Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Encefálicas/secundário , Diabetes Mellitus/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/secundário , Melanoma/secundário , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Diabetes Mellitus/diagnóstico , Diagnóstico Diferencial , Fadiga/etiologia , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/etiologia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Redução de PesoAssuntos
Hemocromatose/diagnóstico , Ferro/sangue , Cardiomiopatias/etiologia , Diabetes Mellitus/etiologia , Diagnóstico Diferencial , Edema/etiologia , Evolução Fatal , Fadiga/etiologia , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Humanos , Ferro/metabolismo , Quelantes de Ferro/uso terapêutico , Perna (Membro) , Masculino , Pessoa de Meia-Idade , Transferrina/metabolismoRESUMO
Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.
Assuntos
Xeroderma Pigmentoso/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterogeneidade Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Reino Unido , Adulto JovemRESUMO
Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.
Assuntos
Síndrome de Cockayne/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Anemia de Fanconi/genética , Predisposição Genética para Doença/genética , Fenótipo , Xeroderma Pigmentoso/genética , Sequência de Aminoácidos , Sequência de Bases , Síndrome de Cockayne/enzimologia , Síndrome de Cockayne/patologia , Primers do DNA/genética , Anemia de Fanconi/enzimologia , Anemia de Fanconi/patologia , Evolução Fatal , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Xeroderma Pigmentoso/enzimologia , Xeroderma Pigmentoso/patologiaRESUMO
Importance: In large academic centers, medical residents work on multiple clinical floors with transient interactions with nursing colleagues. Although teamwork is critical in delivering high-quality medical care, little research has evaluated the effect of interprofessional familiarity on inpatient team performance. Objective: To determine the effectiveness of increased familiarity between medical residents and nurses on team performance, psychological safety, and communication. Design, Setting, and Participants: A 12-month randomized clinical trial in an inpatient general medical service at a large academic medical center was completed from June 25, 2019, to June 24, 2020. Participants included 33 postgraduate year (PGY)-1 residents in an internal medicine residency program and 91 general medicine nurses. Interventions: Fifteen PGY-1 residents were randomized to complete all 16 weeks of their general medicine inpatient time on 1 medical nursing floor (intervention group with 43 nurses). Eighteen PGY-1 residents completed 16 weeks on 4 different general medical floors as per usual care (control group with 48 nurses). Main Outcomes and Measures: The primary outcome was an assessment of team performance in physician-nurse simulation scenarios completed at 6 and 12 months. Interprofessional communication was assessed via a time-motion study of both work rounds and individual resident clinical work. Psychological safety and teamwork culture were assessed via surveys of both residents and nurses at multiple time points. Results: Of the intervention and control PGY-1 residents, 8 of 15 (54%) and 8 of 18 (44%) were women, respectively. Of the nurses in the intervention and control groups with information available, 37 of 40 (93%) and 34 of 38 (90%) were women, respectively, and more than 70% had less than 10 years of clinical experience. There was no difference in overall team performance during the first simulation. At the 12-month simulation, the intervention teams received a higher mean overall score in leadership and management (mean [SD], 2.47 [0.53] vs 2.17 [0.39]; P = .045, Cohen d = 0.65) and on individually rated items were more likely to work as 1 unit (100% vs 62%; P = .003), negotiate with the patient (61% vs 10%; P = .001), support other team members (61% vs 24%; P = .02), and communicate as a team (56% vs 19%; P = .02). The intervention teams were more successful in achieving the correct simulation case outcome of negotiating a specific insulin dose with the patient (67% vs 14%; P = .001). Time-motion analysis noted intervention teams were more likely to have a nurse present on work rounds (47% vs 28%; P = .03). At 6 months, nurses in the intervention group were more likely to report their relationship with PGY-1 residents to be excellent to outstanding (74% vs 40%; P = .003), feel that the input of all clinical practitioners was valued (95% vs 53%; P < .001), and say that feedback between practitioners was delivered in a way to promote positive interactions (90% vs 60%; P = .003). These differences diminished at the 12-month survey. Conclusions and Relevance: In this randomized clinical trial, increased familiarity between nurses and residents promoted more rapid improvement of nursing perception of team relationships and, over time, led to higher team performance on complex cognitive tasks in medical simulations. Medical centers should consider team familiarity as a potential metric to improve physician-nursing teamwork and patient care. Trial Registration: ClinicalTrials.gov Identifier: NCT05213117.
