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1.
Microbiol Resour Announc ; : e0067624, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39345196

RESUMO

BK polyomavirus (BKPyV) is associated with disease in transplant patients. BKPyV genomic diversity is thought to contribute to functional differences in virulence factors. Here, we present the near full-length BKPyV genome sequence from a patient who underwent hematopoietic cell transplant and was infected with subtype III, a rare subtype.

2.
Transplant Cell Ther ; 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39277113

RESUMO

The Third Annual Workshop of the American Society for Transplantation and Cellular Therapy (ASTCT) and National Marrow Donor Program (NMDP) ACCESS Initiative occurred on July 23 and 24, 2024. Content from the workshop is provided to inform the hematopoietic cell transplantation (HCT) and cellular therapy (CT) ecosystem about progress and direction of the collaborative. Highlights from the meeting are reviewed, including the inaugural Corporate Roundtable and Advocacy Day, new partnerships with non-profit organizations, and updates on projects from the Awareness, Poverty and Race and Ethnicity Inequity Committees. In addition, the Junior Faculty and Trainee Immersion Program-sponsored efforts in workforce diversity and physician advocacy are presented. Lastly, continued education was provided on patient and caregiver participation as well as community engagement. As it enters its third year, the ASTCT-NMDP ACCESS Initiative will transition from foundation building as a grass roots collaborative to intentional impact in reducing barriers and improving outcome disparities for all patients in need of HCT/CT. Enthusiasm for and participation in the ACCESS Initiative remain high. Both are needed to sustain progress in achieving its goal in enabling all patients in need to receive HCT/CT.

4.
Pediatr Blood Cancer ; : e31336, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39289854

RESUMO

BACKGROUND: Pediatric and young adult patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) face a crucial, yet understudied, risk of invasive fungal infections (IFI), especially compared to allogeneic transplants. This gap underscores the need for research in pediatric patients undergoing auto-HSCT. Our objective was to evaluate the incidence of IFI in pediatric and young adult patients during the first year after auto-HSCT. MATERIALS AND METHODS: We conducted a single-center retrospective analysis of 150 pediatric and young adult auto-HSCT patients who underwent transplant from January 2013 to January 2023. We focused on IFI incidence within the first-year post transplant, using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria for IFI identification. RESULTS: Among the 150 patients analyzed, with 240 unique transplant episodes, the primary indication was neuroblastoma (37.3%), and micafungin was extensively used for prophylaxis (82.7%). There was an absence of IFI from yeast and mold species, suggesting a low IFI risk in this cohort. The incidence of IFI in pediatric auto-HSCT recipients receiving micafungin primary antifungal prophylaxis is rare. CONCLUSIONS: The findings advocate for further research to refine prophylaxis guidelines and highlight the need for individualized risk assessment to optimize post-transplant care.

5.
Biomedicines ; 12(8)2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39200127

RESUMO

One of theories explaining the development of long-lasting symptoms after an acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include changes in the methylation pattern of the host. The current study aimed to investigate whether DNA methylation levels associated with the angiotensin-converting enzyme 2 (ACE2) promoter are different when comparing individuals previously hospitalized due to COVID-19 who then developed long-lasting post-COVID pain with those previously hospitalized due to COVID-19 who did not develop post-COVID-19 pain symptoms. Non-stimulated saliva samples were obtained from a cohort of 279 (mean age: 56.5, SD: 13.0 years old, 51.5% male) COVID-19 survivors who needed hospitalization. Clinical data were collected from hospital medical records. Participants were asked to disclose pain symptoms developed during the first three months after hospital admission due to COVID-19 and persisting at the time of the interview. Methylations of five CpG dinucleotides in the ACE2 promoter were quantified (as percentages). Participants were evaluated up to 17.8 (SD: 5.3) months after hospitalization. Thus, 39.1% of patients exhibited post-COVID-19 pain. Most patients (77.05%) in the cohort developed localized post-COVID-19 pain. Headache and pain in the lower extremity were experienced by 29.4% of the patients. Seven patients received a post-infection diagnosis of fibromyalgia based on the presence of widespread pain characteristics (11.6%) and other associated symptoms. No significant differences in methylation percentages at any CpG location of the ACE2 promoter were identified when comparing individuals with and without post-COVID-19 pain. The current study did not observe differences in methylation levels of the ACE2 promoter depending on the presence or absence of long-lasting post-COVID-19 pain symptoms in individuals who needed hospitalization due to COVID-19 during the first wave of the pandemic.

