Anti-thymocyte globulin combined with post-transplantation cyclophosphamide reduce graft-versus-host disease in hematopoietic stem cell transplantation for pediatric leukemia.

This retrospective analysis evaluated the use of anti-thymocyte globulin (ATG) with or without post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis in children with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT). The study included 57 children, with 35 in the ATG-PTCy group and 22 in the ATG group. While overall incidence of acute and chronic GvHD did not differ significantly between groups, the ATG-PTCy group had lower rates of grade II-IV acute GvHD (p = 0.013) and moderate-to-severe chronic GvHD (p = 0.001) compared to the ATG group. Importantly, ATG-PTCy significantly improved GvHD/relapse-free survival (GRFS) compared to ATG (65.71% vs. 36.63%; p = 0.003). There were no differences in engraftment, infection rates, immune reconstitution, overall survival, leukemia-free survival, relapse rate, or non-relapse mortality between the two groups. Combining ATG with PTCy may reduce moderate-to-severe GvHD and improve GRFS in children undergoing HSCT for acute leukemia.

Tumoral EIF4EBP1 regulates the crosstalk between tumor-associated macrophages and tumor cells in MRTK.

Malignant renal rhabdoid tumor (MRTK) is an aggressive and rare malignancy primarily affecting infants and young children. The intricate interactions within the Tumor Microenvironment (TME) are crucial in shaping MRTK's progression. This study elucidates the significance of tumor-associated macrophages(TAMs) within this milieu and their interplay with eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) in tumor cells, collectively contributing to MRTK's malignant advancement. Through comprehensive analysis of clinical samples and the TARGET database, EIF4EBP1 emerges as a central macrophage-associated gene with robust prognostic implications. Elevated EIF4EBP1 expression correlates with poor prognosis and heightened infiltration of TAMs. Functional validation demonstrates that EIF4EBP1 knockdown in G401 cells significantly attenuates self-proliferation, migration, and invasion. Moreover, EIF4EBP1 regulates macrophage recruitment and M2 polarization through the ERK/P38 MAPK-MIF axis. Notably, M2 macrophages reciprocally foster the malignant behavior of MRTK tumor cells. This study unveils the pivotal role of EIF4EBP1 in propelling MRTK's malignant progression, unraveling a complex regulatory network involving EIF4EBP1 and TAMs. These findings underscore EIF4EBP1 as a promising biomarker and highlight its therapeutic potential in MRTK management.

Luteolin ameliorates hypoxic pulmonary vascular remodeling in rat via upregulating KV1.5 of pulmonary artery smooth muscle cells.

BACKGROUND: Hypoxic pulmonary vascular remodeling (HPVR) is a key pathological feature of hypoxic pulmonary hypertension (HPH). Oxygen-sensitive potassium (K+) channels in pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPVR. Luteolin (Lut) is a plant-derived flavonoid compound with variety of pharmacological actions. Our previous study found Lut alleviated HPVR in HPH rat. PURPOSE: To elucidate the mechanism by which Lut mitigated HPVR, focusing on oxygen-sensitive voltage-dependent potassium channel 1.5 (Kv1.5). METHODS: HPH rat model was established using hypobaric chamber to simulate 5000 m altitude. Isolated perfused/ventilated rat lung, isolated pulmonary arteriole ring was utilized to investigate the impact of Lut on K+ channels activity. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was assessed. CyclinD1, CDK4, PCNA, Bax, Bcl-2, cleaved caspase-3 levels in lung tissue of HPH rat were tested. The effect of Lut on Kv1.5, cytoplasmic free calcium concentration ([Ca2+]cyt), CyclinD1, CDK4, PCNA, Bax/Bcl-2 was examined in PASMCs under hypoxia, with DPO-1 as a Kv1.5 specific inhibitor. The binding affinity between Lut and Kv1.5 in PASMCs was detected by drug affinity responsive target stability (DARTS). The overexpression of KCNA5 gene (encoding Kv1.5) in HEK293T cells was utilized to confirm the interaction between Lut and Kv1.5. Furthermore, the impact of Lut on mitochondrial structure, SOD, GSH, GSH-Px, MDA and HIF-1α levels were evaluated in lung tissue of HPH rat and PASMCs under hypoxia. RESULTS: Lut dilated pulmonary artery by directly activating Kv and Ca2+-activated K+ channels (KCa) in smooth muscle. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was upregulated by Lut. Lut downregulated CyclinD1, CDK4, PCNA while upregulating Bax/Bcl-2/caspase-3 axis in lung tissue of HPH rat. Lut decreased [Ca2+]cyt, reduced CDK4, CyclinD1, PCNA, increased Bax/Bcl-2 ratio, in PASMCs under hypoxia, by upregulating Kv1.5. The binding affinity and the interaction between Lut and Kv1.5 was verified in PASMCs and in HEK293T cells. Lut also decreased [Ca2+]cyt and inhibited proliferation via targeting Kv1.5 of HEK293T cells under hypoxia. Furthermore, Lut protected mitochondrial structure, increased SOD, GSH, GSH-Px, decreased MDA, in lung tissue of HPH rat. Lut downregulated HIF-1α level in both lung tissue of HPH rat and PASMCs under hypoxia. CONCLUSION: Lut alleviated HPVR by promoting vasodilation of pulmonary artery, reducing cellular proliferation, and inducing apoptosis through upregulating of Kv1.5 in PASMCs.

Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma.

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.

An ensemble deep learning diagnostic system for determining Clinical Activity Scores in thyroid-associated ophthalmopathy: integrating multi-view multimodal images from anterior segment slit-lamp photographs and facial images.

Background: Thyroid-associated ophthalmopathy (TAO) is the most prevalent autoimmune orbital condition, significantly impacting patients' appearance and quality of life. Early and accurate identification of active TAO along with timely treatment can enhance prognosis and reduce the occurrence of severe cases. Although the Clinical Activity Score (CAS) serves as an effective assessment system for TAO, it is susceptible to assessor experience bias. This study aimed to develop an ensemble deep learning system that combines anterior segment slit-lamp photographs of patients with facial images to simulate expert assessment of TAO. Method: The study included 156 patients with TAO who underwent detailed diagnosis and treatment at Shanxi Eye Hospital Affiliated to Shanxi Medical University from May 2020 to September 2023. Anterior segment slit-lamp photographs and facial images were used as different modalities and analyzed from multiple perspectives. Two ophthalmologists with more than 10 years of clinical experience independently determined the reference CAS for each image. An ensemble deep learning model based on the residual network was constructed under supervised learning to predict five key inflammatory signs (redness of the eyelids and conjunctiva, and swelling of the eyelids, conjunctiva, and caruncle or plica) associated with TAO, and to integrate these objective signs with two subjective symptoms (spontaneous retrobulbar pain and pain on attempted upward or downward gaze) in order to assess TAO activity. Results: The proposed model achieved 0.906 accuracy, 0.833 specificity, 0.906 precision, 0.906 recall, and 0.906 F1-score in active TAO diagnosis, demonstrating advanced performance in predicting CAS and TAO activity signs compared to conventional single-view unimodal approaches. The integration of multiple views and modalities, encompassing both anterior segment slit-lamp photographs and facial images, significantly improved the prediction accuracy of the model for TAO activity and CAS. Conclusion: The ensemble multi-view multimodal deep learning system developed in this study can more accurately assess the clinical activity of TAO than traditional methods that solely rely on facial images. This innovative approach is intended to enhance the efficiency of TAO activity assessment, providing a novel means for its comprehensive, early, and precise evaluation.

African swine fever virus pB318L, a trans-geranylgeranyl-diphosphate synthase, negatively regulates cGAS-STING and IFNAR-JAK-STAT signaling pathways.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by the ASF virus (ASFV). ASFV has evolved multiple strategies to escape host antiviral immune responses. Here, we reported that ASFV pB318L, a trans-geranylgeranyl-diphosphate synthase, reduced the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs). Mechanically, pB318L not only interacted with STING to reduce the translocation of STING from the endoplasmic reticulum to the Golgi apparatus but also interacted with IFN receptors to reduce the interaction of IFNAR1/TYK2 and IFNAR2/JAK1. Of note, ASFV with interruption of B318L gene (ASFV-intB318L) infected PAMs produces more IFN-I and ISGs than that in PAMs infected with its parental ASFV HLJ/18 at the late stage of infection. Consistently, the pathogenicity of ASFV-intB318L is attenuated in piglets compared with its parental virus. Taken together, our data reveal that B318L gene may partially affect ASFV pathogenicity by reducing the production of IFN-I and ISGs. This study provides a clue to design antiviral agents or live attenuated vaccines to prevent and control ASF.

