Relationship between heart failure and intestinal inflammation in infants with congenital heart disease.

OBJECTIVE: The association between heart failure (HF) and intestinal inflammation caused by a disturbed intestinal microbiota in infants with congenital heart disease (CHD) was investigated. METHODS: Twenty infants with HF and CHD who were admitted to our hospital between October 2021 and March 2022 were included in this study. Twenty age- and sex-matched infants without HF at our hospital were selected as the control group. Faecal samples were obtained from each participant and analysed by enzyme-linked immunoassay and 16 S rDNA sequencing to assess intestinal inflammatory factors and the microbiota. RESULTS: The levels of intestinal inflammatory factors, including IL-1ß, IL-4, IL-6, IL-17 A and TNF-α, were greatly increased, while the levels of IL-10 were significantly decreased in the HF group compared to the control group (p < 0.05). The intestinal microbial diversity of patients in the HF group was markedly lower than that in the control group (p < 0.05). The abundance of Enterococcus was significantly increased in the HF group compared to the control group (p < 0.05), but the abundance of Bifidobacterium was significantly decreased in the HF group compared to the control group (p < 0.05). The diversity of the intestinal microbiota was negatively correlated with the levels of IL-1ß, IL-4, IL-6 and TNF-α in the intestinal tract but was positively correlated with that of IL-10. The abundance of Enterococcus was positively associated with the levels of IL-1ß, IL-4, IL-6 and TNF-α in the intestinal tract but was negatively correlated with that of IL-10. NT-proBNP was positively associated with the levels of IL-1ß, IL-4, IL-6 and TNF-α in the HF group but was negatively correlated with that of IL-10. The heart function score was positively associated with the levels of IL-1ß, IL-4, IL-6 and TNF-α in the HF group but was negatively correlated with that of IL-10. CONCLUSIONS: Infants with CHD-related HF had a disordered intestinal microbiota, decreased diversity of intestinal microbes, increased levels of pathogenic bacteria and decreased levels of beneficial bacteria. The increased abundance of Enterococcus and the significant decrease in the diversity of the intestinal microbiota may exacerbate the intestinal inflammatory response, which may be associated with the progression of HF.

Baicalein attenuates oxidative damage in mice haematopoietic cells through regulation of PDGFRß.

Platelet-derived growth factor receptor ß (PDGFRß) plays a crucial role in murine haematopoiesis. Baicalein (BAI), a naturally occurring flavonoid, can alleviate disease damage through anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms. However, whether BAI attenuates oxidative damage in murine haematopoietic cells by PDGFRß remains unexplored. In this study, we utilized a tert-butyl hydroperoxide (TBHP)-induced BaF3 cell injury model and an ionising radiation (IR)-induced mice injury model to investigate the impact of the presence or absence of PDGFRß on the pharmacological effects of BAI. In addition, the BAI-PDGFRß interaction was characterized by molecular docking and dynamics simulations. The results show that a specific concentration of BAI led to increased cell viability, reduced reactive oxygen species (ROS) content, upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression, and its downstream target genes heme oxygenase 1 (HO-1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), and activated protein kinase B (AKT) pathway in cells expressing PDGFRß plasmid and experiencing damage. Similarly, BAI elevated lineage-Sca1+cKIT+ (LSK) cell proportion, promoted haematopoietic restoration, enhanced NRF2-mediated antioxidant response in PDGFRß+/+ mice. However, despite BAI usage, PDGFRß knockout mice (PDGFRß-/-) showed lower LSK proportion and less antioxidant capacity than the total body irradiation (TBI) group. Furthermore, we demonstrated an interaction between BAI and PDGFRß at the molecular level. Collectively, our results indicate that BAI attenuates oxidative stress injury and helps promote haematopoietic cell recovery through regulation of PDGFRß.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Sternal Pin Used to Close Sternum in Infants after Cardiac Surgery.

OBJECTIVE: A retrospective study was conducted to explore the efficacy of bioabsorbable poly-L-lactic acid sternal pins in sternal closure in infants after cardiac surgery. METHODS: A total of 170 infantile patients who underwent cardiac surgery were divided into the steel wire group (group A), the PDS cord group (group B), and the steel wire + sternal pin group (group C). The occurrence of the thoracic deformity was evaluated by vertebral index (VI), frontosagittal index (FSI), and Haller index (HI) values; the stability of the sternum was evaluated by detecting sternal dehiscence and displacement. RESULTS: By comparing the absolute values of the differences in VI, FSI, and HI in the three groups, it was found that the difference values of VI and HI in group C were significantly lower than those in group B (p = 0.028 and 0.005). For the highest deformation index, the deformation rate of infants in group C before discharge and during the 1-year follow-up was lower than that in group A and group B (p = 0.009 and 0.002, respectively). The incidence of sternal displacement in group C was also significantly lower than that in groups A and B (p = 0.009 and 0.009). During the 1-year follow-up, there was no sternal dehiscence, and the sternum healed completely in the three groups. CONCLUSION: The use of "steel wire + sternal pin" for sternal closure in infants after cardiac surgery can reduce the occurrence of sternal deformity, reduce anterior and posterior displacement of the sternum, and improve sternal stability.

Comparison of high-flow nasal cannula oxygenation and non-invasive ventilation for postoperative pediatric cardiac surgery: a meta-analysis.