6.
Curr Issues Mol Biol ; 46(8): 7986-7996, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39194689

RESUMO

Lipoatrophia semicircularis is a benign pathology characterized by subcutaneous tissue atrophy that affects the skin and related structures. Its etiology remains unclear; however, in the recent few years, it has been proposed that electrostatic charges could be a potential factor. Based on this hypothesis, the aim of this work is to study the cause-effect relation between electrostatic energy and LS, providing insights into the molecular mechanisms. For this purpose, an experimental murine model was created using obese mice. One group served as a control and the other groups involved charging clothes with varying connections to the ground: through the skin, through the clothes or not connected to the ground). Skin biopsies showed that the most significant lesions, including lipophagic granulomas with inflammatory infiltrate, were found in the first group (connected to the ground through the skin). Lipophagic reactions without an inflammatory infiltrate were observed in the other groups subjected to electrical discharges. In the control mice, no histological changes were observed. Oxidative processes were also measured in lower limbs tissue. Malondialdehyde levels significantly increased in the lower limbs after electrostatic discharges. However, the presence of ground through a wire attached to highly conductive clothes around the thigh significantly reduced the effect of electrostatic charges on lipid peroxidation. To our knowledge, this is the first study in which an experimental model has been used to reproduce LS induced by electrostatic energy, suggesting a cause-effect relationship between electrostatic charge and discharge with fat tissue lesion.

7.
Heliyon ; 10(13): e33409, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39035482

RESUMO

Pateamines, derived from the sponge Mycale hentscheli, function as inhibitors of the RNA helicase eIF4A and exhibit promising antiviral and anticancer properties. eIF4A plays a pivotal role in unwinding stable RNA structures within the 5'-UTR of selected mRNAs, facilitating the binding of the 43S preinitiation complex during translation initiation. Pateamines function by clamping RNA substrates onto the eIF4A surface, effectively preventing eIF4A from carrying out the unwinding step. Rocaglates, a compound class isolated from plants of the genus Aglaia, target the same binding pocket on eIF4A, and based on structural data, a similar mode of action has been proposed for pateamines and rocaglates. In this study, we conducted a detailed characterization of pateamines' binding mode and assessed their antiviral activity against human pathogenic coronaviruses (human coronavirus 229E (HCoV-229E), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)). Our findings reveal significant differences in the binding behavior of pateamines compared to rocaglates when interacting with an eIF4A-RNA complex. We also observed that pateamines do not depend on the presence of a polypurine tract in the RNA substrate for efficient RNA clamping, as it is the case for rocaglates. Most notably, pateamines demonstrate potent antiviral activity against coronaviruses in the low nanomolar range. Consequently, pateamines broaden our toolbox for combating viruses that rely on the host enzyme eIF4A to conduct their viral protein synthesis, indicating a possible future treatment strategy against new or re-emerging pathogenic viruses.

8.
Transplant Cell Ther ; 30(8): 760-769, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38897861

RESUMO

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.


Assuntos
Síndrome de Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Síndrome de Bronquiolite Obliterante/diagnóstico , Síndrome de Bronquiolite Obliterante/etiologia , Síndrome de Bronquiolite Obliterante/terapia , Volume Expiratório Forçado , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Guias de Prática Clínica como Assunto , Testes de Função Respiratória
9.
Am J Respir Crit Care Med ; 210(3): 262-280, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38889365

RESUMO

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.


Assuntos
Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/terapia , Criança , Estados Unidos , Testes de Função Respiratória , Pré-Escolar , Síndrome de Bronquiolite Obliterante
10.
Int J Cancer ; 155(7): 1248-1256, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38898626