Exosomes From Human Umbilical Cord Stem Cells Suppress Macrophage-to-myofibroblast Transition, Alleviating Renal Fibrosis.

Renal fibrosis, a progressive scarring of the kidney, lacks effective treatment. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exos) hold promise for treating kidney diseases due to their anti-inflammatory properties. This study investigates their potential to lessen renal fibrosis by targeting macrophage-to-myofibroblast transformation (MMT), a key driver of fibrosis. We employed a mouse model of unilateral ureteral obstruction (UUO) and cultured cells exposed to transforming growth factor-ß (TGF-ß) to mimic MMT. HucMSC-Exos were administered to UUO mice, and their effects on kidney function and fibrosis were assessed. Additionally, RNA sequencing and cellular analysis were performed to elucidate the mechanisms by which HucMSC-Exos inhibit MMT. HucMSC-Exos treatment significantly reduced kidney damage and fibrosis in UUO mice. They downregulated markers of fibrosis (Collagen I, vimentin, alpha-smooth muscle actin) and suppressed MMT (α-SMA + F4/80 + cells). Furthermore, ARNTL, a specific molecule, emerged as a potential target of HucMSC-Exos in hindering MMT and consequently preventing fibrosis. HucMSC-Exos effectively lessen renal fibrosis by suppressing MMT, suggesting a novel therapeutic strategy for managing kidney damage and fibrosis.

Unrelated umbilical cord blood transplantation with low-dose anti-thymocyte globulin for children with severe aplastic anemia: A case series.

OBJECTIVE: This study aimed to investigate the prognosis of unrelated umbilical cord blood transplantation (UCBT) using low-dose anti-thymocyte globulin (ATG) in children diagnosed with severe aplastic anemia (SAA). METHODS: This retrospective case series study was conducted involving pediatric SAA patients treated at the Capital Institute of Pediatrics from January 2020 to February 2023. All patients underwent a reduced-intensity conditioning (RIC) regimen alongside low-dose ATG. RESULTS: The study comprised nine patients (five males) with a median age of 5 years (range: 1.7 to 7 years). The median follow-up duration was 799 days (range: 367 to 1481 days), during which all patients survived. The median time interval from diagnosis to transplantation was 3 months (range: 1 to 9 months). The median dosage of ATG administered was 5 mg/kg (range: 2.5 to 7.5 mg/kg). The median durations for granulocyte and platelet engraftment were 15 days (range: 12 to 23 days) and 26 days (range: 12 to 41 days), respectively. Three patients experienced grade 2-4 acute graft-versus-host disease (aGVHD). Epstein-Barr virus (EBV) reactivation was observed in three patients, while cytomegalovirus (CMV) reactivation occurred in seven patients, with no cases of CMV disease or post-transplant lymphoproliferative disorder (PTLD). One patient experienced recurrence 15 months after transplantation due to influenza A infection. CONCLUSION: These findings indicate that SAA patients may attain a favorable prognosis following UCBT with a RIC regimen combined with low-dose ATG.

Enhancing Efficiency and High-Value Chemicals Generation through Coupling Photocatalytic CO2 Reduction with Propane Oxidation.

Conversion of CO2 into high-value chemicals using solar energy is one of promising approaches to achieve carbon neutrality. However, the oxidation of water in the photocatalytic CO2 reduction is kinetically unfavorable due to multi-electron and proton transfer processes, along with the difficulty in generating O-O bonds. To tackle these challenges, this study investigated the coupling reaction of photocatalytic CO2 reduction and selective propane oxidation using the Pd/P25 (1 wt%) catalyst. Our findings reveal a significant improvement in CO2 reduction, nearly fivefold higher, achieved by substituting water oxidation with selective propane oxidation. This substitution not only accelerates the process of CO2 reduction but also yields valuable propylene. The relative ease of propane oxidation, compared to water, appears to increase the density of photogenerated electrons, ultimately enhancing the efficiency of CO2 reduction. We further found that hydroxyl radicals and reduced intermediate (carboxylate species) played important roles in the photocatalytic reaction. These findings not only propose a potential approach for the efficient utilization of CO2 through the coupling of selective propane oxidation into propylene, but also provide insights into the mechanistic understanding of the coupling reaction.

Integrative analysis with machine learning identifies diagnostic and prognostic signatures in neuroblastoma based on differentially DNA methylated enhancers between INSS stage 4 and 4S neuroblastoma.

