Search Results (579)

Sickle Cell Disease (SCD) is a pervasive monogenic disorder characterized by chronic hemolytic anemia, unpredictable vaso-occlusive crises, and progressive multi-organ damage, representing a significant global health burden. Driven by a point mutation in the β-globin gene, the resulting abnormal Hemoglobin S (HbS) polymerizes under deoxygenated conditions, leading to erythrocyte sickling and systemic endothelial dysfunction. While supportive therapies such as hydroxyurea and transfusions manage symptoms, the mandate for definitive curative therapies is urgent. Historically, allogeneic hematopoietic stem cell transplantation (HSCT) utilizing matched sibling donors (MSD) has been the sole curative option, offering high survival rates but constrained by limited donor availability and the risk of graft-versus-host disease (GVHD). Consequently, alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical donors, have expanded patient access, particularly with the integration of post-transplant cyclophosphamide (PTCy) to mitigate alloreactivity. Concurrently, the advent of autologous gene therapy, encompassing lentiviral gene addition (Lyfgenia) and CRISPR-Cas9 gene editing (Casgevy) offers a revolutionary donor-independent approach that eliminates GVHD risk. Lyfgenia employs a lentiviral vector to introduce an anti-sickling βT87Q hemoglobin variant into autologous hematopoietic stem cells, while Casgevy employs CRISPR-Cas9 to disrupt the erythroid-specific enhancer of the BCL11A transcription factor, derepressing γ-globin expression and elevating fetal hemoglobin. This review synthesizes the pathophysiological mechanisms of SCD, evaluates the clinical outcomes and limitations of both allogeneic HSCT and autologous gene therapies, and outlines the clinical decision-making paradigms and future innovations required to achieve equitable global access to these transformative treatments. Full article

Perinatal lymphangiomas are rare benign congenital malformations of the lymphatic system, whose potential for rapid growth and local invasiveness may pose significant risks to fetal well-being. This report presents a case of a large fetal lymphangioma diagnosed prenatally during a second-trimester ultrasound examination. The lesion was initially asymptomatic but subsequently progressed, resulting in ascites and pericardial effusion. In light of progressive fetal deterioration, prenatal sclerotherapy was performed using ultrasound-guided transabdominal administration of bleomycin. Despite the technical success of this procedure, the neonate developed severe cardiorespiratory failure and died shortly after delivery. This case highlights both the potential benefits and limitations of prenatal intervention in severe lymphatic malformations. This study also includes a concise review of current perinatal and postnatal management strategies. Despite advances in prenatal imaging and therapy, further studies are needed to optimize treatment and improve neonatal outcomes. Full article

Cell replacement therapy is a promising investigational approach for Parkinson’s disease (PD), a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although current PD therapies provide symptomatic relief, none halt or reverse disease progression. Early transplantation studies using fetal dopaminergic neurons provided proof of concept for PD cell replacement, with recent efforts focusing on pluripotent stem cell-derived dopaminergic progenitors that are now entering clinical testing. These strategies face challenges, however, including immune compatibility, tumorigenic risk, and the need for controlled differentiation and functional integration. Multi-lineage differentiating stress-enduring (Muse) cells are endogenous, non-tumorigenic pluripotent-like stem cells that home to sites of tissue injury and differentiate in response to the host microenvironment. A targeted literature search of PubMed and Scopus, however, did not identify prior reviews specifically addressing Muse cells in the context of PD, highlighting a gap in the literature. Here, we examine current limitations of established cell-replacement approaches and consider whether Muse cells may represent a mechanistically distinct cell source. Early clinical studies of Muse cell therapy in stroke and amyotrophic lateral sclerosis suggest an encouraging safety profile and preliminary signals of potential therapeutic benefit, although these findings are based on small, early-stage trials and require confirmation. The evidence supporting Muse cell therapy in PD is currently limited to a single preclinical animal study, supported by mechanistic in vitro findings and indirect evidence from other neurologic disease models; therefore, its relevance to PD remains to be established, and current evidence is insufficient to support conclusions regarding clinical efficacy. Together, these observations provide a rationale for further targeted preclinical investigation and support the systematic evaluation of Muse cells as a mechanistically distinct candidate for regenerative therapy in PD. Full article

