RESUMO
The incidence of early-onset colorectal cancer (EO-CRC) is surging, and by 2030, one-third of all CRCs will occur before the commonly recommended screening age of 50 years. The time required for EO-CRC to reach the metastatic stage is unknown, yet this knowledge is critical to tailor early-diagnosis screening strategies. Here, we discuss how defining a key biological feature of EO-CRC may be central to protecting young adults from an alarming and probably unprecedented tumor epidemic.
Assuntos
Idade de Início , Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Adulto , Pessoa de Meia-IdadeRESUMO
The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what the representational stability of simple well-rehearsed actions is, particularly in humans, and their adaptability to new contexts. Using an electrocorticography brain-computer interface (BCI) in tetraplegic participants, we found that the low-dimensional manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. The manifold's absolute location, however, demonstrated constrained day-to-day drift. Strikingly, neural statistics, especially variance, could be flexibly regulated to increase representational distances during BCI control without somatotopic changes. Discernability strengthened with practice and was BCI-specific, demonstrating contextual specificity. Sampling representational plasticity and drift across days subsequently uncovered a meta-representational structure with generalizable decision boundaries for the repertoire; this allowed long-term neuroprosthetic control of a robotic arm and hand for reaching and grasping. Our study offers insights into mesoscale representational statistics that also enable long-term complex neuroprosthetic control.
Assuntos
Interfaces Cérebro-Computador , Imaginação , Movimento , Plasticidade Neuronal , Humanos , Masculino , Imaginação/fisiologia , Adulto , Feminino , Eletrocorticografia , Pessoa de Meia-Idade , Quadriplegia/fisiopatologia , Robótica , Adulto JovemRESUMO
Industrialization adversely affects the gut microbiome and predisposes individuals to chronic non-communicable diseases. We tested a microbiome restoration strategy comprising a diet that recapitulated key characteristics of non-industrialized dietary patterns (restore diet) and a bacterium rarely found in industrialized microbiomes (Limosilactobacillus reuteri) in a randomized controlled feeding trial in healthy Canadian adults. The restore diet, despite reducing gut microbiome diversity, enhanced the persistence of L. reuteri strain from rural Papua New Guinea (PB-W1) and redressed several microbiome features altered by industrialization. The diet also beneficially altered microbiota-derived plasma metabolites implicated in the etiology of chronic non-communicable diseases. Considerable cardiometabolic benefits were observed independently of L. reuteri administration, several of which could be accurately predicted by baseline and diet-responsive microbiome features. The findings suggest that a dietary intervention targeted toward restoring the gut microbiome can improve host-microbiome interactions that likely underpin chronic pathologies, which can guide dietary recommendations and the development of therapeutic and nutritional strategies.
Assuntos
Dieta , Microbioma Gastrointestinal , Humanos , Adulto , Masculino , Feminino , Limosilactobacillus reuteri/fisiologia , Pessoa de Meia-Idade , Canadá , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/prevenção & controle , Adulto JovemRESUMO
Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
Assuntos
Cromotripsia , Evolução Clonal , Mutação , Osteossarcoma , Proteína Supressora de Tumor p53 , Osteossarcoma/genética , Osteossarcoma/patologia , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Perda de Heterozigosidade , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Criança , Adulto , Genoma Humano , Translocação Genética , Sequenciamento Completo do Genoma , Masculino , Prognóstico , FemininoRESUMO
Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.
Assuntos
Imunoterapia , Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias/imunologia , Neoplasias/terapia , Criança , Adolescente , Pré-Escolar , Feminino , Masculino , Mutação , Linfócitos T Citotóxicos/imunologia , Lactente , Estudos de Coortes , Adulto , Inflamação/imunologiaRESUMO
This study investigated the cervicovaginal microbiome's (CVM's) impact on Chlamydia trachomatis (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the molBV algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM's contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.
Assuntos
Colo do Útero , Infecções por Chlamydia , Chlamydia trachomatis , Microbiota , RNA Ribossômico 16S , Vagina , Humanos , Feminino , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Adolescente , Infecções por Chlamydia/microbiologia , Vagina/microbiologia , Adulto Jovem , RNA Ribossômico 16S/genética , Colo do Útero/microbiologia , Adulto , Vaginose Bacteriana/microbiologia , Fatores de Risco , Doença Inflamatória Pélvica/microbiologia , Estudos de Casos e Controles , Hispânico ou Latino/genética , BrancosRESUMO
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
Assuntos
Mucosa Respiratória/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Vacinas Virais/imunologia , Adulto , Idoso , Animais , Criança , Humanos , Evasão da Resposta Imune , Imunomodulação , Mucosa Respiratória/virologiaRESUMO
Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0-87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.