INTRODUCTION: Accumulating evidence demonstrates that aberrant methylation of enhancers is crucial in gene expression profiles across several cancers. However, the latent effect of differently expressed enhancers between INSS stage 4S and 4 neuroblastoma (NB) remains elusive. METHODS: We utilized the transcriptome and methylation data of stage 4S and 4 NB patients to perform Enhancer Linking by Methylation/Expression Relationships (ELMER) analysis, discovering a differently expressed motif within 67 enhancers between stage 4S and 4 NB. Harnessing the 67 motif genes, we established the INSS stage related signature (ISRS) by amalgamating 12 and 10 distinct machine learning (ML) algorithms across 113 and 101 ML combinations to precisely diagnose stage 4 NB among all NB patients and to predict the prognosis of NB patients. Based on risk scores calculated by prognostic ISRS, patients were categorized into high and low-risk groups according to median risk score. We conducted comprehensive comparisons between two risk groups, in terms of clinical applications, immune microenvironment, somatic mutations, immunotherapy, chemotherapy and single-cell analysis. Ultimately, we empirically validated the differential expressions of two ISRS model genes, CAMTA2 and FOXD1, through immunochemistry staining. RESULTS: Through leave-one-out cross-validation, in both feature selection and model construction, we selected the random forest algorithm to diagnose stage 4 NB, and Enet algorithm to develop prognostic ISRS, due to their highest average C-index across five NB cohorts. After validations, the ISRS demonstrated a stable predictive capability, outperforming the previously published NB signatures and several clinic variables. We stratified NB patients into high and low-risk group based on median risk score, which showed the low-risk group with a superior survival outcome, an abundant immune infiltration, a decreased mutation landscape, and an enhanced sensitivity to immunotherapy. Single-cell analysis between two risk groups reveals biologically cellular variations underlying ISRS. Finally, we verified the significantly higher protein levels of CAMTA2 and FOXD1 in stage 4S NB, as well as their protective prognosis value in NB. CONCLUSION: Based on multi-omics data and ML algorithms, we successfully developed the ISRS to enable accurate diagnosis and prognostic stratification in NB, which shed light on molecular mechanisms of spontaneous regression and clinical utilization of ISRS.

Establishment and validation of nomograms to predict the overall survival and cancer-specific survival for non-metastatic bladder cancer patients: A large population-based cohort study and external validation.

This study aimed to develop nomograms to accurately predict the overall survival (OS) and cancer-specific survival (CSS) of non-metastatic bladder cancer (BC) patients. Clinicopathological information of 260,412 non-metastatic BC patients was downloaded from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020. LASSO method and Cox proportional hazard regression analysis were utilized to discover the independent risk factors, which were used to develop nomograms. The accuracy and discrimination of models were tested by the consistency index (C-index), the area under the subject operating characteristic curve (AUC) and the calibration curve. Decision curve analysis (DCA) was used to test the clinical value of nomograms compared with the TNM staging system. Nomograms predicting OS and CSS were constructed after identifying independent prognostic factors. The C-index of the training, internal validation and external validation cohort for OS was 0.722 (95%CI: 0.720-0.724), 0.723 (95%CI: 0.721-0.725) and 0.744 (95%CI: 0.677-0.811). The C-index of the training, internal validation and external validation cohort for CSS was 0.794 (95%CI: 0.792-0.796), 0.793 (95%CI: 0.789-0.797) and 0.879 (95%CI: 0.814-0.944). The AUC and the calibration curves showed good accuracy and discriminability. The DCA showed favorable clinical potential value of nomograms. Kaplan-Meier curve and log-rank test uncovered statistically significance survival difference between high- and low-risk groups. We developed nomograms to predict OS and CSS for non-metastatic BC patients. The models have been internally and externally validated with accuracy and discrimination and can assist clinicians to make better clinical decisions.

Toll-Like Receptor 9 Aggravates Pulmonary Fibrosis by Promoting NLRP3-Mediated Pyroptosis of Alveolar Epithelial Cells.