RESUMO

Metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa), including stereotactic body radiotherapy (SBRT), has shown promise but is still considered investigational. This is the 5-year analysis of the TRANSFORM trial, the largest prospective cohort of men with oligometastatic PCa treated with SBRT-based MDT. The primary endpoint was 5-year treatment escalation-free survival (TE-FS), defined as freedom from any new cancer therapy other than further SBRT. In total, 199 men received SBRT; 76.4% were hormone-naïve at baseline. The rate of 5-year TE-FS was 21.7% (95% confidence interval [CI]: 15.7%-28.7%) overall and 25.4% (95% CI: 18.1%-33.9%) in the hormone-naïve subgroup. The subgroups with International Society of Urological Pathology Grade Groups 4-5 disease (hazard ratio [HR] = 1.48, 95% CI: 1.05-2.01, p = .026), a higher baseline prostate-specific antigen (PSA) (HR = 1.06, 95% CI: 1.03-1.09, p < .001) and those who received prior androgen deprivation therapy (ADT) (HR = 2.13, 95% CI: 1.40-3.26, p < .001), were at greater risk of treatment escalation. Outcomes for participants with four or five initial lesions were comparable to those with one to three lesions. At last follow-up, 18.9% (95% CI: 13.2%-25.7%) of participants were free from treatment escalation (median follow-up of 67.9 months) and two participants had an undetectable PSA level. No treatment-related grade three or higher adverse events were reported. The findings of this study demonstrate that SBRT-based MDT is an effective option for delaying systemic treatment escalation in the context of oligometastatic PCa. Future randomised trials comparing SBRT-based MDT to standard-of-care ADT-based approaches are required to evaluate the impact of delaying ADT on survival.


Assuntos
Neoplasias da Próstata , Radiocirurgia , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Radiocirurgia/métodos , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Metástase Neoplásica , Idoso de 80 Anos ou mais , Resultado do Tratamento , Antígeno Prostático Específico/sangue , Fracionamento da Dose de Radiação
11.
Genes (Basel) ; 15(6)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38927713

RESUMO

Members of the SOX (SRY-related HMG box) family of transcription factors are crucial for embryonic development and cell fate determination. This review investigates the role of SOX3 in cancer, as aberrations in SOX3 expression have been implicated in several cancers, including osteosarcoma, breast, esophageal, endometrial, ovarian, gastric, hepatocellular carcinomas, glioblastoma, and leukemia. These dysregulations modulate key cancer outcomes such as apoptosis, epithelial-mesenchymal transition (EMT), invasion, migration, cell cycle, and proliferation, contributing to cancer development. SOX3 exhibits varied expression patterns correlated with clinicopathological parameters in diverse tumor types. This review aims to elucidate the nuanced role of SOX3 in tumorigenesis, correlating its expression with clinical and pathological characteristics in cancer patients and cellular modelsBy providing a comprehensive exploration of SOX3 involvement in cancer, this review underscores the multifaceted role of SOX3 across distinct tumor types. The complexity uncovered in SOX3 function emphasizes the need for further research to unravel its full potential in cancer therapeutics.


Assuntos
Carcinogênese , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Carcinogênese/genética , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Regulação Neoplásica da Expressão Gênica , Animais
12.
Subst Use Misuse ; 59(9): 1416-1423, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38733118

RESUMO

Background: Chronic non-cancer pain affects 20% of Americans. This is significantly impacted by the ongoing opioid crisis and reduced opioid dispensing. Public perceptions additionally shape pain management strategies. Purpose: This study explores public attitudes toward prescription opioids for chronic non-cancer pain. We aim to understand how public attitudes are influenced by the evolving opioid crisis and shifting opioid use patterns. Methods: In Michigan, 823 adults participated in a Qualtrics survey on attitudes toward nonmedical and medical prescription opioid use. Multivariable logistic regression was performed to identify factors associated with beliefs that doctors prescribe opioids for too long (Model 1) and chronic pain patients should transition to alternative treatments (Model 2). Results: About half (49.4%) of respondents believed doctors keep patients on prescription opioids for too long, while two-thirds (65.7%) agreed chronic pain patients should be tapered off medications. Knowing someone who misused opioids and perceptions of substance use (e.g. perceived risk of prescription opioid misuse, stigma toward chronic pain patients, perceived prevalence of prescription opioid misuse, and awareness of fentanyl) were associated with greater odds of believing doctors keep patients on opioids too long. Demographics (age and education), substance use histories and perceptions (e.g. perceived risk and stigma) were associated with greater odds of believing patients should be tapered off their medication. Conclusions: These findings inform strategies to correct public misperceptions, emphasizing the importance of personal experience, perceived risks, and stigmatization of chronic pain patients. This insight can guide effective pain management for those with chronic non-cancer pain.


