The role of genetic factors in pediatric myelodysplastic syndromes with different outcomes.

BACKGROUND: Pediatric myelodysplastic syndromes (MDS) are rare disorders with an unrevealed pathogenesis. Our aim is to explore the role of genetic factors in the pathogenesis of MDS in children with different outcomes and to discover the correlation between genetic features and clinical outcomes as well as disease characteristics. METHODS: We conducted an analysis of archived genetic data from 26 patients diagnosed with pediatric MDS at our institution between 2015 and 2021, examining the association between different genetic characteristics and clinical manifestations as well as prognosis. Additionally, We presented three cases with distinct genetic background and outcomes as examples to elaborate the role of genetic factors in pediatric MDS with different prognoses. RESULTS: Genetic variations were detected in 13 out of the 26 patients, including 8 patients with co-occurrence of somatic and germline mutations (CSGMs) and 5 patients with somatic mutations alone. Our analysis revealed that advanced MDS (4/8, 50% vs. 1/5, 20% and 4/11, 36.4%), PD (3/8, 37.5% vs. 1/5, 20% and 1/11 9.1%), and TD (6/8, 75% vs. 2/5, 40% and 2/11, 18.2%) were more common in patients with CSGMs than those with somatic mutations alone or without any mutations. We also found out in our study that 8 patients with CSGMs had evidently different clinical outcomes, and we presented 3 of them as examples for elaboration. Case 1 with germline and somatic mutations of unknown significance had a relatively slow disease course and a good prognosis. Case 2 with compound heterozygous germline SBDS variants and somatic mutations like del20q had a stable disease course and a reversed outcome. Case 3 with a germline GATA2 variant and somatic mutations including - 7 had a rapidly progressive disease course and a worst prognosis. CONCLUSION: Our findings indicate that genetic background of pediatric MDS is closely linked with disease characteristics as well as outcomes and that CSGMs may lead to disease progression. It should be emphasized that the interaction between certain germline variants and somatic mutations, such as SBDS and del20q, may result in hematopoietic stem cell adaptation (improved hematopoiesis) and reversed clinical outcomes, which can facilitate the development of targeted therapy.

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

The study of sleep disorder factors in patients with Guillain-Barré syndrome.

In this study, we explore the sleep disorders and its associated factors in patients with Guillain-Barré syndrome (GBS), so as to work out appropriate interventions to promote early recovery of the patients. This study subjects included 49 patients with GBS who had been admitted to the Department of Neurology at The Affiliated Hospital of Hebei University, fulfilling National Institute of Neurological and Communicative Diseases and Stroke (NINCDS) criteria for GBS; 37 cases were male and 12 female (age: 27-68 years). Patients were evaluated once daily for two consecutive weeks. By using Wong and Baker Face Scale (WBFS) to evaluate the numbness and pain in patients, 0 points representing completely no pain and 10 points represents the most severity of the pain reactions; the same applies for numbness. The GBS Disability Scale (GBS DS) is used to evaluate the severity of GBS. The Hospital Anxiety and Depression Scale (HADS) is used to evaluate the anxiety and depression the patient is experiencing. All patients take routine EMG and sleep EEG. The sleep quality of the subjects was evaluated by the Pittsburgh Sleep Quality Index Scale (PSQI) and Richard Campbell Sleep Rating Scale. This study found that the application of ventilators, numbness, anxiety and severe limb movement disorders are the main factors causing sleep disorders. Cerebrospinal fluid (CSF) protein concentration is also associated with sleep disorders. But, no obvious abnormalities were found in sleep EEG. The application of the ventilator, numbness, anxiety and severe limb movement disorder are main factors causing sleep disorders. CSF protein concentration is also associated with sleep disorders.

Clinical utility of plasma Epstein-Barr virus DNA monitoring in pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: a Chinese retrospective observational study.

