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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with increasing incidence worldwide. Growing evidence suggests that ubiquitin-specific proteases (USPs) play a role in cancer treatment. Dysregulation of miR-146a has been found in both adult and pediatric patients with acute leukemia. Knockdown of glutaminase-1 (GLS1) resulted in inhibition of tumor growth. However, the role of miR-146a-5p/USP6/GLS1 in leukemia and chemoresistance of leukemia cells remains to be elucidated. In the current study, USP6 level was increased in bone marrow aspiration specimens of patients with CML and associated with poor prognosis. USP6 was significantly upregulated in imatinib (IM)-resistant clinical samples compared with IM-sensitive samples. USP6 overexpression significantly inhibited IM-induced apoptosis of leukemia cells. Overexpressing USP6 significantly increased GLS1 ubiquitination to decrease GLS protein. A mechanism study indicated that USP6 regulation of IM resistance of CML cells was GLS1 dependent and regulated by miR-146a-5p. Administration of human umbilical cord mesenchymal stem cell (hucMSC) exosomes promoted IM-induced cell apoptosis through miR-145a-5p/USP6. Therefore, hucMSC exosomes promoted IM-induced apoptosis of K562-R cells by suppressing GLS1 ubiquitination to increase GLS protein via miR-146a-5p and its target GLS1. The findings highlight the importance of miR-146a-5p/USP6/GLS1 signaling in chemoresistance of leukemia and provide new insights into therapeutic strategies for chemoresistant leukemia.

Biofilms are a common survival strategy employed by bacteria in healthcare settings, which enhances their resistance to antimicrobial and biocidal agents making infections difficult to treat. Mechanisms of biofilm-induced antimicrobial resistance involve reduced penetration of antimicrobial agents, increased expression of efflux pumps, altered microbial physiology, and genetic changes in the bacterial population. Factors contributing to the formation of biofilms include nutrient availability, temperature, pH, surface properties, and microbial interactions. Biofilm-associated infections can have serious consequences for patient outcomes, and standard antimicrobial therapies are often ineffective against biofilm-associated bacteria, making diagnosis and treatment challenging. Novel strategies, including antibiotics combination therapies (such as daptomycin and vancomycin, colistin and azithromycin), biofilm-targeted agents (such as small molecules (LP3134, LP3145, LP4010, LP1062) target c-di-GMP), and immunomodulatory therapies (such as the anti-PcrV IgY antibodies which target Type IIIsecretion system), are being developed to combat biofilm-induced antimicrobial resistance. A multifaceted approach to diagnosis, treatment, and prevention is necessary to address this emerging problem in healthcare settings.

This study aimed to establish a predictive model to identify children with hematologic malignancy at high risk for delayed clearance of high-dose methotrexate (HD–MTX) based on machine learning. A total of 205 patients were recruited. Five variables (hematocrit, risk classification, dose, SLC19A1 rs2838958, sex) and three variables (SLC19A1 rs2838958, sex, dose) were statistically significant in univariable analysis and, separately, multivariate logistic regression. The data was randomly split into a “training cohort” and a “validation cohort”. A nomogram for prediction of delayed HD–MTX clearance was constructed using the three variables in the training dataset and validated in the validation dataset. Five machine learning algorithms (cart classification and regression trees, naïve Bayes, support vector machine, random forest, C5.0 decision tree) combined with different resampling methods were used for model building with five or three variables. When developed machine learning models were evaluated in the validation dataset, the C5.0 decision tree combined with the synthetic minority oversampling technique (SMOTE) using five variables had the highest area under the receiver operating characteristic curve (AUC 0.807 [95% CI 0.724–0.889]), a better performance than the nomogram (AUC 0.69 [95% CI 0.594–0.787]). The results support potential clinical application of machine learning for patient risk classification.

Background Mucormycosis is a life-threatening complication that occurs in haematopoietic stem cell transplantation (HSCT) recipients. Among mucormycosis patients, those infected with Cunninghamella bertholletiae have the poorest prognosis because of the high virulence and angioinvasive nature of this organism. Despite its high vascular invasiveness, pseudoaneurysm caused by C. bertholletiae in HSCT recipients has rarely been reported. Case presentation An 8-year-old HSCT recipient experienced recurrent fever, cough and pain after HSCT. Teicoplanin, acyclovir, posaconazole and caspofungin were used for infection prophylaxis. The sputum, stool, urine, peripheral blood and central venous catheter (CVC) blood culture results were negative. Next-generation sequencing (NGS) of the peripheral blood, pleural effusion and bronchoalveolar lavage fluid revealed the presence of C. bertholletiae , and amphotericin B combined with posaconazole was administered; however, the infection progressed. Fibreoptic bronchoscopies revealed that C. bertholletiae had invaded the bronchial wall, and enhanced computerized tomography (CT) revealed a pseudoaneurysm of the descending aorta resulting from C. bertholletiae . Debridement and vessel replacement were considered but not performed because of the severity of the infection and the patient’s poor physical condition. Unfortunately, the patient died from pseudoaneurysm rupture with no presymptoms 56 d after HSCT. Conclusion For the first time, we report pseudoaneurysm secondary to C. bertholletiae infection in a HSCT recipient, highlighting the importance of clinical awareness of vessel lesions resulting from C. bertholletiae and emphasizing the value of enhanced CT for the early detection of vessel lesions in this rare infection.

