RESUMO
Fanconi anemia (FA) is a heritable malformation, bone marrow failure and cancer predisposition syndrome that confers an exceptionally high risk of squamous carcinomas. These carcinomas originate in epithelia lining the mouth, proximal esophagus, vulva and anus: their origins are not understood, and no effective ways have been identified to prevent or delay their appearance. Many FA-associated carcinomas are also therapeutically challenging: they may be multi-focal and stage-advanced at diagnosis, and most individuals with FA cannot tolerate standard-of-care systemic therapies such as DNA cross-linking drugs or ionizing radiation due to constitutional DNA damage hypersensitivity. We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from five individuals with FA-associated HNSCC, and five individuals with sporadic HNSCC. Sporadic, isogenic HNSCC cell line pairs were generated in parallel with FA patient-derived isogenic cell line pairs to provide comparable experimental material to use to identify cell and molecular phenotypes driven by germline or somatic loss of Fanconi pathway function, and the subset of these FA-dependent phenotypes that can be modified, complemented or suppressed. All 10 FANC-isogenic cell line pairs are available to academic, non-profit and industry investigators via the "Fanconi Anemia Research Materials" Resource and Repository at Oregon Health & Sciences University, Portland OR.
Assuntos
Carcinoma de Células Escamosas , Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Feminino , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Anemia de Fanconi/genética , Anemia de Fanconi/complicações , Anemia de Fanconi/patologia , Ciência Translacional Biomédica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular TumoralRESUMO
Sex chromosomes are highly variable in some taxonomic groups, but the evolutionary mechanisms underlying this diversity are not well understood. In terrestrial isopod crustaceans, evolutionary turnovers in sex chromosomes are frequent, possibly caused by Wolbachia, a vertically-transmitted endosymbiont causing male-to-female sex reversal. Here, we use surgical manipulations and genetic crosses, plus genome sequencing, to examine sex chromosomes in the terrestrial isopod Trachelipus rathkei. Although an earlier cytogenetics study suggested a ZZ/ZW sex chromosome system in this species, we surprisingly find multiple lines of evidence that in our study population, sex is determined by an XX/XY system. Consistent with a recent evolutionary origin for this XX/XY system, the putative male-specific region of the genome is small. The genome shows evidence of Y-linked duplications of the gene encoding the androgenic gland hormone, a major component of male sexual differentiation in isopods. Our analyses also uncover sequences horizontally acquired from past Wolbachia infections, consistent with the hypothesis that Wolbachia may have interfered with the evolution of sex determination in T. rathkei. Overall, these results provide evidence for the co-occurrence of multiple sex chromosome systems within T. rathkei, further highlighting the relevance of terrestrial isopods as models for the study of sex chromosome evolution.
Assuntos
Isópodes , Animais , Evolução Molecular , Feminino , Genoma , Hormônios , Humanos , Isópodes/genética , Masculino , Cromossomos Sexuais/genética , Processos de Determinação Sexual/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: The novel severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has had drastic effects on global healthcare with the UK amongst the countries most severely impacted. The aim of this study was to examine how COVID-19 challenged the neurosurgical delivery of care in a busy tertiary unit serving a socio-economically diverse population. METHODS: A prospective single-centre cohort study including all patients referred to the acute neurosurgical service or the subspecialty multidisciplinary teams (MDT) as well as all emergency and elective admissions during COVID-19 (18th March 2020-15th May 2020) compared to pre-COVID-19 (18th of January 2020-17th March 2020). Data on demographics, diagnosis, operation, and treatment recommendation/outcome were collected and analysed. RESULTS: Overall, there was a reduction in neurosurgical emergency referrals by 33.6% and operations by 55.6% during the course of COVID-19. There was a significant increase in the proportion of emergency operations performed during COVID-19 (75.2% of total, n=155) when compared to pre-COVID-19 (n = 198, 43.7% of total, p < 0.00001). In contrast to other published series, the 30-day perioperative mortality remained low (2.0%) with the majority of post-operative COVID-19-infected patients (n = 13) having underlying medical co-morbidities and/or suffering from post-operative complications. CONCLUSION: The capacity to safely treat patients requiring urgent or emergency neurosurgical care was maintained at all times. Strategies adopted to enable this included proactively approaching the referrers to maintain lines of communications, incorporating modern technology to run clinics and MDTs, restructuring patient pathways/facilities, and initiating the delivery of NHS care within private sector hospitals. Through this multi-modal approach we were able to minimize service disruptions, the complications, and mortality.