Importance: Immune checkpoint inhibitors (ICIs) have transformed the management of cancers affecting reproductive-age patients, yet their impact on pregnancy outcomes remains incompletely understood. We describe two cases of maternal and fetal outcomes associated with ICI exposure during pregnancy and present a comprehensive literature review. Methods: A retrospective chart review was conducted at MD Anderson Cancer Center (1 January 2015 to 31 December 2024) to identify patients exposed to ICIs during pregnancy. Clinical data including cancer type, treatment timing, pregnancy course, and maternal and neonatal outcomes were collected. A narrative literature review was also performed using PubMed to identify reported cases of ICI exposure during pregnancy. Observations: Two patients were identified at our institution, both treated with ICIs for advanced melanoma. One patient received pembrolizumab during early pregnancy, with the final dose administered five days after conception, and subsequently gave birth to a healthy term infant without complications. The second patient conceived while receiving adjuvant nivolumab and experienced a miscarriage at 13 weeks of gestation. Neither patient experienced immune-related toxicity during pregnancy, and both remained without evidence of disease at follow-up. The literature review identified 21 reported pregnancies with ICI exposure and variable outcomes. Most resulted in live births (85.7%), though preterm delivery occurred in approximately 50% of cases, often due to maternal or fetal indications. Additional reported outcomes included miscarriage, neonatal death, fetal growth restriction, preeclampsia, and rare immune-related neonatal effects. Congenital anomalies were reported in a small number of cases. Conclusions and Relevance: These findings suggest that, while many pregnancies exposed to ICIs result in live births, there may be an increased risk of adverse maternal and fetal outcomes. However, causality cannot be established due to the limited quality and quantity of available data. These findings underscore the importance of effective contraception during ICI therapy and careful multidisciplinary counseling when exposure occurs during pregnancy. Full article

Background/Objectives: Hydroxyurea (HU), a cornerstone treatment for sickle cell disease (SCD), exhibits marked interindividual pharmacokinetic/pharmacodynamic (PK/PD) variability that remains poorly understood. This study aimed to establish a population PK model using OPTIMDREP randomized trial data (NCT06464458), quantify parameter variability, and identify covariates influencing HU PK and hematological response. Methods: Plasma sampling data from 22 SCD patients (20 pediatric and 2 adult patients; median age: 11.2 years [range: 2.5–35.7]) on once-daily oral HU underwent a non-compartmental analysis (NCA) followed by nonlinear mixed-effects modeling (MonolixSuite^®). PK variability covariates and PK/PD correlations with the mean corpuscular volume (MCV), reticulocytes, fetal hemoglobin percentage (HbF%) and neutrophils were investigated. Results: NCA identified two absorption phenotypes (rapid/slow), with higher maximum concentration values observed for rapid (36.5 ± 18.8 mg/L) compared to slow (22.3 ± 8.4 mg/L) (p = 0.0013) profiles but not statistically different total exposures, apparent clearances (Cl/F) or volumes of distribution (V_d/F). The population approach identified the one-compartment model (first-order absorption and linear elimination) and confirmed the absorption phenotype as the key absorption rate (k_a) covariate (9.93 vs. 1.36 h⁻¹), explaining half of the k_a interindividual variability (IIV). The median-normalized body weight was retained for both the Cl/F and V_d/F, as it significantly reduced the objective function value. No hematological parameter was correlated to PK parameters. However, rapid absorbers showed a superior response on the MCV (Δ = 9.1 fL, p < 0.0001), reticulocytes (Δ = −42.2 G/L, p < 0.01), and HbF% trend (Δ = 2.8%, p = 0.0835) but not on neutrophil counts (p = 0.8757). Conclusions: The absorption phenotype, a novel covariate explaining half of the k_a IIV, predicts a superior erythropoietic response without toxicity in SCD patients. These findings support absorption phenotype integration into PK-guided dosing algorithms to optimize early-response biomarkers and personalize HU therapy. Full article