BackgroundPrimitive electronic waste (e-waste) recycling is ongoing in Guiyu, so toxic heavy metals may continue to threaten the health of children in the area.ObjectiveThis study primarily aimed to evaluate the effect of e-waste exposure on haemoglobin (Hb) synthesis in preschool children.MethodsMedical examinations were conducted with the permission of children’s guardians and the approval of the Ethics Committee of the Medical College of Shantou University. This study recruited 224 children (aged 3–6 years, exposed group) who lived in Guiyu and 204 children (aged 3–6 years, control group) who lived in a town free of e-waste pollution. Blood levels of lead, Hb, ferritin, folate and vitamin B12 were tested in all children. Furthermore, all children were assessed for thalassemia, and their parents were asked to fill in questionnaires.ResultsThere were no significant differences in the level of ferritin, folate, or vitamin B12 between the exposed and control groups (P > 0.05). No children were identified as having thalassemia in all study participants. Blood lead level (BLL) and the risk of children with BLL ≥ 10 µg/dL in the exposed group were significantly higher than those in the control group (all P < 0.01). Three subgroups of each group were created according to BLL (Group A: < 5.0 µg/dL; Group B: 5.0–9.9 µg/dL; Group C: ≥ 10.0 µg/dL). Hb level decreased with elevated BLL in the exposed group (P = 0.03), but not in the control group (P = 0.14). Hb levels in group B and group C were also significantly lower in the exposed group than in the control group (Group B: 122.6 ± 9.5 g/L versus 125.8 ± 8.2 g/L, P = 0.01; Group C: 120.3 ± 7.3 g/L versus 123.6 ± 8.3 g/L, P = 0.03). In addition, the prevalence of anaemia associated with BLLs above 10 µg/dL and between 5.0 and 9.9 µg/dL were both significantly higher in the exposed group than in the control group (4.0% vs. 0.5%, 5.4% vs. 1.5%, respectively, both P < 0.05).ConclusionLead exposure more significantly inhibits Hb synthesis in children who live in e-waste dismantling areas than in those who live in non-e-waste dismantling areas. Other toxins released from e-waste may also contribute to the inhibition of Hb synthesis and may lead to anaemia in local children. Further investigations are needed to provide evidence for the development of relevant protective measures.

The emergence of multidrug-resistant poses a global threat, but the distribution and resistance profiling are unclear, especially in young children. Infections due to are common, associated with high mortality, and increasingly β-lactam drug resistant. We studied the molecular epidemiology and antibiotic resistance mechanisms in 294 clinicalisolates of from a pediatric hospital in China. Non-duplicate isolates were recovered from clinical cases and were identified using an API-20 kit followed by antimicrobial susceptibility testing using the VITEK®2 compact system (BioMerieux, France) and also by broth dilution method. In addition, a double-disc synergy test for the ESBL/E-test for MBL was performed. The presence of beta-lactamases, plasmid types, and sequence types was determined by PCR and sequencing. Fifty-six percent ( = 164) of the isolates were resistant to piperacillin-tazobactam, followed by cefepime (40%; = 117), ceftazidime (39%; = 115), imipenem (36%; = 106), meropenem (33%; = 97), and ciprofloxacin (32%; = 94). Forty-two percent (n = 126) of the isolates were positive for ESBL according to the double-disc synergy test. The blaCTX-M-15 cephalosporinase was observed in 32% (n = 40/126), while 26% (n = 33/126) werepositive for blaNDM-1 carbapenemase. Aminoglycoside resistance gene was observed in 16% (n = 20/126), and glycylcyclines resistance gene tet(A) was observed in 12% (n = 15/126) of the isolates. A total of 23 sequence types were detected, including ST1963 (12%; n = 16), followed by ST381 (11%; = 14), ST234 (10%; = 13), ST145 (58%; = 10), ST304 (57%; = 9), ST663 (5%; n = 7), and a novel strain. In ESBL-producing , 12 different Incompatibility groups (Inc) were observed, the most common being IncFI, IncFIS, and IncA/C. The MOBP was the most common plasmid type, followed by MOBH, MOBF, and MOBQ. Our data suggest that the spread of antibiotic resistance is likely due toclonal spread and dissemination of different clinical strains of harbouring different plasmids. This is a growing threat in hospitals particularly in young children which needs robust prevention strategies.

