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1.
Blood ; 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38968138

RESUMEN

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

2.
J Immunother Cancer ; 12(7)2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38955420

RESUMEN

BACKGROUND: Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. METHODS: 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. RESULTS: Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. CONCLUSIONS: Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.


Asunto(s)
Clorhidrato de Bendamustina , Productos Biológicos , Linfoma de Células B Grandes Difuso , Humanos , Clorhidrato de Bendamustina/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Adulto , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19/inmunología , Antígenos CD19/uso terapéutico
3.
Lancet ; 404(10450): 353-363, 2024 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-38996463

RESUMEN

BACKGROUND: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study. METHODS: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment. FINDINGS: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome. INTERPRETATION: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach. FUNDING: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.


Asunto(s)
Antígenos CD19 , Inmunoterapia Adoptiva , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos CD19/inmunología , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Dosis Máxima Tolerada , Receptores Quiméricos de Antígenos/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Anciano de 80 o más Años
4.
Cleft Palate Craniofac J ; : 10556656241261918, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38870388

RESUMEN

OBJECTIVE: To investigate the association between the sidedness of orofacial clefts and additional congenital malformations. DESIGN: Linkage of a national registry of cleft births to national administrative data of hospital admissions. SETTING: National Health Service, England. PARTICIPANTS: 2007 children born with cleft lip ± alveolus (CL ± A) and 2724 with cleft lip and palate (CLP) born between 2000 and 2012. MAIN OUTCOME MEASURE: The proportion of children with ICD-10 codes for additional congenital malformations by the sidedness (left, right or bilateral) of orofacial clefts. RESULTS: For CL ± A phenotypes, there was no evidence for a difference in the prevalence of additional anomalies between left (22%, reference), right (22%, aOR 1.02, 95% CI 0.80 to 1.28; P = .90) and bilateral clefts (23%, aOR 1.09, 95% CI 0.75 to 1.57; P = .66). For CLP phenotypes, there was evidence of a lower prevalence of additional malformations in left (23%, reference) compared to right (32%, aOR 1.54, 95% CI 1.25 to 1.91; P < .001) and bilateral clefts (33%, aOR 1.64, 95% CI 1.35 to 1.99; P < .001). CONCLUSIONS: The prevalence of additional congenital malformations was similar across sidedness subtypes with CL ± A phenotypes but was different for sidedness subtypes within CLP cases. These data support the hypothesis that CL ± A has a different underlying aetiology from CLP and that within the CLP phenotype, right sided CLP may lie closer in aetiology to bilateral CLP than it does to left sided CLP.

5.
N Engl J Med ; 390(22): 2047-2060, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38865660

RESUMEN

BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).


Asunto(s)
Antineoplásicos Inmunológicos , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Linfoma de Células T , Neoplasias Primarias Secundarias , Receptores Quiméricos de Antígenos , Femenino , Humanos , Persona de Mediana Edad , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Hematopoyesis Clonal , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/genética , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células T/etiología , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Linfoma de Células T/terapia , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Integración Viral
6.
Influenza Other Respir Viruses ; 18(5): e13284, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38773753

RESUMEN

BACKGROUND: We report 2023/2024 season interim influenza vaccine effectiveness for three studies, namely, primary care in Great Britain, hospital settings in Scotland and hospital settings in England. METHODS: A test negative design was used to estimate vaccine effectiveness. RESULTS: Estimated vaccine effectiveness against all influenzas ranged from 63% (95% confidence interval 46 to 75%) to 65% (41 to 79%) among children aged 2-17, from 36% (20 to 49%) to 55% (43 to 65%) among adults 18-64 and from 40% (29 to 50%) to 55% (32 to 70%) among adults aged 65 and over. CONCLUSIONS: During a period of co-circulation of influenza A(H1N1)pdm09 and A(H3N2) in the United Kingdom, evidence for effectiveness of the influenza vaccine in both children and adults was found.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Subtipo H3N2 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Atención Primaria de Salud , Atención Secundaria de Salud , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Gripe Humana/epidemiología , Adolescente , Adulto , Niño , Preescolar , Persona de Mediana Edad , Adulto Joven , Reino Unido , Anciano , Subtipo H3N2 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/genética , Masculino , Femenino , Subtipo H1N1 del Virus de la Influenza A/inmunología , Estaciones del Año , Eficacia de las Vacunas , Vacunación/estadística & datos numéricos
7.
Influenza Other Respir Viruses ; 18(5): e13295, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38744684