Assuntos
Microbiota , Humanos , Idoso , Pré-Escolar , Adulto , Criança , Pessoa de Meia-Idade , Adolescente , Idoso de 80 Anos ou mais , Masculino , Feminino , Lactente , Adulto Jovem , RNA Ribossômico 16S/genética , Estudos Transversais , Recém-Nascido , Sistema Respiratório/microbiologia , Longevidade , Nasofaringe/microbiologia , Saliva/microbiologia , Meio AmbienteRESUMO
Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.
Assuntos
Blastocystis , Dieta , Microbioma Gastrointestinal , Obesidade , Humanos , Blastocystis/metabolismo , Masculino , Feminino , Infecções por Blastocystis , Adulto , Pessoa de Meia-Idade , Intestinos/parasitologia , Intestinos/microbiologia , Doenças Cardiovasculares/prevenção & controle , MetagenomaRESUMO
We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.
Assuntos
Diabetes Mellitus Tipo 1 , Células-Tronco Pluripotentes Induzidas , Transplante das Ilhotas Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/terapia , Transplante das Ilhotas Pancreáticas/métodos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Hemoglobinas Glicadas/metabolismo , Masculino , Ilhotas Pancreáticas/metabolismo , Reto do Abdome/metabolismo , Adulto , Glicemia/metabolismo , Insulina/metabolismoRESUMO
In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.
Assuntos
Doença de Alzheimer , Biomarcadores , Proteômica , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Proteômica/métodos , Biomarcadores/líquido cefalorraquidiano , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Mutação , Idoso , Aprendizado de MáquinaRESUMO
Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.
Assuntos
Apresentação de Antígeno , Autoantígenos , Antígenos de Histocompatibilidade Classe II , Lúpus Eritematoso Sistêmico , Lúpus Eritematoso Sistêmico/imunologia , Humanos , Animais , Autoantígenos/imunologia , Camundongos , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Linfócitos T CD4-Positivos/imunologia , Feminino , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Diferenciação de Linfócitos B/imunologia , Herpesvirus Humano 4/imunologia , Adulto , Linfócitos T/imunologia , Camundongos Endogâmicos C57BLRESUMO
Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.
Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Miosite , Receptores de Antígenos Quiméricos , Escleroderma Sistêmico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Imunoterapia Adotiva/métodos , Miosite/terapia , Miosite/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante HomólogoRESUMO
Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antiprotozoários , Antígenos de Protozoários , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Humanos , Anticorpos Neutralizantes/imunologia , Plasmodium falciparum/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologia , Vacinas Antimaláricas/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Proteínas de Protozoários/imunologia , Anticorpos Monoclonais/imunologia , Adulto , Linfócitos B/imunologia , Epitopos/imunologia , Feminino , Mali , Proteínas de Transporte/imunologia , Masculino , AdolescenteRESUMO
The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.
Assuntos
Fungos , Microbioma Gastrointestinal , Micobioma , Animais , Humanos , Masculino , Camundongos , Fezes/microbiologia , Fungos/genética , Fungos/classificação , Fungos/isolamento & purificação , Genoma Fúngico/genética , Genômica , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genética , Metagenoma , Filogenia , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Dexametasona , Monócitos , SARS-CoV-2 , Análise de Célula Única , Humanos , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Masculino , Feminino , Transcriptoma , Pessoa de Meia-Idade , Idoso , Glucocorticoides/uso terapêutico , Glucocorticoides/farmacologia , Pulmão/patologia , AdultoRESUMO
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
Assuntos
Hematopoiese Clonal , DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Periodontite , Animais , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Camundongos , Hematopoiese Clonal/genética , Humanos , Periodontite/genética , Periodontite/patologia , Mutação , Masculino , Feminino , Inflamação/genética , Inflamação/patologia , Osteoclastos/metabolismo , Camundongos Endogâmicos C57BL , Adulto , Interleucina-17/metabolismo , Interleucina-17/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Hematopoese/genética , Osteogênese/genética , Células-Tronco Hematopoéticas/metabolismo , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Pessoa de Meia-IdadeRESUMO
Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk. With regard to both children and adults, we review advancements in understanding the intestinal epithelium, the mucosal immune system, and the resident microbiota, describing how dysfunction at any level can lead to diseases like IBD. We conclude with future directions for applying advances in IBD genetics to better understand pathogenesis and develop therapeutics targeting key pathogenic nodes.
Assuntos
Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Adulto , Animais , Criança , Pré-Escolar , Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/terapia , Terapia de Alvo MolecularRESUMO
Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por HIV , HIV-1 , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Masculino , Adulto , Feminino , Humanos , Sangue Fetal , Leucemia Mieloide Aguda/terapiaRESUMO
MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.