Assuntos
Pacientes Internados , Médicos , Feminino , Humanos , Masculino , Comunicação , Equipe de Assistência ao Paciente , LiderançaRESUMO
We have prospectively followed 16 Finnish xeroderma pigmentosum (XP) patients for up to 23 years. Seven patients were assigned by complementation analysis to the group XP-A, two patients to the XP-C group and one patient to the XP-G group. Six of the seven XP-A patients had the identical mutation (Arg228Ter) and the seventh patient had a different mutation (G283A). Further patients were assigned to complementation groups on the basis of their consanguinity to an XP patient with a known complementation group. The first sign of the disease in all the cases was severe sunburn with minimal sun exposure in early infancy. However, at the time the diagnosis was made in only two cases. The XP-A patients developed neurological and cognitive dysfunction in childhood. The neurological disease advanced in an orderly fashion through its successive stages, finally affecting the whole nervous system and leading to death before the age of 40 years. Dermatological and ocular damage of the XP-A patients tended to be limited. The two XP-C patients were neurologically and cognitively intact despite mild brain atrophy as seen by neuroimaging. The XP-G patients had sensorineural hearing loss, laryngeal dystonia and peripheral neuropathy. The XP-C patients had severe skin and ocular malignancies that first presented at pre-school age. They also showed immunosuppression in cell-mediated immunity. Neurological disease appears to be associated with the complementation group and the failure of fibroblasts to recover RNA synthesis following UV irradiation, but not necessarily to the severity of the dermatological symptoms, the hypersensitivity of fibroblasts to UVB killing or the susceptibility of keratinocytes to UVB-induced apoptosis.
Assuntos
Encefalopatias/etiologia , Xeroderma Pigmentoso/psicologia , Adulto , Criança , Pré-Escolar , Reparo do DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Oftalmopatias/etiologia , Feminino , Finlândia , Teste de Complementação Genética , Transtornos da Audição/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Testes Neuropsicológicos , Proteínas Nucleares/genética , Estudos Prospectivos , Dermatopatias/etiologia , Tomografia Computadorizada por Raios X , Fatores de Transcrição/genética , Xeroderma Pigmentoso/complicações , Proteína de Xeroderma Pigmentoso Grupo A/genéticaRESUMO
Replicative DNA polymerases are blocked at DNA lesions. Synthesis past DNA damage requires the replacement of the replicative polymerase by one of a group of specialised translesion synthesis (TLS) polymerases, most of which belong to the Y-family. Each of these has different substrate specificities for different types of damage. In eukaryotes mono-ubiquitination of PCNA plays a crucial role in the switch from replicative to TLS polymerases at stalled forks. All the Y-family polymerases have ubiquitin binding sites that increase their binding affinity for ubiquitinated PCNA at the sites of stalled forks.
Assuntos
Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/fisiologia , Antígeno Nuclear de Célula em Proliferação/fisiologia , Animais , Humanos , Modelos Biológicos , Ubiquitina/metabolismoRESUMO
Smc5-6 is a highly conserved protein complex related to cohesin and condensin involved in the structural maintenance of chromosomes. In yeasts the Smc5-6 complex is essential for proliferation and is involved in DNA repair and homologous recombination. siRNA depletion of genes involved in the Smc5-6 complex in cultured mammalian cells results in sensitivity to some DNA damaging agents. In order to gain further insight into its role in mammals we have generated mice mutated in the Smc6 gene. A complete knockout resulted in early embryonic lethality, demonstrating that this gene is essential in mammals. However, mutation of the highly conserved serine-994 to alanine in the ATP hydrolysis motif in the SMC6 C-terminal domain, resulted in mice with a surprisingly mild phenotype. With the neo gene selection marker in the intron following the mutation, resulting in reduced expression of the SMC6 gene, the mice were reduced in size, but fertile and had normal lifespans. When the neo gene was removed, the mice had normal size, but detailed phenotypic analysis revealed minor abnormalities in glucose tolerance, haematopoiesis, nociception and global gene expression patterns. Embryonic fibroblasts derived from the ser994 mutant mice were not sensitive to killing by a range of DNA damaging agents, but they were sensitive to the induction of sister chromatid exchanges induced by ultraviolet light or mitomycin C. They also accumulated more oxidative damage than wild-type cells.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Mutação de Sentido Incorreto , Fenótipo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Motivos de Aminoácidos , Animais , Domínio Catalítico , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Fertilidade/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Genes Essenciais , Intolerância à Glucose/genética , Hematopoese/genética , Hidrólise , Íntrons , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitomicina/farmacologia , Nociceptividade , Troca de Cromátide Irmã/efeitos dos fármacos , Troca de Cromátide Irmã/efeitos da radiação , Raios UltravioletaAssuntos
Genótipo , Proteína de Xeroderma Pigmentoso Grupo A/genética , Xeroderma Pigmentoso/genética , Adolescente , Adulto , Afeganistão/etnologia , Idoso , Criança , Pré-Escolar , Reparo do DNA , Fácies , Feminino , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Paquistão/etnologia , Fenótipo , Reino Unido/epidemiologia , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/etnologia , Adulto JovemRESUMO
Most types of DNA damage block replication fork progression during DNA synthesis because replicative DNA polymerases are unable to accommodate altered DNA bases in their active sites. To overcome this block, eukaryotic cells employ specialized translesion synthesis (TLS) polymerases, which can insert nucleotides opposite damaged bases. In particular, TLS by DNA polymerase eta (poleta) is the major pathway for bypassing UV photoproducts. How the cell switches from replicative to TLS polymerase at the site of blocked forks is unknown. We show that, in human cells, PCNA becomes monoubiquitinated following UV irradiation of the cells and that this is dependent on the hRad18 protein. Monoubiquitinated PCNA but not unmodified PCNA specifically interacts with poleta, and we have identified two motifs in poleta that are involved in this interaction. Our findings provide an attractive mechanism by which monoubiquitination of PCNA might mediate the polymerase switch.