown (Mt4)-P lambda Mm3(2)-Ifa (Inta)-Cjun-db-D4Rp1-Glut1-Mtv-13-Lck. Several of the genes that are linked to db [Cjun, glucose transporter (Glut1) and Lck] map to human chromosome 1p, suggesting that db may be part of a syntenic group between human 1p and the distal portion of mouse chromosome 4. In addition, phenotyping of the progeny of these crosses revealed a wide range in plasma concentrations of glucose and insulin among the obese progeny, with some animals developing overt diabetes and other remaining euglycemic. Distributions of age-controlled plasma [glucose] and [insulin] among the intraspecific-cross obese progeny were not bimodal, suggesting a role for polygenic differences between the progenitor strains (C57BL/6J and DBA/2J) in the development of overt diabetes.
Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Experimental/genética , Camundongos Mutantes/genética , Mutação , Animais , Cruzamentos Genéticos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos/genética , Fenótipo , Polimorfismo de Fragmento de Restrição , Recombinação GenéticaRESUMO
We have generated a moderate resolution genetic map of mouse chromosomes 4 and 6 utilizing a (C57BL/6J x Mus spretus) F1 x Mus spretus backcross with RFLPs for 31 probes. The map for chromosome 4 covers 77 cM and details a large region of homology to human chromosome 1p. The map establishes the breakpoints in the mouse 4-human 1p region of homology to a 2-cM interval between Ifa and Jun in mouse and to the interval between JUN and ACADM in human. The map for mouse chromosome 6 spans a 65-cM region and contains a large region of homology to human 7q. These maps also provide chromosomal assignment and order for a number of previously unmapped probes. The maps should allow the rapid regional assignment of new markers to mouse chromosomes 4 and 6. In addition, knowledge of the gene order in mouse may prove useful in determining the gene order of the homologous regions in human.
Assuntos
Mapeamento Cromossômico , Animais , Sequência de Bases , Cruzamentos Genéticos , DNA/isolamento & purificação , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Muridae , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
The mouse ob mutation has been mapped relative to a series of RFLPs among the progeny of three separate mouse crosses: an intraspecific backcross, an intraspecific intercross, and an interspecific intercross. Genotypic assignment at the ob locus was made by making use of measurements of body mass index and the plasma concentrations of glucose and insulin. These data have suggested that the development of diabetes in these animals is a consequence of unlinked polygenes. There was also evidence that unlinked Mus spretus alleles can diminish the obesity of ob/ob mice. From these data we have mapped several markers on chromosome 6 with the following order: cen-Cola-2-Met-ob-Cpa-Tcrb. The homologs of markers that flank ob map to human chromosome 7q, suggesting that if there is a human homologue of ob, it maps to 7q31.
Assuntos
Mutação , Obesidade/genética , Animais , Southern Blotting , Mapeamento Cromossômico , Cruzamentos Genéticos , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Mutantes , Linhagem , Fenótipo , Polimorfismo de Fragmento de RestriçãoRESUMO
The autosomal recessive mutations fa (rat) and db (mouse) cause obesity syndromes that develop early and ultimately become severe. Although both fa/fa rats and db/db mice have been studied extensively as models of human obesity and diabetes, the molecular bases of these phenotypes remain unknown. We have mapped fa in 50 fa/fa (obese) offspring of a (13M x Brown Norway) F1 fa/+ intercross relative to two molecular markers, Ifa and Glut-1, which flank db on mouse chromosome 4 and which are located on rat chromosome 5. Ifa and Glut-1 are linked to fa, with a gene order, Ifa-fa-Glut-1, that is identical to that for the region around db in the mouse genome. These results place fa on rat chromosome 5 and suggest that db and fa are mutations in homologous genes.
Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Experimental/genética , Genes , Obesidade/genética , Animais , Sequência de Bases , Cruzamentos Genéticos , Feminino , Ligação Genética , Genótipo , Masculino , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Ratos , Ratos Mutantes , Recombinação Genética , Homologia de Sequência do Ácido NucleicoRESUMO
The development of dense genetic maps of mammalian chromosomes is facilitated when chromosome-specific libraries are used as a source of genetic markers. To saturate the genetic maps of mouse chromosomes 4 and 6, we have made use of fluorescent-activated chromosome sorting to purify a 4:6 Robertsonian chromosome from a cell line harboring the Rb(4:6)2Bnr translocation. After staining with chromomycin A3 and Hoechst 33528, this chromosome was separated from the other mouse chromosomes. DNA was isolated from the fraction containing the Robertsonian chromosome and subcloned into the insertion vector lambda gt10, generating a library with 4.6 x 10(5) independent phage. A total of 19 single-copy sequences were used to type the progeny of a C57BL/6J x Mus spretus backcross that had previously been typed for loci on chromosomes 4 and 6. Approximately 70% of the clones in the library mapped to either chromosome 4 or 6 as assessed by genetic mapping and by use of a somatic cell hybrid panel. Simple sequence repeats have also been isolated from this library. Further characterization of these microsatellites should accelerate efforts to map mouse chromosomes 4 and 6 using PCR. In addition, flow sorting of Robertsonian chromosomes suggests a general approach for making chromosome-specific libraries in mouse.