Assuntos
Analgésicos Opioides , Dor Crônica , Humanos , Dor Crônica/tratamento farmacológico , Dor Crônica/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Analgésicos Opioides/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Transtornos Relacionados ao Uso de Opioides/psicologia , Idoso , Adulto Jovem , Opinião Pública , Michigan , Uso Indevido de Medicamentos sob Prescrição/psicologia , Adolescente , Inquéritos e Questionários
13.
Am J Transplant ; 24(9): 1634-1643, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38643944

RESUMO

Reactivation or primary infection with double-stranded DNA viruses is common in recipients of solid organ transplants (SOTs) and is associated with significant morbidity and mortality. Treatment with conventional antiviral medications is limited by toxicities, resistance, and a lack of effective options for adenovirus (ADV) and BK polyomavirus (BKPyV). Virus-specific T cells (VSTs) have been shown to be an effective treatment for infections with ADV, BKPyV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Most of these studies have been conducted in stem cell recipients, and no large studies have been published in the SOT population to date. In this study, we report on the outcome of quadrivalent third-party VST infusions in 98 recipients of SOTs in the context of an open-label phase 2 trial. The 98 patients received a total of 181 infusions, with a median of 2 infusions per patient. The overall response rate was 45% for BKPyV, 65% for cytomegalovirus, 68% for ADV, and 61% for Epstein-Barr virus. Twenty percent of patients with posttransplant lymphoproliferative disorder had a complete response and 40% of patients had a partial response. All the VST infusions were well tolerated. We conclude that VSTs are safe and effective in the treatment of viral infections in SOT recipients.


Assuntos
Transtornos Linfoproliferativos , Transplante de Órgãos , Linfócitos T , Ativação Viral , Humanos , Transplante de Órgãos/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/virologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Feminino , Linfócitos T/imunologia , Adulto , Complicações Pós-Operatórias , DNA Viral , Idoso , Citomegalovirus , Prognóstico , Seguimentos , Herpesvirus Humano 4 , Adulto Jovem , Infecções por Vírus de DNA/virologia
14.
Lancet Glob Health ; 12(5): e815-e825, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38614630

RESUMO

BACKGROUND: Household air pollution might lead to fetal growth restriction during pregnancy. We aimed to investigate whether a liquefied petroleum gas (LPG) intervention to reduce personal exposures to household air pollution during pregnancy would alter fetal growth. METHODS: The Household Air Pollution Intervention Network (HAPIN) trial was an open-label randomised controlled trial conducted in ten resource-limited settings across Guatemala, India, Peru, and Rwanda. Pregnant women aged 18-34 years (9-19 weeks of gestation) were randomly assigned in a 1:1 ratio to receive an LPG stove, continuous fuel delivery, and behavioural messaging or to continue usual cooking with biomass for 18 months. We conducted ultrasound assessments at baseline, 24-28 weeks of gestation (the first pregnancy visit), and 32-36 weeks of gestation (the second pregnancy visit), to measure fetal size; we monitored 24 h personal exposures to household air pollutants during these visits; and we weighed children at birth. We conducted intention-to-treat analyses to estimate differences in fetal size between the intervention and control group, and exposure-response analyses to identify associations between household air pollutants and fetal size. This trial is registered with ClinicalTrials.gov (NCT02944682). FINDINGS: Between May 7, 2018, and Feb 29, 2020, we randomly assigned 3200 pregnant women (1593 to the intervention group and 1607 to the control group). The mean gestational age was 14·5 (SD 3·0) weeks and mean maternal age was 25·6 (4·5) years. We obtained ultrasound assessments in 3147 (98·3%) women at baseline, 3052 (95·4%) women at the first pregnancy visit, and 2962 (92·6%) at the second pregnancy visit, through to Aug 25, 2020. Intervention adherence was high (the median proportion of days with biomass stove use was 0·0%, IQR 0·0-1·6) and pregnant women in the intervention group had lower mean exposures to particulate matter with a diameter less than 2·5 µm (PM2·5; 35·0 [SD 37·2] µg/m3vs 103·3 [97·9] µg/m3) than did women in the control group. We did not find differences in averaged post-randomisation Z scores for head circumference (0·30 vs 0·39; p=0·04), abdominal circumference (0·38 vs 0·39; p=0·99), femur length (0·44 vs 0·45; p=0·73), and estimated fetal weight or birthweight (-0·13 vs -0·12; p=0·70) between the intervention and control groups. Personal exposures to household air pollutants were not associated with fetal size. INTERPRETATION: Although an LPG cooking intervention successfully reduced personal exposure to air pollution during pregnancy, it did not affect fetal size. Our findings do not support the use of unvented liquefied petroleum gas stoves as a strategy to increase fetal growth in settings were biomass fuels are used predominantly for cooking. FUNDING: US National Institutes of Health and Bill & Melinda Gates Foundation. TRANSLATIONS: For the Kinyarwanda, Spanish and Tamil translations of the abstract see Supplementary Materials section.