The apoptosis-prone property of alveolar epithelial cells plays a crucial role in pulmonary fibrosis(PF), but the role of pyroptosis in it is still unclear. Toll-like receptor 9(TLR9) has been reported to play a vital role in the pathogenesis of many diseases. However, the effect of TLR9 on alveolar epithelial cells in PF has not been fully elucidated. Gene expression microarray related to Idiopathic pulmonary fibrosis(IPF) was obtained from the Gene Expression Omnibus(GEO) database. In the mouse model of bleomycin-induced PF, adeno-associated virus(AAV6) was used to interfere with TLR9 to construct TLR9 knockdown mice to study the role of TLR9 in PF, and the specific mechanism was studied by intratracheal instillation of NLR family pyrin domain containing 3(NLRP3) activator. In vitro experiments were performed using A549 cells. Bleomycin-induced pyroptosis in the lung tissue of PF mice increased, and TLR9 protein levels also increased, especially in alveolar epithelial cells. The levels of fibrosis and pyroptosis in lung tissue of TLR9 knockdown mice were improved. We found that TLR9 can bind to the NLRP3, thereby increasing the activation of the NLRP3/caspase-1 inflammasome pathway. When we use the NLRP3 activator, the levels of fibrosis and pyroptosis in lung tissue of TLR9 knockout mice can be counteracted. Pyroptosis of alveolar epithelial cells plays a vital role in PF, and TLR9 can promote NLRP3-mediated pyroptosis of alveolar epithelial cells to aggravate the progression of PF and may become a feasible target for the prevention and treatment of PF.

Gaucher Disease Coexisting with Cytomegalovirus Infection: A Rare Presentation in an Infant.

BACKGROUND Gaucher disease is a rare autosomal recessive disorder characterized by mutations in the glucocerebrosidase gene, resulting in deficient enzyme activity and accumulation of glucocerebroside in macrophages, which leads to pathological changes in affected organs. The atypical clinical manifestations of Gaucher disease often contribute to delays in diagnosis and treatment. CASE REPORT We present the case of a 4-month-old female infant admitted to the Department of Pediatrics with progressive hepatosplenomegaly since birth. Concurrently, she had cytomegalovirus infection and sensory neurological hearing loss. Gaucher disease diagnosis was confirmed through whole-exome sequencing and validated by a glucocerebrosidase activity test, revealing the mutation site as c.1448T>C. This report outlines the differential diagnosis process for Gaucher disease in this infant before confirmation, contributing valuable insights for early diagnosis. CONCLUSIONS Our case underscores the challenge of diagnosing Gaucher disease due to its atypical presentation. The coexistence of cytomegalovirus infection complicates the clinical picture, emphasizing the need for careful differential diagnosis. Unfortunately, delayed diagnosis is all too common in rare diseases like Gaucher disease, even when the clinical presentation is seemingly typical. This highlights the need for increased awareness and education within the medical community to facilitate early recognition, which is essential for prompt intervention and improved outcomes. This report contributes valuable clinical and genetic information, aiming to enhance awareness and deepen the understanding of Gaucher disease in infants, particularly those with concurrent infections.

Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients / Trasplante de progenitores hematopoyéticos haploidénticos con ciclofosfamida postrasplante en lipofuscinosis neuronal ceroidea: experiencia en 8 pacientes

Background: Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. Material and method: NCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. Results: From January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10–34.41)×108/kg, and the median CD34+ count was 13.7 (8.95–22)×106/kg. Neutrophil reconstitution occurred 12 days (11–14 days) after transplantation, and the median platelet reconstitution time was 12 days (9–14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II–IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5–2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation.(AU)

Antecedentes: Las lipofuscinosis neuronales ceroides (NCL) son trastornos raros del almacenamiento lisosomal caracterizados por retraso mental progresivo y regresión del desarrollo motor y convulsiones mioclónicas. Se ha sugerido que el trasplante de células madre hematopoyéticas (HSCT) se utilice en el tratamiento de trastornos lisosomales y daño cerebral causado por una deficiencia de enzimas lisosomales solubles. No hay informes previos sobre el tratamiento de NCL con HSCT en China. Material y método: Pacientes pediátricos de NCL que se sometieron a alo-TCMH en el Hospital de Niños Afiliado del Instituto Capital de Pediatría involucrados. Se utilizó una combinación de historias clínicas, características clínicas y análisis genéticos para el diagnóstico de todos los pacientes. El formulario de consentimiento por escrito para el allo-TCMH se obtuvo del tutor del paciente, que luego fue revisado y aprobado por el comité de ética antes del procedimiento.Resultados: De enero de 2018 a mayo de 2019, se realizó el haplo-HSCT seguido de TP/Cy en 8 pacientes pediátricos con NCL. La mediana de edad fue de 4,5 años (variando de 2,8 a 7 años). Los donantes eran sus padres haploidénticos compatibles con HLA, ya que no se encontraron donantes idénticos. La mediana del recuento de células nucleadas fue de 25,37 (10–34,41)×108/kg, y la mediana del recuento de CD34+ fue de 13,7 (8,95-22)×106/kg. La reconstitución de neutrófilos ocurrió 12 días (11-14 días) después del trasplante, y el tiempo medio de reconstitución plaquetaria fue de 12 días (9-14 días) después del trasplante. Todos los pacientes alcanzaron quimerismo total del donante y no desarrollaron EICH aguda de grado II-IV o EICH crónica después del trasplante. La mediana del período de seguimiento fue de 2,2 (1,5–2,6) años. Todos los pacientes siguen vivos en la actualidad y no desarrollan complicaciones graves relacionadas con el trasplante...(AU)