Assuntos
Mapeamento Cromossômico/métodos , Camundongos/genética , Translocação Genética , Animais , Linhagem Celular , Clonagem Molecular , DNA/genética , Citometria de Fluxo , Ligação Genética , Marcadores Genéticos , Biblioteca Genômica , Camundongos Endogâmicos C57BL , Muridae , Linhagem , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido NucleicoRESUMO
In a previous report, the ob mutation was mapped to a position 5 cM distal to Met on murine Chromosome (Chr) 6 in tight linkage to Cpa. In order to identify additional RFLPs in the region of ob, we have made use of chromosome microdissection of a 6:16 Robertsonian chromosome. In total, 19 RFLPs were used to type 131 progency of a B6D2 ob/ + x B6 spretus ob/ + intercross. Fifteen of the RFLPs mapped to Chr 6, one of which, D6Rck13, was tightly linked to ob. For refinement of the genetic map around ob, 350 obese progency of a B6 Mus castaneus ob/ + intercross were characterized. DNAs from these animals were typed for microsatellite markers from Chr 6 that flank ob. Recombinants were then typed for D6Rck13. D6Rck13 was nonrecombinant among all the progency of both crosses corresponding to 831 meioses. This probe will be of use as an entry point for physical mapping of the ob mutation.
Assuntos
Mapeamento Cromossômico , Ligação Genética , Mutação , Obesidade/genética , Polimorfismo de Fragmento de Restrição , Animais , Sequência de Bases , Clonagem Molecular , Cruzamentos Genéticos , Primers do DNA , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , MuridaeRESUMO
Thirteen loci, including the obesity gene fatty (fa), were incorporated into a linkage map of rat Chromosome (Chr) 5. These loci were mapped in obese (fa/fa) progeny of a cross between BN x 13M-fal+F1 animals. Obese rats were scored for BN and 13M alleles at four loci (Ifna, D1S85h, C8b, and Lck1) by restriction fragment length polymorphisms and at eight additional loci (Glut1, Sv4j2, R251, R735, R980, R252, R371, and R1138) by simple sequence length polymorphisms (SSLP). The resulting map spans 67.3 cM of Chr5, presenting nine previously unmapped loci and one locus (Lck1) previously assigned to Chr 5 by use of somatic cell hybrid lines. Seven of the eight SSLP loci are newly identified; the SSLP linkage group alone spans 56.8 cM. The order of the loci is Sv4j2-R251-R735-R980-R1138-Ifna-fa-+ ++D1S85h-C8b-(Glut1-R252-R371)-Lck1. One locus, D1S85h, was found to lie only 0.4 cM from fa, close enough to serve as a reliable marker for the prediction of phenotype from genotype, and will be useful also for studies on the development of obesity in the fatty rat.
Assuntos
Mapeamento Cromossômico , Obesidade/genética , Ratos/genética , Alelos , Animais , Sequência de Bases , Ligação Genética , Dados de Sequência Molecular , Polimorfismo Genético , Ratos Endogâmicos BN , Ratos ZuckerRESUMO
In vertebrates, hematopoietic and vascular progenitors develop from ventral mesoderm. The first primitive wave of hematopoiesis yields embryonic red blood cells, whereas progenitor cells of subsequent definitive waves form all hematopoietic cell lineages. In this report we examine the development of hematopoietic and vasculogenic cells in normal zebrafish and characterize defects in cloche and spadetail mutant embryos. The zebrafish homologs of lmo2, c-myb, fli1, flk1, and flt4 have been cloned and characterized in this study. Expression of these genes identifies embryonic regions that contain hematopoietic and vascular progenitor cells. The expression of c-myb also identifies definitive hematopoietic cells in the ventral wall of the dorsal aorta. Analysis of b316 mutant embryos that carry a deletion of the c-myb gene demonstrates that c-myb is not required for primitive erythropoiesis in zebrafish even though it is expressed in these cells. Both cloche and spadetail mutant embryos have defects in primitive hematopoiesis and definitive hematopoiesis. The cloche mutants also have significant decreases in vascular gene expression, whereas spadetail mutants expressed normal levels of these genes. These studies demonstrate that the molecular mechanisms that regulate hematopoiesis and vasculogenesis have been conserved throughout vertebrate evolution and the clo and spt genes are key regulators of these programs.