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The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.
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Deleção Cromossômica , Cromossomos Humanos Par 9 , Anormalidades Craniofaciais , Metilação de DNA , Estudos de Associação Genética , Histona-Lisina N-Metiltransferase , Deficiência Intelectual , Fenótipo , Humanos , Histona-Lisina N-Metiltransferase/genética , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Cromossomos Humanos Par 9/genética , Metilação de DNA/genética , Feminino , Masculino , Criança , Pré-Escolar , Antígenos de Histocompatibilidade/genética , Adolescente , Cardiopatias Congênitas/genética , Haploinsuficiência/genética , MutaçãoRESUMO
Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.
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Proteoglicanas , Retinose Pigmentar , Humanos , Animais , Camundongos , Adulto , Proteoglicanas/genética , Retina , Mutação , Retinose Pigmentar/genética , Progressão da DoençaRESUMO
OBJECTIVES: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery. METHODS: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking. CONCLUSION: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care.
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Pais , Medicina Estatal , Gravidez , Humanos , Masculino , Feminino , Sequenciamento do Exoma , Pais/psicologia , Inglaterra , Aconselhamento , Pesquisa QualitativaRESUMO
Distributed clean, reliable energy resources like solar plus battery storage (solar + storage) can reduce harmful emissions while supporting resilience. Solar + storage-powered resilience hubs provide energy for critical services during disasters while increasing human adaptive capacity year round. We studied where utility rates, local climate, and historical injustice make solar + storage resilience hubs more valuable and more challenging. We modeled the economic and climate impacts of outfitting candidate hub sites across California with solar + storage for everyday operations and identified designs and costs required to withstand a range of outages considering weather impacts on energy needs and availability. We integrated sociodemographic data to prioritize the siting of resilience hubs, to focus potential policy and funding priorities on regions where solar + storage for resilience hubs is hard or expensive, and where populations are most in need. We identified almost 20,000 candidate buildings with more than 8 GW of total rooftop solar potential capable of reducing CO2 emissions by 5 million tons per year while providing energy for community resilience. Hub capacity for one of the most challenging missions-providing emergency shelter during a power outage and smoke event-could have a statewide average lifetime cost of less than $2000 per seat. We identified regional challenges including insufficient rooftop solar capacity in cities, low sunlight in northern coastal California, and high costs driven by utility rate structures in Sacramento and the Imperial Valley. Results show that rates and net metering rules that incentivize solar + storage during everyday operations decrease resilience costs.
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Anxiety disorders occur at higher rates in youth with ASD than in neurotypical youth. Although the efficacy of CBT for anxiety in children with ASD is widely supported, factors that influence treatment outcomes are not well understood. This study examined the role of maternal anxiety in treatment outcomes for youth with ASD. Youth with ASD and anxiety (ages 8 to 14), along with their mothers (n = 87), participated in a group CBT intervention. Results indicated that maternal anxiety did not improve over the course of treatment. However, findings suggest that high levels of maternal anxiety at pre-treatment predicted higher levels of youth anxiety post-treatment. Importantly, the relationship between parent anxiety and youth outcomes was moderated by child age. The findings of the present study may provide initial insight into the role that maternal anxiety plays in treatment outcomes for children with ASD and co-occurring anxiety, particularly when considering child age.
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Transtorno do Espectro Autista , Criança , Feminino , Humanos , Adolescente , Transtorno do Espectro Autista/terapia , Ansiedade/terapia , Transtornos de Ansiedade/terapia , Resultado do Tratamento , MãesRESUMO
B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.
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Leucemia Linfocítica Crônica de Células B , Proteínas de Ciclo Celular/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Nucleares , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Fatores de Transcrição , Microambiente TumoralRESUMO
BACKGROUND: Adolescents with Autism Spectrum Disorder (ASD) and intellectual disability evidence significant anxiety. This study aimed to adapt a group cognitive behaviour therapies (CBT) programme designed for youth with ASD and anxiety to meet the cognitive, communication, and behavioural needs of adolescents with intellectual disability, and assess initial feasibility and efficacy of the intervention. METHODS: Structural, content and procedural adaptations were made to a 14-week family-focused CBT intervention. Twenty-three adolescents with ASD, intellectual disability and anxiety were included. Treatment acceptability along with adolescent anxiety symptoms was assessed via parent report measures. RESULTS: Of the 23 participants, 19 completed treatment and attended 94% of sessions. Parent acceptability was high. Significant reductions were noted on anxiety symptoms post-intervention. CONCLUSIONS: Results indicate that the CBT group was feasible and acceptable. Preliminary outcomes suggest that adolescent anxiety improved, although replication with a larger sample and comparison to a control group is needed.