African swine fever virus pH240R enhances viral replication via inhibition of the type I IFN signaling pathway.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by ASF virus (ASFV) infection. At present, there are still no safe and effective drugs and vaccines to prevent ASF. Mining the important proteins encoded by ASFV that affect the virulence and replication of ASFV is the key to developing effective vaccines and drugs. In this study, ASFV pH240R, a capsid protein of ASFV, was found to inhibit the type I interferon (IFN) signaling pathway. Mechanistically, pH240R interacted with IFNAR1 and IFNAR2 to disrupt the interaction of IFNAR1-TYK2 and IFNAR2-JAK1. Additionally, pH240R inhibited the phosphorylation of IFNAR1, TYK2, and JAK1 induced by IFN-α, resulting in the suppression of the nuclear import of STAT1 and STAT2 and the expression of IFN-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induced more ISGs in porcine alveolar macrophages compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs expression. Taken together, our results clarify that pH240R enhances ASFV replication by inhibiting the JAK-STAT signaling pathway, which highlights the possibility of pH240R as a potential drug target.IMPORTANCEThe innate immune response is the host's first line of defense against pathogen infection, which has been reported to affect the replication and virulence of African swine fever virus (ASFV) isolates. Identification of ASFV-encoded proteins that affect the virulence and replication of ASFV is the key step in developing more effective vaccines and drugs. In this study, we found that pH240R interacted with IFNAR1 and IFNAR2 by disrupting the interaction of IFNAR1-TYK2 and IFNAR2-JAK1, resulting in the suppression of the expression of interferon (IFN)-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induces more ISGs' expression compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs' expression. Taken together, our findings showed that pH240R enhances ASFV replication by inhibiting the IFN-JAK-STAT axis, which highlights the possibility of pH240R as a potential drug target.

Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. MATERIAL AND METHOD: NCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. RESULTS: From January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10-34.41)×108/kg, and the median CD34+ count was 13.7 (8.95-22)×106/kg. Neutrophil reconstitution occurred 12 days (11-14 days) after transplantation, and the median platelet reconstitution time was 12 days (9-14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II-IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5-2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation. CONCLUSION: This study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT. Transplantation should be performed at an early stage for the survival quality of pediatric patients.

Doxycycline hydrochloride inhibits the progress of malignant rhabdoid tumor of kidney by targeting MMP17 and MMP1 through PI3K-Akt signaling pathway.

OBJECTIVE: To identify therapeutic targets for malignant rhabdoid tumors of kidney (MRTK) and to investigate the effects and underlying mechanism of doxycycline hydrochloride on these tumors. METHODS: Gene expression and clinical data of MRTK were retrieved from the TARGET database. Differentially expressed genes (DEGs) and prognostic-related genes (PRGs) were selected through a combination of statistical analyses. The functional roles of MMP17 and MMP1 were elucidated through RNA overexpression and intervention experiments. Furthermore, in vitro and in vivo studies provided evidence for the inhibitory effect of doxycycline hydrochloride on MRTK. Additionally, transcriptome sequencing was employed to investigate the underlying molecular mechanisms. RESULTS: 3507 DEGs and 690 PRGs in MRTK were identified. Among these, we focused on 41 highly expressed genes associated with poor prognosis and revealed their involvement in extracellular matrix regulatory pathways. Notably, MMP17 and MMP1 stood out as particularly influential genes. When these genes were knocked out, a significant inhibition of proliferation, invasion and migration was observed in G401 cells. Furthermore, our study explored the impact of the matrix metalloproteinase inhibitor, doxycycline hydrochloride, on the malignant progression of G401 both in vitro and in vivo. Combined with sequencing data, the results indicated that doxycycline hydrochloride effectively inhibited MRTK progression, due to its ability to suppress the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway. CONCLUSION: Doxycycline hydrochloride inhibits the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway, thereby inhibiting the malignant progression of MRTK in vivo and in vitro.