Assuntos
Poluentes Atmosféricos , Desenvolvimento Fetal , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Biomassa , Culinária , Índia , Estados Unidos , Adolescente , Adulto Jovem , Adulto
15.
Microbiol Resour Announc ; 13(6): e0000524, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38647278

RESUMO

The role of viral diversity in the pathogenesis of BK polyomavirus (BKPyV)-associated disease is poorly understood. Here, we report near full-length BKPyV genome sequences from two allogeneic hematopoietic cell transplant recipients infected with BKPyV genotype II, which is uncommon in the USA.

16.
Transplant Cell Ther ; 30(6): 632.e1-632.e5, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38580095

RESUMO

Disrupted sleep is commonly reported during hematopoietic stem cell transplant. In this study, we use actigraphy to measure sleep parameters, and qualitative measures of quality of life, depression, and sleep in pediatric and young adult transplant recipients to describe their time course through transplant. Eight patients had evaluable actigraphy data, and 10 patients completed the surveys. The median age of the 6 male and 7 female participants was 13.94 years old. Sleep duration and efficiency measured by actigraphy were suboptimal prior to transplant, then declined to a nadir between Day +7 to +14. Self-reported sleep quality, depression, and quality of life were worst at Day +14 to +30 but improved by Day +100. Findings support efforts to improve sleep, which may improve recovery, mental health and quality of life.


Assuntos
Actigrafia , Depressão , Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Sono , Humanos , Qualidade de Vida/psicologia , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/psicologia , Adolescente , Criança , Depressão/psicologia , Sono/fisiologia , Adulto Jovem , Qualidade do Sono , Transtornos do Sono-Vigília/psicologia , Transtornos do Sono-Vigília/epidemiologia , Inquéritos e Questionários , Adulto
17.
Gene Ther ; 31(5-6): 304-313, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38528117

RESUMO

Efficient manufacturing of recombinant Adeno-Associated Viral (rAAV) vectors to meet rising clinical demand remains a major hurdle. One of the most significant challenges is the generation of large amounts of empty capsids without the therapeutic genome. There is no standardized analytical method to accurately quantify the viral genes, and subsequently the empty-to-full ratio, making the manufacturing challenges even more complex. We propose the use of CRISPR diagnostics (CRISPR-Dx) as a robust and rapid approach to determine AAV genome titers. We designed and developed the CRISPR-AAV Evaluation (CRAAVE) assay to maximize sensitivity, minimize time-to-result, and provide a potentially universal design for quantifying multiple transgene constructs encapsidated within different AAV serotypes. We also demonstrate an on-chip CRAAVE assay with lyophilized reagents to minimize end user assay input. The CRAAVE assay was able to detect AAV titers as low as 7e7 vg/mL with high precision (<3% error) in quantifying unknown AAV titers when compared with conventional quantitative PCR (qPCR) method. The assay only requires 30 min of assay time, shortening the analytical workflow drastically. Our results suggest CRISPR-Dx could be a promising tool for efficient rAAV genome titer quantification and has the potential to revolutionize biomanufacturing process analytical technology (PAT).


Assuntos
Sistemas CRISPR-Cas , Dependovirus , Genoma Viral , Dependovirus/genética , Humanos , Vetores Genéticos/genética , Células HEK293
18.
Blood Adv ; 8(12): 3027-3037, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38522093