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Transtorno do Espectro Autista , Transtorno Autístico , Terapia Cognitivo-Comportamental , Deficiência Intelectual , Adolescente , Ansiedade/terapia , Transtorno do Espectro Autista/terapia , Cognição , Estudos de Viabilidade , HumanosRESUMO
Interest in alternative fuels to petroleum and classical fuels has been growing very rapidly in recent years. Furan and its alkyl derivatives, such as methylfuran (2MF), have been identified as valid alternative biofuels. This study focuses on the self-reaction of the peroxy radical generated in the first oxidation step of 2MF, initiated by Cl atoms at 323 K and 4 Torr. The experiments have been carried out by a multiplexed synchrotron photoionization mass spectrometer (mSPIMS) at the Advanced Light Source (ALS) of Lawrence Berkeley National Laboratory (USA). The presence of a peak at m/z = 96 reveals that furfural is the dominant product of 2MF oxidation. Various reaction mechanisms for furfural formation are proposed here. The potential energy surfaces for singlet and triplet spin states have been mapped using quantum mechanical methods, such as CCSD(T), DFT-B3LYP, and composites models (CBS-QB3), to optimize the products, transition states, and intermediates. Experimental and theoretical results provide evidence that furfural does not form by primary reaction chemistry. Self-reaction of the peroxy radical generated in the first oxidation step of 2MF has been proposed as the pathway leading to the formation of furfural. Among various reaction channels, we indentified some entirely exothermic pathways involving oxygen-oxygen coupling and the formation of ROOOOR Russell intermediates.
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BACKGROUND: Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships. METHODS: Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene. RESULTS: Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype. CONCLUSIONS: We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme.
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Artrogripose/genética , Retardo do Crescimento Fetal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteína MyoD/genética , Feto Abortado , Animais , Artrogripose/patologia , Exoma/genética , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Pulmão/patologia , Camundongos , Mutação , Linhagem , Fenótipo , GravidezAssuntos
Sequenciamento do Exoma , Perda Auditiva/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Retrospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
BillingsMentor is an automated Web-based service for the Billings Method of natural family planning in which the guidance and interpretation previously communicated from teacher to student is provided by programmed algorithms. There are two functions: (1) to instruct the client to generate proper descriptions of her fertility symptoms; and (2) to interpret the symptoms efficiently according to the Billings Method and to communicate the results to the client. The efficiency of billingsMentor was tested by using the historical records of students who were under the guidance of a teacher to emulate their experience under the guidance of billingsMentor. The results indicate that billingsMentor performs as well as the teacher/student in recognizing the peak of fertility but it is slightly less efficient than the teacher/student in establishing the basic infertile pattern. Advantages that arise from adapting natural family planning to information technology are discussed.
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Background Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still not well characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the underlying neuropathology by examining the progression of myelination in an AS mouse model. Methods We conducted magnetic resonance imaging (MRI) on children with AS (n=32) and neurotypical controls (n=99) aged 0.5-12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice ( Ube3a m-/p+ ; AS model), Ube3a paternal-null mice ( Ube3a m+/p- ), and wildtype controls ( Ube3a m+/p+ ) using immunohistochemistry, Western blotting, and electron microscopy. Results Our data revealed that AS individuals exhibit significant reductions in brain volume by ~1 year of age, with WM reduced by 26% and gray matter by 21% by 6-12 years of age-approximately twice the reductions observed in the adult AS mouse model. In our AS mouse model, we saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal any abnormalities in myelinated or unmyelinated axons. Limitations: It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. Conclusions This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show that these deficits may be associated with delayed onset of myelination due to the loss of neuronal (but not glial) UBE3A. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments.
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Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.