Background/Objectives: Teratomas of the sacrococcygeal region are rare, but the most common tumors found in fetuses. They develop from the three germ layers—mesoderm, ectoderm, and endoderm—and occur at a rate of 1 in 27,000 to 1 in 40,000, with a fourfold higher incidence in female fetuses. 63.9–74% of sacrococcygeal teratomas are detected prenatally, most often in the second trimester. Methods: This study reports the case of a woman in her second pregnancy at 29 weeks and 2 days gestation who was incidentally diagnosed with tumor-like lesion in the sacrococcygeal region of fetus. The clinical situation required the pregnancy to be delivered by emergency cesarean section, and the tumor was surgically removed within the first few days of life. The lesion was finally diagnosed as an immature teratoma, and appropriate management was initiated, resulting in stabilization of the child’s general condition and proper development. Results: Detailed imaging and characterization of the lesion are essential for determining the appropriate management and minimizing foreseeable obstetric and neonatal complications. Fetal echocardiography in cases of suspected teratoma in the sacrococcygeal region is essential for identifying life-threatening risk factors and influences the planning of further management. The choice of treatment depends on the clinical situation; among intrauterine interventions and pharmacological therapy, it has been demonstrated that surgical removal of the lesion within the first days of life reduces the risk of recurrence. Conclusions: In any case where lesion such as tumor of the sacrococcygeal region of fetus is suspected, the pregnant woman should be managed at a tertiary care center to ensure multidisciplinary care involving obstetricians, neonatologists, pediatric surgeons, and oncologists. This study provides a review of the literature on methods of diagnosis and treatment of sacrococcygeal teratomas in fetuses. It emphasizes the importance of accurate diagnosis and prenatal care in such cases and their impact on further management. Full article

Preterm birth is a major cause of neonatal morbidity and mortality, and many spontaneous cases remain idiopathic. Increasing evidence suggests that intrauterine inflammation may occur in the absence of detectable infection, leading to the recognition of sterile intrauterine inflammation as an important mechanism contributing to threatened preterm labor and spontaneous preterm birth. This review summarizes current knowledge regarding the role of damage-associated molecular patterns (DAMPs), alarmins, pattern recognition receptors, inflammasome activation, cellular senescence, and pyroptosis in the initiation of sterile inflammatory pathways associated with labor. Key mediators including HMGB1, IL-1α, fetal cell-free DNA, platelet-activating factor, and S100 proteins appear to promote inflammatory activation within fetal membranes and the amniotic cavity. The review also discusses the emerging contribution of fetal immune activation, maternal–fetal immune dysregulation, maternal microchimerism, and epigenetic mechanisms to idiopathic preterm birth. Current diagnostic and therapeutic options remain limited, and no targeted treatment for sterile intrauterine inflammation has yet been established. Future approaches may include precision biomarkers, multiomics-based risk stratification, targeted immunomodulatory therapies, and modulation of maternal–fetal immune interactions. Improved understanding of sterile inflammatory mechanisms may ultimately support development of personalized strategies to prevent preterm birth and improve perinatal outcomes. Full article

Background: Human dental pulp stem cells (hDPSCs) are a promising source of multipotent mesenchymal stem cells (MSCs) for regenerative neurology because of their inherent neurogenic potential. However, robust and reproducible protocols for driving their terminal neuronal maturation in a fully defined, xeno-free environment are lacking. Methods: hDPSCs were isolated from a donor tooth and characterized for mesenchymal (CD105, CD90, CD73, CD13) and stemness-associated markers (SOX2, Oct3/4 and Nanog). Cells were differentiated in a novel, fully chemically defined medium 1% ITS medium (ITS: Insulin, Transferrin, Selenium) supplemented with glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF). Neuronal commitment and partial maturation were assessed via immunofluorescence, Western blot, and RT-PCR for markers such as NeuN (Neuronal nuclei) and NF-M (Neurofilament medium chain), and functionally by whole-cell patch-clamp electrophysiology. Results: Although undifferentiated hDPSCs expressed neural progenitor markers (βIII-tubulin and Nestin), only GDNF treatment in a chemically defined medium significantly upregulated mature neuronal markers (NeuN and NF-M) and downregulated mesenchymal markers. Importantly, GDNF-treated cells exhibited key functional changes, including hyperpolarized resting membrane potentials, increased membrane capacitance, and elevated input resistance, which are electrophysiological hallmarks of neural precursor or early neuronal maturation, compared to control cells cultured in medium containing fetal bovine serum (FBS). Although action potentials were not elicited, this represents a significant advancement toward achieving a functional neuronal state. Conclusion: This study demonstrates that a fully chemically defined medium enables GDNF to drive hDPSCs beyond the neural progenitor state towards a partially mature neuronal phenotype. This defined medium protocol eliminates serum variability, enhances reproducibility, and provides a critical step towards standardizing hDPSC-derived neuronal cells for disease modeling and cell-based therapy. Full article