RESUMO

ABSTRACT: Fanconi anemia (FA) is a complex inherited bone marrow failure syndrome characterized by chromosomal instability and defective DNA repair, causing sensitivity to DNA interstrand crosslinking agents. Our understanding of the full adult phenotype of the disease continues to evolve, because most patients with FA died of marrow failure in the first decade of life before more recent advances in allogeneic hematopoietic cell transplantation. Herein, we report a previously undescribed, clinically concerning, progressive neurologic syndrome in patients with FA. Nine nonimmunosuppressed pediatric patients and young adults with FA presented with acute and chronic neurological signs and symptoms associated with distinct neuroradiological findings. Symptoms included, but were not limited to, limb weakness, papilledema, gait abnormalities, headaches, dysphagia, visual changes, and seizures. Brain imaging demonstrated a characteristic radiographic appearance of numerous cerebral and cerebellar lesions with associated calcifications and often a dominant ring-enhancing lesion. Tissue from the dominant brain lesions in 4 patients showed nonspecific atypical glial proliferation, and a small number of polyomavirus-infected microglial cells were identified by immunohistochemistry in 2 patients. Numerous interventions were pursued across this cohort, in general with no improvement. Overall, these patients demonstrated significant progressive neurologic decline. This cohort highlights the importance of recognizing FA neuroinflammatory syndrome, which is distinct from malignancy, and warrants careful ongoing evaluation by clinicians.


Assuntos
Encéfalo , Anemia de Fanconi , Doenças Neuroinflamatórias , Humanos , Anemia de Fanconi/complicações , Anemia de Fanconi/patologia , Anemia de Fanconi/diagnóstico , Masculino , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/patologia , Feminino , Criança , Adolescente , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Adulto Jovem , Adulto , Pré-Escolar , Imageamento por Ressonância Magnética
19.
Transplant Cell Ther ; 30(4): 454.e1-454.e6, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311212

RESUMO

Loss of intestinal L cells and reduced levels of glucagon-like peptide-2 (GLP-2) have been implicated in acute graft-versus-host disease (GVHD) in murine models. Teduglutide, a human recombinant GLP-2 analog, may be beneficial in acute gastrointestinal (GI) GVHD owing to its known tissue protective and regenerative functions. We retrospectively reviewed patients who received teduglutide for treatment of GI GVHD. Endoscopy was performed at diagnosis and at completion of the teduglutide course. GLP-1 immunohistochemistry (IHC) was performed at diagnosis and the end of teduglutide therapy in 2 patients to evaluate L cells. We initiated daily teduglutide 0.05 mg/kg subcutaneously as adjunctive therapy in 3 pediatric patients with refractory GI GVHD. All 3 patients had resolution of GI GVHD following completion of the teduglutide course, as evidenced by reduced apoptosis and regenerative changes on post-treatment endoscopy. Reportable GLP-1 IHC in 2 patients demonstrated increased L cells at the end of teduglutide treatment compared to at diagnosis. No adverse effects to teduglutide were observed. Teduglutide is a promising adjunctive and non-immune suppressive agent for managing acute GI GVHD.


Assuntos
Peptídeo 2 Semelhante ao Glucagon , Doença Enxerto-Hospedeiro , Peptídeos , Humanos , Adulto Jovem , Criança , Animais , Camundongos , Estudos Retrospectivos , Peptídeo 2 Semelhante ao Glucagon/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/diagnóstico , Endoscopia Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon
20.
Pediatr Blood Cancer ; 71(4): e30892, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38302730

RESUMO

BACKGROUND: Pediatric hematopoietic stem cell transplantation (HCT) is an intensive medical procedure that places substantial financial and logistical burdens on families and is associated with significant health risks, such as graft-versus-host disease (GVHD), and infections. The influence of the social determinants of health (SDoH) on outcomes following pediatric HCT is understudied. This study aimed to examine whether SDoH predicts outcomes following pediatric HCT. PROCEDURE: Data were collected from 84 children who received HCT (Mage  = 5.8 years, SD = 3.7) and their primary caregiver. Detailed demographic information was collected from caregivers at baseline, and child health information was extracted from the electronic medical records. Multivariate logistic regression was used to examine the association between SDoH and health outcomes within a 24-month period following pediatric HCT. RESULTS: After controlling for malignancy as reason for transplant and donor type, lower family income predicted the incidence of chronic GVHD. Neighborhood deprivation, total family income, public health insurance, caregiver relationship status, caregiver educational attainment, and perceived family financial difficulties did not predict acute GVHD or the number of infections. CONCLUSIONS: Total family income is a simple family indicator of SDoH that predicts chronic GVHD after pediatric allogeneic HCT. These findings provide further support for the importance of screening of child and family SDoH risks to ensure that fundamental needs can be met to mitigate potential health disparities for up to 2 years following pediatric HCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Pré-Escolar , Determinantes Sociais da Saúde , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Avaliação de Resultados em Cuidados de Saúde
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