RESUMEN

BACKGROUND: The 2022/23 influenza season in the United Kingdom saw the return of influenza to prepandemic levels following two seasons with low influenza activity. The early season was dominated by A(H3N2), with cocirculation of A(H1N1), reaching a peak late December 2022, while influenza B circulated at low levels during the latter part of the season. From September to March 2022/23, influenza vaccines were offered, free of charge, to all aged 2-13 (and 14-15 in Scotland and Wales), adults up to 49 years of age with clinical risk conditions and adults aged 50 and above across the mainland United Kingdom. METHODS: End-of-season adjusted vaccine effectiveness (VE) estimates against sentinel primary-care attendance for influenza-like illness, where influenza infection was laboratory confirmed, were calculated using the test negative design, adjusting for potential confounders. METHODS: Results In the mainland United Kingdom, end-of-season VE against all laboratory-confirmed influenza for all those > 65 years of age, most of whom received adjuvanted quadrivalent vaccines, was 30% (95% CI: -6% to 54%). VE for those aged 18-64, who largely received cell-based vaccines, was 47% (95% CI: 37%-56%). Overall VE for 2-17 year olds, predominantly receiving live attenuated vaccines, was 66% (95% CI: 53%-76%). CONCLUSION: The paper provides evidence of moderate influenza VE in 2022/23.


Asunto(s)
Subtipo H3N2 del Virus de la Influenza A , Virus de la Influenza B , Vacunas contra la Influenza , Gripe Humana , Atención Primaria de Salud , Eficacia de las Vacunas , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Gripe Humana/epidemiología , Persona de Mediana Edad , Adolescente , Adulto , Atención Primaria de Salud/estadística & datos numéricos , Reino Unido/epidemiología , Anciano , Adulto Joven , Niño , Femenino , Masculino , Preescolar , Subtipo H3N2 del Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Estaciones del Año , Vacunación/estadística & datos numéricos
8.
bioRxiv ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38798338

RESUMEN

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

9.
Euro Surveill ; 29(15)2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38606570

RESUMEN

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.


Asunto(s)
COVID-19 , Gripe Humana , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Adulto , Humanos , Gripe Humana/epidemiología , Europa (Continente)/epidemiología , Estaciones del Año , Infecciones por Virus Sincitial Respiratorio/epidemiología
10.
J Acoust Soc Am ; 155(4): 2707-2723, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38647257

RESUMEN

A compact analytical solution obtained in the paraxial approximation is used to investigate focused and unfocused vortex beams radiated by a source with a Gaussian amplitude distribution. Comparisons with solutions of the Helmholtz equation are conducted to determine bounds on the parameter space in which the paraxial approximation is accurate. A linear relation is obtained for the dependence of the vortex ring radius on the topological charge, characterized by its orbital number, in the far field of an unfocused beam and in the focal plane of a focused beam. For a focused beam, it is shown that as the orbital number increases, the vortex ring not only increases in radius but also moves out of the focal plane in the direction of the source. For certain parameters, it is demonstrated that with increasing orbital number, the maximum amplitude in a focused beam becomes localized along a spheroidal surface enclosing a shadow zone in the prefocal region. This field structure is described analytically by ray theory developed in the present work, showing that the spheroidal surface in the prefocal region coincides with a simple expression for the coordinates of the caustic surface formed in a focused vortex beam.

11.
Leukemia ; 38(5): 963-968, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38491306

RESUMEN

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores Quiméricos de Antígenos , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Humanos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Niño , Adulto , Femenino , Masculino , Adolescente , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Adulto Joven , Receptores Quiméricos de Antígenos/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Preescolar , Persona de Mediana Edad , Linfocitos T/inmunología , Linfocitos T/metabolismo
12.
Blood Adv ; 8(12): 3314-3326, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38498731

RESUMEN

ABSTRACT: Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.


Asunto(s)
Antígenos CD19 , Inmunofenotipificación , Inmunoterapia Adoptiva , Humanos , Masculino , Antígenos CD19/inmunología , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Femenino , Anciano , Receptores Quiméricos de Antígenos/inmunología , Adulto , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/sangre , Anciano de 80 o más Años , Productos Biológicos
13.
Brain ; 147(5): 1822-1836, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38217872

RESUMEN

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.


Asunto(s)
Discapacidad Intelectual , Enfermedades Musculares , Receptores de Sulfonilureas , Humanos , Discapacidad Intelectual/genética , Femenino , Receptores de Sulfonilureas/genética , Masculino , Animales , Niño , Enfermedades Musculares/genética , Preescolar , Adolescente , Pez Cebra , Mutación con Pérdida de Función/genética , Adulto , Linaje , Adulto Joven
14.
Am J Obstet Gynecol ; 230(2): 251.e1-251.e17, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37598997