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited by donor availability and transplant-related toxicity. The approval of two autologous gene therapy products in 2023, exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel), marked a turning point for the SCD population and the gene therapy field in general. This review proposes a molecular rationale for fetal hemoglobin reactivation and β-globin gene addition, describes the engineering of lentiviral and CRISPR-based platforms, and highlights the clinical evidence accumulated to date that demonstrated durable disease modification with acceptable short-term toxicity. We then assess the clinical positioning of gene therapy within the broader spectrum of curative options compared to current available treatments and address the financial, ethical and psychosocial barriers that limit access to gene therapy both within high-income countries and globally. Critical research priorities include long-term safety surveillance, comparative effectiveness studies, pediatric trials below 12 years, and validated patient-reported outcome instruments. Base editing, non-genotoxic conditioning, and in vivo delivery represent the most promising avenues to broaden access and reduce treatment burden. Full article

Objective: To investigate whether gestational diabetes mellitus (GDM), including insulin-treated GDM, affects cerebroplacental ratio (CPR) values in monochorionic diamniotic (MCDA) twin pregnancies. Methods: This retrospective single-center cohort study included a total of 262 MCDA twin pregnancies managed at a tertiary referral center, comprising pregnancies without GDM (n = 120), with diet-controlled GDM (n = 80), and with insulin-treated GDM (n = 62). Doppler ultrasound examinations were performed at three gestational time points between 24 and 36 weeks of gestation. CPR, umbilical artery pulsatility index (UA-PI), and middle cerebral artery pulsatility index (MCA-PI) were compared longitudinally between groups. Doppler indices were compared between groups without adjustment for baseline differences such as BMI and parity Results: Maternal body mass index was significantly higher in pregnancies complicated by GDM, particularly in those requiring insulin therapy (p < 0.001). Estimated fetal weight was higher in the insulin-treated GDM group at mid-gestation (28–32 weeks; p = 0.01). However, CPR values remained within normal ranges throughout all screening points across all three groups. No relevant differences in UA-PI, MCA-PI, gestational age at delivery, Apgar scores, or umbilical cord pH were observed between groups. Conclusions: In MCDA twin pregnancies, gestational diabetes—regardless of insulin treatment—does not appear to significantly influence cerebroplacental ratio values throughout gestation. No statistically significant differences in CPR values were observed between groups. No statistically significant differences in CPR values were detected between groups. However, given the exploratory design and lack of adjustment for confounders, subtle effects cannot be excluded. The clinical utility of CPR in this population requires further investigation. Full article

Severe aplastic anemia (SAA) in pregnancy represents a rare but life-threatening clinical challenge. Standard therapies such as hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy are limited during pregnancy due to safety concerns, leaving supportive care as the mainstay. Thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag have emerged as promising agents in refractory SAA, though evidence of their safety in pregnancy remains scarce. We present the case of a 27-year-old woman with SAA post-allogeneic bone marrow transplant who relapsed during subsequent pregnancies. Her disease course was characterized by recurrent pancytopenia, mixed chimerism, and repeated need for stem cell boosts. During pregnancy in 2023, discontinuation of cyclosporine led to worsening cytopenias, prompting reintroduction of cyclosporine and the continuation of eltrombopag. This combined approach, alongside G-CSF and stem cell boosts, contributed to favorable hematologic stabilization. She successfully delivered a healthy infant and achieved hematologic recovery following a third stem cell boost postpartum. This report highlights the potential utility of TPO-RAs during pregnancy when conventional therapy is limited, while emphasizing the need for vigilant monitoring of maternal–fetal outcomes. A review of the literature suggests that although routine use of eltrombopag in pregnancy is not recommended, it may be considered in refractory SAA cases with careful risk–benefit assessment. The case underscores the role of multidisciplinary care, individualized therapeutic planning, and the need for further studies on TPO-RAs in pregnancy-associated bone marrow failure syndromes. Full article