BACKGROUND: Epstein-Barr virus DNA (EBV-DNA) is closely related to the pathogenesis and prognosis of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The quantitative measurement of blood EBV-DNA is widely used in EBV-HLH, but there remains a lack of evidence to guide clinicians. METHODS: A retrospective analysis was conducted on clinical manifestations, laboratory tests, 310 blood EBV-DNA loads, and prognosis of 51 pediatric patients diagnosed with EBV-HLH. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cutoff values of EBV-DNA for predicting mortality and evaluating the active status of EBV-HLH. RESULTS: EBV-positive- lymphoma-HLH had higher initial plasma EBV-DNA load(1.10 × 106copies/ml) compared to the EBV-HLH group (1.98 × 104 copies/ml) (P = 0.006), and experienced recurrently elevated plasma EBV-DNA levels during treatment. The optimal cut-off value of initial plasma EBV-DNA load in predicting mortality was 2.68 × 105 copies/ml, with a sensitivity of 88.57% and a specificity of 56.25%. For determining the active status of HLH, the optimal cutoff value of PBMC EBV-DNA load during treatment was 2.95 × 105 copies/ml, with a sensitivity of 69.14% and a specificity of 64.71%. The cut-off value of plasma EBV-DNA for determining active status was 1.32 × 103 copies/ml, with a sensitivity of 84.34%, and a specificity of 87.67%. Patients with higher PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses (P < 0.05). CONCLUSION: Dynamic monitoring of EBV-DNA is a valuable tool for assessing disease status and predicting the prognosis of EBV-HLH, with plasma EBV-DNA being more effective than PBMC EBV-DNA. Patients with high levels of PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses.

Clinical significance and different strategies for re-elevation of plasma EBV-DNA during treatment in pediatric EBV-associated hemophagocytic lymphohistiocytosis.

OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.

Industrial co-agglomeration, Internet utilization, and the development of green and low-carbon cycle - based on the empirical study of 41 cities in the Yangtze River Delta of China.

The construction of green and low-carbon circular (GLC) development economic system is conducive to the promotion of "carbon peaking and carbon neutral." The level of GLC development in the Yangtze River Delta (YRD) region is related to the realization of the ambitious goal of "carbon peaking and carbon neutrality" in the region. This paper use principal component analysis (PCA) to process GLC development level of 41 cities in the YRD from 2008 to 2020. Then, we constructed panel Tobit model and threshold model from the perspective of industrial co-agglomeration and Internet utilization and empirically tested the influence of the two key variables on GLC development of the YRD. We found that (1) the YRD's level of GLC development showed a dynamic evolution trend of "fluctuation, convergence, and rise." The four provincial-level administrative regions of the YRD are in the order of  GLC development level: Shanghai, Zhejiang, Jiangsu, and Anhui. (2) There is an inverted "U" Kuznets curve (KC) between industrial co-agglomeration and the development of GLC of the YRD. In the left segment of KC, the industrial co-agglomeration promotes GLC development of the YRD. In the right segment of KC, the industrial co-agglomeration inhibits GLC development of the YRD. Internet utilization enhances GLC development of the YRD. And the interaction of industrial co-agglomeration and Internet utilization cannot significantly enhance GLC development. (3) Double-threshold effect of opening-up is manifested as follows: industrial co-agglomeration on GLC development of the YRD goes through an insignificant-inhibited-improved evolutionary trajectory. Single-threshold effect of government intervention is manifested as follows: the impact of Internet utilization on GLC development of the YRD shifts from insignificant role to significant enhancement. In addition, there is an inverted-N type KC effect between industrialization and GLC development. Based on the above findings, we proposed suggestions in terms of industrial co-agglomeration, Internet-like digital technology application, anti-monopoly, and rational industrialization.

(4Z)-4-[(4-Chloro-anilino)(phen-yl)methyl-ene]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one.

The title compound, C(23)H(18)ClN(3)O, was synthesized by the reaction of 4-chloro-aniline and 4-benzoyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one. The terminal benzene rings are twisted at dihedral angles of 48.3 (2), 71.4 (2) and 36.1 (2)° with respect to the central eight-atom methyl-pyrazolone/amino-methyl-ene unit. An intra-molecular N-H⋯O hydrogen bond stabilizes the planar conformation [mean deviation = 0.0398 (5) Å] of the central unit, generating an S(6) ring motif. The crystal packing is stabilized by van der Waals forces.