RESUMEN

BACKGROUND: Zika virus congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta without causing overt cellular or tissue damage is fundamental to deciphering mechanisms of maternal-fetal vertical transmission. OBJECTIVE: Placenta-specific microRNAs are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that the Zika virus functionally disrupts placental microRNAs, enabling viral persistence and fetal pathogenesis. STUDY DESIGN: To test this hypothesis, we used orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation to identify any significant alterations in the functional loading of microRNAs and their targets onto the RNA-induced silencing complex. Trophoblasts from same-donors were split and infected with a contemporary first-passage Zika virus strain HN16 (multiplicity of infection=1 plaque forming unit per cell) or mock infected. To functionally cross-validate microRNA-messenger RNA interactions, we compared our Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation results with an independent analysis of published bulk RNA-sequencing data from human placental disk specimens (n=3 subjects; Zika virus positive in first, second, or third trimester, CD45- cells sorted by flow cytometry) and compared it with uninfected controls (n=2 subjects). To investigate the importance of these microRNA and RNA interference networks in Zika virus pathogenesis, we used a gnotobiotic mouse model uniquely susceptible to the Zika virus. We evaluated if small-molecule enhancement of microRNA and RNA interference pathways with enoxacin influenced Zika virus pathogenesis (n=20 dams total yielding 187 fetal specimens). Lastly, placentae (n=14 total) from this mouse model were analyzed with Visium spatial transcriptomics (9743 spatial transcriptomes) to identify potential Zika virus-associated alterations in immune microenvironments. RESULTS: We found that Zika virus infection of primary human trophoblast cells led to an unexpected disruption of placental microRNA regulation networks. When compared with uninfected controls, Zika virus-infected placentae had significantly altered SLC12A8, SDK1, and VLDLR RNA-induced silencing complex loading and transcript levels (-22; adjusted P value <.05; Wald-test with false discovery rate correction q<0.05). In silico microRNA target analyses revealed that 26 of 119 transcripts (22%) in the transforming growth factor-ß signaling pathway were targeted by microRNAs that were found to be dysregulated following Zika virus infection in trophoblasts. In gnotobiotic mice, relative to mock controls, Zika virus-associated fetal pathogenesis included fetal growth restriction (P=.036) and viral persistence in placental tissue (P=.011). Moreover, spatial transcriptomics of murine placentae revealed that Zika virus-specific placental niches were defined by significant up-regulation of complement cascade components and coordinated changes in transforming growth factor-ß gene expression. Finally, treatment of Zika virus-infected mice with enoxacin abolished placental Zika virus persistence, rescued the associated fetal growth restriction, and the Zika virus-associated transcriptional changes in placental immune microenvironments were no longer observed. CONCLUSION: These results collectively suggest that (1) Zika virus infection and persistence is associated with functionally perturbed microRNA and RNA interference pathways specifically related to immune regulation in placental microenvironments and (2) enhancement of placental microRNA and RNA interference pathways in mice rescued Zika virus-associated pathogenesis, specifically persistence of viral transcripts in placental microenvironments and fetal growth restriction.


Asunto(s)
MicroARNs , Infección por el Virus Zika , Virus Zika , Embarazo , Humanos , Femenino , Animales , Ratones , Virus Zika/genética , Infección por el Virus Zika/genética , MicroARNs/genética , MicroARNs/metabolismo , Retardo del Crecimiento Fetal/metabolismo , Enoxacino/metabolismo , Placenta/metabolismo , Perfilación de la Expresión Génica , Complejo Silenciador Inducido por ARN/metabolismo , Factores de Crecimiento Transformadores/metabolismo , Trofoblastos/metabolismo
16.
IEEE Trans Biomed Eng ; 71(2): 621-630, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37665711

RESUMEN

OBJECTIVE: Ultrasound transient elastography (TE) technologies for liver stiffness measurement (LSM) utilize vibration of small, flat pistons, which generate shear waves that lack directivity. The most common cause for LSM failure in practice is insufficient shear wave signal at the needed depths. We propose to increase shear wave amplitude by focusing the waves into a directional beam. Here, we demonstrate the generation and propagation of focused shear wave beams (fSWBs) in gelatin. METHODS: Directional fSWBs are generated by vibration at 200-400 Hz of a concave piston embedded near the surface of gelatin phantoms and measured with high-frame-rate ultrasound imaging. Five phantoms with a range of stiffnesses are employed. Shear wave speeds assessed by fSWBs are compared with those by radiation-force-based methods (2D SWE). fSWB amplitudes are compared to predictions using an analytical model. RESULTS: fSWB-derived shear wave speeds are in good agreement with 2D SWE. The amplitudes of fSWBs are localized to the LSM region and are significantly greater than unfocused shear waves. Overall agreement with theory is observed, with some discrepancies in the theoretical source condition. CONCLUSION: Focusing shear waves can increase the signal in the LSM region for TE. Challenges for translation include coupling piston vibration with the patient skin and increased attenuation in vivo compared to the phantoms employed here. SIGNIFICANCE: Fibrosis is the most predictive measure of patient outcome in non-alcoholic fatty liver disease. Increased shear wave amplitude in the LSM region can reduce fibrosis assessment failure rates by TE, thus reducing the need for invasive methods like biopsy.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Gelatina , Humanos , Cirrosis Hepática , Diagnóstico por Imagen de Elasticidad/métodos , Ultrasonografía , Vibración , Fantasmas de Imagen , Hígado/diagnóstico por imagen
17.
Proc Biol Sci ; 290(2008): 20231601, 2023 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-37788704