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Síndrome de Angelman , Modelos Animais de Doenças , Neurônios , Ubiquitina-Proteína Ligases , Síndrome de Angelman/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Camundongos , Neurônios/metabolismo , Humanos , Masculino , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Encéfalo/metabolismoRESUMO
LAY ABSTRACT: Autistic youth frequently experience anxiety that can negatively affect them at home, with friends, and at school. Autistic youth have difficulty accessing mental health care, and this is particularly true for youth from traditionally underserved backgrounds. Providing mental health programs in schools may increase access to care for autistic youth with anxiety. The purpose of the study was to train interdisciplinary school providers to deliver school-based Facing Your Fears, a cognitive behavior therapy program for anxiety in autistic youth. Seventy-seven interdisciplinary school providers across 25 elementary/middle schools were trained by their colleagues and members of the research (train-the-trainer approach). Eighty-one students with autism or suspected autism, ages 8-14 years, were randomly assigned to either school-based Facing Your Fears or usual care. Students in school-based Facing Your Fears showed significant reductions in anxiety compared to students in usual care according to caregiver and student report. Other measures involved examining change in provider cognitive behavior therapy knowledge after training and determining how well interdisciplinary school providers were able to deliver school-based Facing Your Fears. Results indicated that interdisciplinary school providers showed significant improvements in cognitive behavior therapy knowledge after training. Interdisciplinary school providers were able to deliver most of school-based Facing Your Fears activities and with good quality. The positive outcomes in this study are encouraging. Training interdisciplinary school providers to deliver school-based Facing Your Fears may increase access to care for anxious autistic students. Future directions and limitations are discussed.
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Transtorno do Espectro Autista , Transtorno Autístico , Terapia Cognitivo-Comportamental , Adolescente , Humanos , Ansiedade/psicologia , Transtorno do Espectro Autista/psicologia , Terapia Cognitivo-Comportamental/métodos , Estudantes , CriançaRESUMO
Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.
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Leucemia Linfocítica Crônica de Células B , Transdução de Sinais , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Humanos , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Linhagem Celular Tumoral , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , NF-kappa B/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Receptores de Antígenos de Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed-direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer-Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16-known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.
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Citotoxicidade Celular Dependente de Anticorpos , Células Matadoras Naturais , Receptor Toll-Like 9 , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Receptores de IgG/metabolismo , Receptores de IgG/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/efeitos dos fármacosRESUMO
Introduction: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS. Methods: A survey (n = 159) and semi-structured interviews (n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future. Results: Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions. Conclusion: Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals.
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Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eµ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.
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Leucemia Linfocítica Crônica de Células B , Linfócitos T , Microambiente Tumoral , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Humanos , Animais , Camundongos , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Proliferação de Células/efeitos dos fármacos , Proteínas que Contêm Bromodomínio , ProteínasRESUMO
OBJECTIVE: The unprecedented events of 2020 required a pivot in scientific training to better prepare the biomedical research workforce to address global pandemics, structural racism, and social inequities that devastate human health individually and erode it collectively. Furthermore, this pivot had to be accomplished in the virtual environment given the nation-wide lockdown. METHODS: These needs and context led to leveraging of the San Francisco Building Infrastructure Leading to Diversity (SF BUILD) theories of change to innovate a Virtual BUILD Research Collaboratory (VBRC). The purpose of VBRC was to train Black, Indigenous, and people of color (BIPOC) students to apply their unique perspectives to biomedical research. These training activities were evaluated using a pre-post survey design that included both validated and new psychosocial scales. A new scale was piloted to measure culturally relevant pedagogy. RESULTS: VBRC scholars increased science identity on two items: thinking of myself as a scientist (+1point, p = 0.006) and belonging to a community of scientists (+1point, p = 0.069). Overall, scholars perceived stress also decreased over VBRC (-2.35 points, p = 0.02). Post VBRC, scholars had high agency scores (µ = 11.02, Md = 12, range = 6-12, σ = 1.62) and cultural humility scores (µ = 22.11, Md = 23, range = 12-24, σ = 2.71). No notable race/ethnic differences were found in any measures. CONCLUSIONS: Taken together, our innovative approach to data science training for BIPOC in unprecedented times shows promise for better preparing the workforce critically needed to address the fundamental gaps in knowledge at the intersection of public health, structural racism, and biomedical sciences.
Assuntos
Pesquisa Biomédica , Racismo , Humanos , Racismo/prevenção & controle , Ciência de Dados , Recursos Humanos , Pesquisa Biomédica/educação , EstudantesRESUMO
In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.