Inflammation is a physiological and tightly regulated component of normal pregnancy, contributing to implantation, placental development, and the initiation of parturition. The placenta functions as an active immunological hub, coordinating innate and adaptive immune responses to maintain tolerance while protecting against infection. Preeclampsia and fetal growth restriction (FGR) are major causes of maternal and perinatal morbidity worldwide and represent central manifestations of placental disease. Increasing evidence indicates that these conditions share key pathophysiological mechanisms, including placental dysfunction and maladaptive maternal immune responses. When immune regulation at the maternal–fetal interface becomes disrupted, inflammatory pathways contribute to impaired placental development and vascular maladaptation. In this context, excessive immune activation—driven by inflammasome signaling, Th1/Th17 polarization, and altered natural killer and macrophage function—can compromise placental perfusion, promote antiangiogenic imbalance, and lead to systemic endothelial dysfunction. This review, therefore, focuses on how immune dysregulation contributes to placental dysfunction in preeclampsia and FGR, synthesizing current knowledge of the maternal–fetal immune interface and exploring therapeutic strategies that link pathogenic mechanisms to targeted interventions. A deeper understanding of placental immunology and inflammatory signaling is essential to develop precision therapies. Established therapies, including low-dose aspirin, low-molecular-weight heparin, and antenatal corticosteroids, aim to mitigate inflammation and optimize fetal outcomes, while adjunctive strategies target oxidative stress, nutritional deficits, and the maternal microbiome. Emerging approaches such as cytokine-targeted biologics, inflammasome inhibitors, and mesenchymal stem cell therapies show promise but require rigorous safety and efficacy evaluation. Future research should prioritize biomarker validation, pathway-specific interventions, and equitable implementation to reduce inflammation-driven pregnancy complications. Full article

Although transplantation of induced oligodendrocyte progenitor cells (iOPCs) is a promising strategy for white matter injury, the therapeutic efficacy of in vitro-generated iOPCs remains limited due to insufficient differentiation potential. Here, we aimed to identify key transcription factors and small-molecule drugs to optimize iOPC quality. Through transcriptome sequencing and bioinformatics analysis, we identified the transcription factor SOX10, which is differentially expressed between endogenous fetal OPCs and exogenous iOPCs. We established lentivirus-mediated SOX10 overexpression in neural stem cells (NSCs) before iOPC induction and performed cellular assays and multi-omics analysis. Early SOX10 overexpression reduced cell migration but promoted maturation into oligodendrocytes and suppressed astrocyte differentiation. Multi-omics analyses revealed that SOX10 overexpression is associated with the extensive redistribution of SOX10 chromatin binding and enrichment of regulatory programs linked to oligodendroglial differentiation, including the activation of the key signaling downstream transcription factors JUN/FOS. Moreover, TSA, Dabrafenib, and Fedratinib effectively upregulated SOX10 and improved iOPC differentiation. This study identifies SOX10 as a core upstream regulator governing the fate of iOPCs, providing a potential strategy for optimizing iOPC induction for future investigation of white matter injury therapy. Full article

Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation. Full article

Background/Objectives: Maternal valaciclovir therapy is increasingly used to reduce fetal viral replication in cases of primary cytomegalovirus (CMV) infection during pregnancy. However, data on its impact on early neurodevelopmental outcomes remain limited. This study aimed to evaluate the association between prenatal valaciclovir exposure and early neurodevelopment in infants with confirmed congenital CMV infection (cCMV). Methods: In this retrospective monocentric cohort study, 30 infants with PCR-confirmed cCMV infection were assessed at 4–8 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants were stratified according to prenatal exposure to maternal valaciclovir. Univariate analyses and multivariable linear regression models were performed to evaluate the association between prenatal antiviral exposure and cognitive outcome, adjusting for brain MRI findings and selected clinical variables. Results: Fifteen infants (50%) were exposed to prenatal valaciclovir. Exposed infants demonstrated higher cognitive composite scores compared with unexposed infants (median 105 [IQR 100–110] vs. 90 [85–110]; p = 0.030). In multivariable analysis, prenatal valaciclovir exposure remained significantly associated with higher cognitive scores (β = 11.89, 95% CI 2.86–20.92; p = 0.012), while neonatal MRI abnormalities were not independently associated with outcome. No significant differences were observed in language or motor domains. The final model explained 30% of the variance in cognitive scores (R² = 0.30). Conclusions: Prenatal valaciclovir exposure was associated with higher cognitive composite scores after adjustment for selected covariates. Although causality cannot be inferred, these findings suggest a potential association with early neurodevelopmental outcomes and support the inclusion of functional neurodevelopmental endpoints in future prospective studies. These results should be considered exploratory and hypothesis-generating Full article