Gastrointestinal acute graft-versus-host disease (GI-aGVHD) is a severe early complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has been shown that the intestinal microbiota plays a critical role in this process. As metabolites of the intestinal microbiota, short-chain fatty acids (SCFAs) are vital for maintaining the host-microbiota symbiotic equilibrium. This article provides an overview of the protective effect of SCFAs in the gastrointestinal tract, emphasizes their association with GI-aGVHD, and explores relevant research progress in prevention and treatment research. Plain language summary Research advances on short-chain fatty acids in gastrointestinal acute graft-versus-host disease Gastrointestinal acute graft-versus-host disease (GI-aGVHD) is a severe early complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has been shown that the intestinal microbiota plays a critical role in this process. As metabolites of the intestinal microbiota, short-chain fatty acids (SCFAs) are vital for maintaining the host-microbiota symbiotic equilibrium. This article provides an overview of the protective effect of SCFAs in the gastrointestinal tract, emphasizes their association with GI-aGVHD and explores relevant research progress in prevention and treatment research.

Background The clinical significance of circulating tumor cell (CTC) clusters in highly metastatic tumors hasn’t yet been revealed. Here, we demonstrated the diagnostic and prognostic value of CTC clusters in neuroblastoma (NB) which is the most prevalent childhood extracranial solid tumor. Methods We employed cascaded filter deterministic lateral displacement microfluidic chips to enrich CTCs and CTC clusters in 64 newly diagnosed NB patients. CTCs and CTC clusters were identified by CD45-, GD2+/PHOX2B+, DAPI + immunofluorescence staining, with cells displaying characteristic neoplastic morphology. Results Among NB patients, 85.94% and 50.00% were positive for CTCs and CTC clusters, respectively; no CTCs or CTC clusters were detected in healthy children. Moreover, CTC and CTC cluster numbers differed significantly across different primary sites, clinical and pathologic features, and risk stratifications, while no significant differences in CTC and CTC cluster counts were observed in relation to sex, age, and MYCN gene amplification. CTCs and CTC clusters indicated metastasis and strongly correlated with minimal residual disease. Of note, CTC clusters ≥ 2.5/2 mL were closely associated with bone marrow metastasis and demonstrated significant differences in the hazard ratio of overall survival. Conclusions CTCs and CTC clusters are sensitive non-invasive biomarkers for NB diagnosis and prognosis, especially the prominent role in tumor emergencies. CTC clusters closely correlate with bone marrow metastasis and represent promising indicator for the monitoring of metastasis in NB emergencies. The mechanisms of CTC cluster formation and their specific role in the metastasis cascade deserve further elucidation which may serve as targets to inhibit NB bone marrow metastasis. Highlights CTC and CTC cluster counts correlate with NB tumor site and risk stage. CTCs and CTC clusters predict metastasis and CTC clusters indicate BM metastasis. CTC and CTC cluster detection play a vital role in liquid biopsy for NB emergency. CTCs and CTC clusters demonstrate prominent significance in NB OS prognosis. Importance of the study Studies investigating the diagnostic and prognostic value of CTC clusters in neuroblastoma are exceedingly limited. Here the authors harnessed microfluidic chip to isolate CTCs and CTC clusters and demonstrated that CTCs and CTC clusters are sensitive indicators of metastasis and risk stratification in neuroblastoma, differ significantly across different primary sites, clinical and pathologic features, and may serve as noninvasive diagnostic and prognostic biomarkers of neuroblastoma. Notably, CTC clusters may serve as promising indicators of bone marrow metastasis when bone marrow aspiration is not feasible in neuroblastoma emergencies.

The cGAS-STING pathway is essential in innate immunity, especially in antiviral responses and cellular stress management. cGAS acts as a cytoplasmic DNA sensor by initiating the synthesis of the second messenger cyclic GMP-AMP synthase (cGAMP), which subsequently activates the STING pathway, leading to the production of type I interferons and other cytokines, as well as the activation of inflammatory mediators. Recent studies have demonstrated that ubiquitination changes closely regulate the function of the cGAS-STING pathway. Ubiquitination modifications influence the stability and activity of cGAS and STING, while also influencing the accuracy of the immune response by adjusting their degradation and signal intensity. E3 ubiquitin ligase specifically facilitates the degradation or modulates the signaling of cGAS-STING-associated proteins via ubiquitination alterations. Furthermore, the ubiquitination of the cGAS-STING pathway serves distinct functions in various cell types and engages with NF-κB, IRF3/7, autophagy, and endoplasmic reticulum stress. This ubiquitin-mediated regulation is crucial for sustaining the balance of innate immunity, while excessive or inadequate ubiquitination can result in autoimmune disorders, cancers, and viral infections. An extensive examination of the ubiquitination process within the cGAS-STING pathway elucidates its specific regulatory mechanisms in innate immunity and identifies novel targets for the intervention of associated diseases.