Assuntos
COVID-19/complicações , Neurocirurgia , COVID-19/fisiopatologia , Estudos de Coortes , Comorbidade , Procedimentos Cirúrgicos Eletivos , Serviços Médicos de Emergência , Feminino , Saúde Global , Hospitalização , Humanos , Comunicação Interdisciplinar , Masculino , Procedimentos Neurocirúrgicos , Pandemias , Equipe de Assistência ao Paciente , Segurança do Paciente , Estudos Prospectivos , Encaminhamento e Consulta , SARS-CoV-2 , Medicina Estatal , Reino UnidoRESUMO
BACKGROUND: The clinical significance of GLI1 expression either through canonical Hedgehog signal transduction or through non-canonical mechanisms in rhabdomyosarcoma (RMS) or Ewing sarcoma (EWS) is incompletely understood. We tested a role for Hedgehog (HH) signal transduction and GL11 expression in development of vincristine (VCR) resistance in RMS and EWS. METHODS: We characterized baseline expression and activity of HH pathway components in 5 RMS (RD, Rh18, Ruch-2, Rh30, and Rh41) and 5 EWS (CHLA9, CHLA10, TC32, CHLA258, and TC71) cell lines. We then established VCR-resistant RMS and EWS cell lines by exposing cells to serially increasing concentrations of VCR and determining the IC50. We defined resistance as a ≥ 30-fold increase in IC50 compared with parental cells. We determined changes in gene expression in the VCR-resistant cells compared with parental cells using an 86-gene cancer drug resistance array that included GLI1 and tested the effect of GLI1 inhibition with GANT61 or GLI1 siRNA on VCR resistance. RESULTS: We found evidence for HH pathway activity and GLI1 expression in RMS and EWS cell lines at baseline, and evidence that GLI1 contributes to survival and proliferation of these sarcoma cells. We were able to establish 4 VCR-resistant cell lines (Ruch-2VR, Rh30VR, Rh41VR, and TC71VR). GLI1 was significantly up-regulated in the Rh30VR, Rh41VR, and TC71VR cells. The only other gene in the drug resistance panel that was significantly up-regulated in each of these VCR-resistant cell lines compared with their corresponding parental cells was the GLI1 direct target and multidrug resistance gene, ATP-binding cassette sub-family B member 1 (MDR1). We established major vault protein (MVP), which was up-regulated in both vincristine-resistant alveolar RMS cell lines (Rh30VR and Rh41VR), as another direct target of GLI1 during development of drug resistance. Treatment of the VCR-resistant cell lines with the small molecule inhibitor GANT61 or GLI1 siRNA together with VCR significantly decreased cell viability at doses that did not reduce viability individually. CONCLUSIONS: These experiments demonstrate that GLI1 up-regulation contributes to VCR resistance in RMS and EWS cell lines and suggest that targeting GLI1 may benefit patients with RMS or EWS by reducing multidrug resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Vincristina/farmacologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Concentração Inibidora 50 , Piridinas/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima , Vincristina/uso terapêutico , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/genéticaRESUMO
For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis.
Assuntos
Drosophila melanogaster/genética , Epistasia Genética , Patrimônio Genético , Mutação , Asas de Animais/metabolismo , Alelos , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Teste de Complementação Genética , Genótipo , Discos Imaginais/crescimento & desenvolvimento , Discos Imaginais/metabolismo , Masculino , Proteínas Nucleares/genética , Fenótipo , Fatores de Transcrição/genética , Asas de Animais/crescimento & desenvolvimentoRESUMO
The premise of genetic analysis is that a causal link exists between phenotypic and allelic variation. However, it has long been documented that mutant phenotypes are not a simple result of a single DNA lesion, but are instead due to interactions of the focal allele with other genes and the environment. Although an experimentally rigorous approach focused on individual mutations and isogenic control strains has facilitated amazing progress within genetics and related fields, a glimpse back suggests that a vast complexity has been omitted from our current understanding of allelic effects. Armed with traditional genetic analyses and the foundational knowledge they have provided, we argue that the time and tools are ripe to return to the underexplored aspects of gene function and embrace the context-dependent nature of genetic effects. We assert that a broad understanding of genetic effects and the evolutionary dynamics of alleles requires identifying how mutational outcomes depend upon the 'wild type' genetic background. Furthermore, we discuss how best to exploit genetic background effects to broaden genetic research programs.