RESUMEN

Coral reef fisheries supply nutritious catch to tropical coastal communities, where the quality of reef seafood is determined by both the rate of biomass production and nutritional value of reef fishes. Yet our understanding of reef fisheries typically uses targets of total reef fish biomass rather than individual growth (i.e. biomass production) and nutrient content (i.e. nutritional value of reef fish), limiting the ability of management to sustain the productivity of nutritious catches. Here, we use modelled growth coefficients and nutrient concentrations to develop a new metric of nutrient productivity of coral reef fishes. We then evaluate this metric with underwater visual surveys of reef fish assemblages from four tropical countries to examine nutrient productivity of reef fish food webs. Species' growth coefficients were associated with nutrients that vary with body size (calcium, iron, selenium and zinc), but not total nutrient density. When integrated with fish abundance data, we find that herbivorous species typically dominate standing biomass, biomass turnover and nutrient production on coral reefs. Such bottom-heavy trophic distributions of nutrients were consistent across gradients of fishing pressure and benthic composition. We conclude that management restrictions that promote sustainability of herbivores and other low trophic-level species can sustain biomass and nutrient production from reef fisheries that is critical to the food security of over 500 million people in the tropics.


Asunto(s)
Antozoos , Arrecifes de Coral , Humanos , Animales , Explotaciones Pesqueras , Conservación de los Recursos Naturales , Biomasa , Nutrientes , Peces , Ecosistema
19.
Heliyon ; 9(6): e16993, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37484245

RESUMEN

Background: The spleen is the most commonly injured organ in abdominal trauma. Guidelines suggest non-operative management (NOM) is preferred over splenectomy for all haemodynamically stable patients, regardless of injury severity. The availability of splenic angioembolization has been shown to improve outcomes for high-grade splenic injuries by decreasing failure rates of NOM. Trauma incidence and fatality rates are higher in regional and remote areas, and rurality is associated with increased mortality from trauma. Additionally, rural hospitals have difficulty with staff retention and may offer less specialist services compared with urban centres. Methods: A single-centre retrospective cohort study was conducted at the Royal Darwin Hospital, using the National Critical Care and Trauma Response Centre database. All patients with splenic injury admitted between January 2018 and December 2021 were selected, and divided into control and intervention cohorts, before and after January 1, 2020, correlating with interventional radiology availability. Demographic information included age, gender, mechanism of injury, AIS grade of splenic injury, injury severity score, and shock index. The primary outcome was management of splenic injury and failure rate of NOM. Secondary outcomes included mortality, ICU length of stay and hospital length of stay. Results: Sixty-six patients met inclusion criteria, 32 controls and 34 interventions. Intervention and control groups were statistically similar for baseline demographics, and outcome measures of mortality and ICU length of stay. There was significant difference in the management of splenic injury, either OM or NOM, between intervention and control cohorts among high-grade splenic injury patients (AIS grade 4 and 5). In logistic regression analysis, the absence of interventional radiology was associated with increased OM (OR 12.8, SE 15.7, p = 0.04, 95%CI 1.15-142). Conclusion: The absence of an interventional radiology service was associated with an increased risk of operative management, suggesting interventional radiology helps to prevent splenectomy, improving long term outcomes for splenic trauma patients in regional settings. The effects of availability of IR seen in international publications on decreased mortality and shorter length of stay were not replicated in this study.

20.
Health Technol (Berl) ; 13(3): 523-533, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37303978

RESUMEN

Purpose: The emergence of the COVID-19 (SARS-CoV-2) pandemic has led to public health restrictions and a shift towards virtual care and telehealth. The aim of this study was to explore barriers and facilitators of virtual care from the perspective of neurological and psychiatric patients. Methods: One-on-one interviews were conducted remotely using telephone and online video teleconferencing. There was a total of 57 participants, and a thematic content analysis was conducted using NVivo software. Results: The two main themes were (1) virtual health service delivery and (2) virtual physician/patient interaction, with subthemes around how virtual care improved accessibility of care for patients and improved patient-centered care; how privacy and technical issues impact patients using virtual care; and the need for relationality and connection between health care providers and patients while using virtual care. Conclusions: This study showed that virtual care can increase accessibility and efficiency for patients and providers, indicating its potential for ongoing use in the delivery of clinical care. Virtual care was found to be an acceptable mode of healthcare delivery from the perspective of patients; however, there is a continued need for relationship-building between care providers and patients.

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