Efficacy and late kidney effects of nephron-sparing surgery in the management of unilateral Wilms tumor: a systematic review and meta-analysis.

To evaluate the efficiency and long-term renal function of nephron sparing surgery (NSS) in unilateral WT patients compared with radical nephrectomy (RN). The review was performed following Cochrane Handbook guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched five databases (Pubmed, Embase, Scopus, Web of Science and Cochrane) for studies reporting the efficiency and late renal function of NSS and/or RN on February 10, 2023. Comparative studies were evaluated by Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) and RoB 2.0. Assessed outcomes included survival rate, relapse rate, eGFR, renal dysfunction and hypertension. 26 studies involving 10322 unilateral WT cases underwent RN and 657 unilateral WT cases underwent NSS were enrolled. Overall effect estimates demonstrated that NSS significantly increased eGFR at follow-up (SMD, 0.38; 95% CI 0.05-0.72; p = 0.025) compared to that at diagnosis, and RN did not significantly decrease eGFR at follow-up (SMD, - 0.33; 95% CI - 0.77-0.11; p = 0.142) compared to that at diagnosis. Moreover, no significant difference was found in outcomes of survivability (OR, 1.38; 95% CI 0.82-2.32; p = 0.226), recurrence (OR, 0.62; 95% CI 0.34-1.12; p = 0.114), eGFR at follow-up (SMD, 0.16; 95% CI - 0.36-0.69; p = 0.538), renal dysfunction (OR, 0.36; 95% CI 0.07-1.73; p = 0.200) and hypertension (OR, 0.17; 95% CI 0.03-1.10; p = 0.063). Current evidence suggests that NSS is safe and effective for unilateral WT patients, because it causes better renal function and similar oncological outcomes compared with RN. Future efforts to conduct more high-quality studies and explore sources of heterogeneity is recommended.

The PI3K-AKT-mTOR signaling pathway mediates the cytoskeletal remodeling and epithelial-mesenchymal transition in bladder outlet obstruction.

Objective: Partial bladder outlet obstruction(pBOO) is the most common cause of lower urinary tract symptoms (LUTS) and significantly affects the quality of life. Long-term pBOO can cause changes in bladder structure and function, referred to as bladder remodeling. The pathogenesis of pBOO-induced bladder remodeling has yet to be fully understood, so effective treatment options are lacking. Our study aimed to explore how pBOO-induced bladder remodeling brings new strategies for treating pBOO. Methods: A rat model of pBOO was established by partial ligation of the bladder neck, and the morphological changes and fibrosis changes in the bladder tissues were detected by H&E and Masson trichrome staining. Furthermore, EMT(epithelial-mesenchymal transition) related indicators and related pathway changes were further examined after TGF- ß treatment of urothelial cells SV-HUC-1. Finally, the above indicators were tested again after using the PI3K inhibitor. Subsequently, RNA sequencing of bladder tissues to identify differential genes and related pathways enrichment and validated by immunofluorescence and western blotting analysis. Results: The pBOO animal model was successfully established by partially ligating the bladder neck. H&E staining showed significant changes in the bladder structure, and Masson trichrome staining showed significantly increased collagen fibers. RNA sequencing results significantly enriched in the cytoskeleton, epithelial-mesenchymal transformation, and the PI3K-AKT-mTOR signaling pathway. Immunofluorescence and western blotting revealed EMT and cytoskeletal remodeling in SV-HUC-1 cells after induction of TGF- ß and in the pBOO bladder tissues. The western blotting showed significant activation of the PI3K-AKT-mTOR signaling pathway in SV-HUC-1 cells after induction of TGF-ß and in pBOO bladder tissues. Furthermore, EMT and cytoskeletal damage were partially reversed after PI3K pathway inhibition using PI3K inhibitors. Conclusions: In the pBOO rat model, the activation of the PI3K-AKT-mTOR signaling pathway can mediate the cytoskeletal remodeling and the EMT to induce fibrosis in the bladder tissues. PI3K inhibitors partially reversed EMT and cytoskeletal damage.