Assuntos
Evolução Molecular , Variação Genética , Genótipo , Fenótipo , Animais , Estudos de Associação Genética , Humanos , Mutação , Característica Quantitativa HerdávelRESUMO
PURPOSE: The occurrence of spinal epidural haematoma of 'spontaneous' origin in adults is a well-documented entity, though it is rare in children. In the literature to date, there are few cases of this kind of spontaneous haematoma proven to be due to an underlying vascular abnormality. METHOD: Retrospective review of two cases of children under 15 years of age with spontaneous epidural spinal haematoma. RESULTS: Underlying arteriovenous malformations were identified in both cases. Intra-operative photographs and histological sections of these anomalies are presented. CONCLUSION: These are the first two such cases described with clinico-pathological correlation.
Assuntos
Malformações Arteriovenosas/complicações , Hematoma Epidural Espinal/etiologia , Adolescente , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/cirurgia , Criança , Feminino , Hematoma Epidural Espinal/diagnóstico , Hematoma Epidural Espinal/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
Plants belonging to the genus Veratrum have been used throughout history for their medicinal properties. During the nineteenth and twentieth centuries, phytochemical investigations revealed a host of steroidal alkaloids in Veratrum species, some of which are potent bioactives. This review discusses Veratrum species that grow in North America with a focus on the medicinal history of these plants and the steroidal alkaloids they contain. While significant reviews have been devoted to singularly describing the plant species within the genus Veratrum (botany), the staggering breadth of alkaloids isolated from these and related plants (phytochemistry), and the intricacies of how the various alkaloids act on their biological targets (physiology and biochemistry), this review will straddle the margins of the aforementioned disciplines in an attempt to provide a unified, coherent picture of the Veratrum plants of North America and the medicinal uses of their bioactive steroidal alkaloids.
RESUMO
The "paradox of sex" refers to the question of why sexual reproduction is maintained in the wild, despite how costly it is compared to asexual reproduction. Because of these costs, one might expect nature to select for asexual reproduction, yet sex seems to be continually selected for. Multiple hypotheses have been proposed to explain this incongruence, including the niche differentiation hypothesis, the Red Queen hypothesis, and accumulation of harmful mutations in asexual species due to inefficient purifying selection. This study focuses on the accumulation of mutations in two terrestrial isopods, Trichoniscus pusillus, which has sexual diploid and parthenogenic triploid forms, and Hyloniscus riparius, an obligately sexual relative. We surveyed sex ratios of both species in an upstate New York population and obtained RNA-seq data from wild-caught individuals of both species to examine within- and between-species patterns of molecular evolution in protein-coding genes. The sex ratio and RNA-seq data together provide strong evidence that this T. pusillus population is entirely asexual and triploid, while the H. riparius population is sexual and diploid. Although all the wild T. pusillus individuals used for sequencing shared identical genotypes at nearly all SNPs, supporting a clonal origin, heterozygosity and SNP density were much higher in T. pusillus than in the sexually reproducing H. riparius. This observation suggests this parthenogenic lineage may have arisen via mating between two divergent diploid lineages. Between-species sequence comparisons showed no evidence of ineffective purifying selection in the asexual T. pusillus lineage, as measured by the ratio of nonsynonymous to synonymous substitutions (dN/dS ratios). Likewise, there was no difference between T. pusillus and H. riparius in the ratios of nonsynonymous to synonymous SNPs overall (pN/pS). However, pN/pS ratios in T. pusillus were significantly higher when considering only SNPs that may have arisen via recent mutation after the transition to parthenogenesis. Thus, these recent SNPs are consistent with the hypothesis that purifying selection is less effective against new mutations in asexual lineages, but only over long time scales. This system provides a useful model for future studies on the evolutionary tradeoffs between sexual and asexual reproduction in nature.
Assuntos
Evolução Molecular , Isópodes , Partenogênese , Animais , Partenogênese/genética , Isópodes/genética , Isópodes/fisiologia , Masculino , Razão de Masculinidade , Feminino , Reprodução Assexuada/genética , MutaçãoAssuntos
Neoplasias Encefálicas/patologia , Neoplasias da Mama/patologia , Genes do Retinoblastoma , Neoplasias Primárias Múltiplas/patologia , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Adolescente , Adulto , Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Evolução Fatal , Feminino , Humanos , Neoplasias Primárias Múltiplas/genética , Neoplasias da Retina/genética , Retinoblastoma/genética , Adulto JovemRESUMO
Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a benign but rare disorder associated with febrile cervical lymphadenopathy in young adults. Here, we discuss a case of a young female patient presenting with left tender cervical lymphadenopathy that progressed bilaterally with a fever of unknown origin. Laboratory parameters showed persistent leukopenia, especially neutropenia, which fluctuated with the degree of symptom severity. Two months were taken to confirm the diagnosis of KFD based on the histological interpretation of the lymph node biopsy. Supportive management with analgesics and paracetamol formed the main treatment. This case highlights the challenges and importance of diagnosing KFD to exclude other serious conditions such as lymphoma, tuberculosis, or lupus lymphadenitis that share similar clinical manifestations as KFD.
RESUMO
Cancers and autoimmune diseases commonly co-exist and immune checkpoint inhibitor therapy (ICI) exacerbates autoimmune pathologies. We recently described a lipidic peptide, designated IK14004, that promotes expansion of immunosuppressive T regulatory (Treg) cells and uncouples interleukin-2 from interferon-gamma production while activating CD8+ T cells. Herein, we report IK14004-mediated inhibition of Lewis lung cancer (LLC) growth and re-invigoration of splenocyte-derived exhausted CD4+ T cells. In human immune cells from healthy donors, IK14004 modulates expression of the T cell receptor α/ß subunits, induces Type I IFN expression, stimulates natural killer (NK) cells to express NKG2D/NKp44 receptors and enhances K562 cytotoxicity. In both T and NK cells, IK14004 alters the IL-12 receptor ß1/ß2 chain ratio to favour IL-12p70 binding. Taken together, this novel peptide offers an opportunity to gain further insight into the complexity of ICI immunotherapy so that autoimmune responses may be minimised without promoting tumour evasion from the immune system.
Assuntos
Doenças Autoimunes , Carcinoma Pulmonar de Lewis , Animais , Humanos , Autoimunidade , Células Matadoras Naturais , Linfócitos T Reguladores , Doenças Autoimunes/metabolismo , Carcinoma Pulmonar de Lewis/metabolismoRESUMO
Associations between neighborhood greenness and socioeconomic status (SES) are established, yet intra-neighborhood context and SES-related barriers to tree planting remain unclear. Large-scale tree planting implementation efforts are increasingly common and can improve human health, strengthen climate adaptation, and ameliorate environmental inequities. Yet, these efforts may be ineffective without in-depth understanding of local SES inequities and barriers to residential planting. We recruited 636 residents within and surrounding the Oakdale Neighborhood of Louisville, Kentucky, USA, and evaluated associations of individual and neighborhood-level sociodemographic indicators with greenness levels at multiple scales. We offered no-cost residential tree planting and maintenance to residents within a subsection of the neighborhood and examined associations of these sociodemographic indicators plus baseline greenness levels with tree planting adoption among 215 eligible participants. We observed positive associations of income with Normalized Difference Vegetation Index (NDVI) and leaf area index (LAI) within all radii around homes, and within yards of residents, that varied in strength. There were stronger associations of income with NDVI in front yards but LAI in back yards. Among Participants of Color, associations between income and NDVI were stronger than with Whites and exhibited no association with LAI. Tree planting uptake was not associated with income, education, race, nor employment status, but was positively associated with lot size, home value, lower population density, and area greenness. Our findings reveal significant complexity of intra-neighborhood associations between SES and greenness that could help shape future research and equitable greening implementation. Results show that previously documented links between SES and greenspace at large scales extend to residents' yards, highlighting opportunities to redress greenness inequities on private property. Our analysis found that uptake of no-cost residential planting and maintenance was nearly equal across SES groups but did not redress greenness inequity. To inform equitable greening, further research is needed to evaluate culture, norms, perceptions, and values affecting tree planting acceptance among low-SES residents.
Assuntos
Classe Social , Árvores , Humanos , Plantas , Características de Residência , RendaRESUMO
Ultraviolet radiation (UVR) induces immunosuppression and DNA damage, both of which contribute to the rising global incidence of skin cancer including melanoma. Nucleotide excision repair, which is activated upon UVR-induced DNA damage, is linked to expression of interleukin-12 (IL-12) which serves to limit immunosuppression and augment the DNA repair process. Herein, we report an immunomodulating peptide, designated IK14800, that not only elicits secretion of IL-12, interleukin-2 (IL-2) and interferon-gamma (IFN-γ) but also reduces DNA damage in the skin following exposure to UVR. Combined with re-invigoration of exhausted CD4+ T cells, inhibition of UVR-induced MMP-1 release and suppression of B16F10 melanoma metastases, IK14800 offers an opportunity to gain further insight into mechanisms underlying the development and progression of skin cancers.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Raios Ultravioleta/efeitos adversos , Terapia de Imunossupressão/efeitos adversos , Dano ao DNA , Reparo do DNA , Melanoma/etiologia , Interleucina-12 , Neoplasias Cutâneas/complicaçõesRESUMO
Background: While prior work examining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern focused on hospitalization and death, less is known about differences in clinical presentation. We compared the prevalence of acute symptoms across pre-Delta, Delta, and Omicron. Methods: We conducted an analysis of the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE), a cohort study enrolling symptomatic SARS-CoV-2-positive participants. We determined the association between the pre-Delta, Delta, and Omicron time periods and the prevalence of 21 coronavirus disease 2019 (COVID-19) acute symptoms. Results: We enrolled 4113 participants from December 2020 to June 2022. Pre-Delta vs Delta vs Omicron participants had increasing sore throat (40.9%, 54.6%, 70.6%; P < .001), cough (50.9%, 63.3%, 66.7%; P < .001), and runny noses (48.9%, 71.3%, 72.9%; P < .001). We observed reductions during Omicron in chest pain (31.1%, 24.2%, 20.9%; P < .001), shortness of breath (42.7%, 29.5%, 27.5%; P < .001), loss of taste (47.1%, 61.8%, 19.2%; P < .001), and loss of smell (47.5%, 55.6%, 20.0%; P < .001). After adjustment, those infected during Omicron had significantly higher odds of sore throat vs pre-Delta (odds ratio [OR], 2.76; 95% CI, 2.26-3.35) and Delta (OR, 1.96; 95% CI, 1.69-2.28). Conclusions: Participants infected during Omicron were more likely to report symptoms of common respiratory viruses, such as sore throat, and less likely to report loss of smell and taste. Trial registration: NCT04610515.
RESUMO
Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.
Assuntos
Neoplasias Peritoneais , Radioimunoterapia , Humanos , Animais , Camundongos , Radioimunoterapia/métodos , Camundongos Nus , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/radioterapia , Neoplasias Peritoneais/tratamento farmacológico , Radioisótopos/uso terapêutico , Linhagem Celular TumoralRESUMO
Myelomeningocoele remains a significant neurosurgical challenge. We have carried out a retrospective study evaluating the practices of myelomeningocoele repair at our institute over the last 5 years. Additionally, for patients that have been followed up for at least 12 months, we have investigated parameters describing functional outcome up to this period. With the recent Management of Myelomeningocoele (MOMS) study re-igniting interest in the condition, we aim to provide contemporary practice and outcome data to add to the literature.
Assuntos
Meningomielocele/cirurgia , Derivação Ventriculoperitoneal/métodos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Meningomielocele/patologia , Estudos Retrospectivos , Resultado do Tratamento , Derivação Ventriculoperitoneal/efeitos adversosRESUMO
T cell-dendritic cell (DC) interactions contribute to reciprocal stimulation leading to DC maturation that results in production of interleukin-12 (IL-12) and interferon-gamma (IFN-γ). Both cytokines have been implicated in autoimmune diseases while being necessary for effective immune responses against foreign antigens. We describe a lipidic peptide, designated IK14004, that modifies crosstalk between T cells and DCs resulting in suppression of IL-12p40/IFN-γ production. T cell production of interleukin-2 (IL-2) and IFN-γ is uncoupled and IL-12p70 production is enhanced. IK14004 induces expression of activating co-receptors in CD8+ T cells and increases the proportion of Foxp3-expressing CD4+ T regulatory cells. The potential for IK14004 to impact on signalling pathways required to achieve a balanced immune response upon stimulation of DCs and T cells is highlighted. This novel compound provides an opportunity to gain further insights into the complexity of T cell-DC interactions relevant to autoimmunity associated with malignancies and may have therapeutic benefit.