OBJECTIVE: To evaluate the efficacy of high-flow nasal cannula oxygenation (HFNC) versus non-invasive ventilation (NIV) in pediatric patients post-congenital heart surgery (CHS) through a meta-analysis. METHODS: A comprehensive literature search was conducted across the Chinese biomedical literature database, Vip database, CNKI, Wanfang, PubMed, Embase, Cochrane Library, and Web of Science until December 20, 2022. We selected RCTs or cohort studies that met inclusion criteria for a meta-analysis using RevMan 5.4 software. RESULTS: Our search yielded five publications, comprised of one randomized controlled trial and four cohort studies. Meta-analysis revealed a significant reduction in reintubation rates in children post-CHS treated with HFNC as compared to NIV [RR = 0.36, 95%CI(0.25 ~ 0.53), P < 0.00001]. There was also a notable reduction in the duration of ICU stay [MD = -4.75, 95%CI (-9.38 ~ -0.12), P = 0.04]. No statistically significant differences were observed between HFNC and NIV in terms of duration of mechanical ventilation, 24 h PaO2, and PaCO2 post-treatment (P > 0.05). Furthermore, both groups showed no significant difference in the duration of extracorporeal circulation [MD = -8.27, 95%CI(-17.16 ~ 0.62), P = 0.07]. CONCLUSIONS: For pediatric patients post-CHS, HFNC appears to be more effective than NIV in reducing reintubation rates and shortening the CICU stay.

Metabolomic insights into pulmonary fibrosis: a mendelian randomization study.

BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.

Using cerebral regional oxygen saturation and amplitude-integrated electroencephalography in neonates on extracorporeal membrane oxygenation: preliminary experience from a single center.

OBJECTIVE: This study aims to evaluate the application value in neurological outcome of cerebral regional oxygen saturation (CrSO2) and amplitude-integrated electroencephalography (aEEG) monitoring during neonatal extracorporeal membrane oxygenation (ECMO) courses. METHODS: We retrospectively analyzed 18 neonates receiving veno-arterial ECMO (V-A ECMO) support at our hospital from July 2021 to December 2022. Continuous monitoring of CrSO2 and brain electrical activity was conducted using near-infrared spectroscopy (NIRS) and aEEG throughout the ECMO treatment. We collected and analyzed related clinical data. RESULTS: Among the 11 survivors, 5 were categorized as the normal group (N group) and 6 as the abnormal group (AN group) based on post-ECMO brain MRI outcomes. The N group exhibited shorter time percentage of significant CrSO2 reduction (> 25% from baseline or absolute value < 40%), better fractional tissue oxygen extraction (FTOE) rates, and more stable mean percentage changes in CrSO2 compared to the AN group. Neonates in the N group predominantly showed mildly abnormal aEEG readings, with one patient displaying disrupted sleep-wake cycles. This particular patient also had more significant CrSO2 reduction and poorer FTOE compared to others in the N group. Additionally, the Test of Infant Motor Performance (TIMP) scores indicated hypoevolutism in this patient before discharge, while others in the N group had normal TIMP scores. In the AN group, 4 exhibited moderate and 2 severe aEEG abnormalities; 5 had hypoevolutism TIMP scores, and 1 with moderate aEEG abnormalities maintained a normal TIMP score, exhibiting lesser CrSO2 reduction and improved FTOE. CONCLUSION: CrSO2 and aEEG monitoring show potential as routine assessments for neurological outcomes during neonatal ECMO. In our cohort, a tendency was observed where neonates with greater reductions in CrSO2 and more severe aEEG abnormalities experienced poorer neurological outcomes.

Comparative Analysis of Chloroplast Pan-Genomes and Transcriptomics Reveals Cold Adaptation in Medicago sativa.

Alfalfa (Medicago sativa) is a perennial forage legume that is widely distributed all over the world; therefore, it has an extremely complex genetic background. Though population structure and phylogenetic studies have been conducted on a large group of alfalfa nuclear genomes, information about the chloroplast genomes is still lacking. Chloroplast genomes are generally considered to be conservative and play an important role in population diversity analysis and species adaptation in plants. Here, 231 complete alfalfa chloroplast genomes were successfully assembled from 359 alfalfa resequencing data, on the basis of which the alfalfa chloroplast pan-genome was constructed. We investigated the genetic variations of the alfalfa chloroplast genome through comparative genomic, genetic diversity, phylogenetic, population genetic structure, and haplotype analysis. Meanwhile, the expression of alfalfa chloroplast genes under cold stress was explored through transcriptome analysis. As a result, chloroplast genomes of 231 alfalfa lack an IR region, and the size of the chloroplast genome ranges from 125,192 bp to 126,105 bp. Using population structure, haplotypes, and construction of a phylogenetic tree, it was found that alfalfa populations could be divided into four groups, and multiple highly variable regions were found in the alfalfa chloroplast genome. Transcriptome analysis showed that tRNA genes were significantly up-regulated in the cold-sensitive varieties, while rps7, rpl32, and ndhB were down-regulated, and the editing efficiency of ycf1, ycf2, and ndhF was decreased in the cold-tolerant varieties, which may be due to the fact that chloroplasts store nutrients through photosynthesis to resist cold. The huge number of genetic variants in this study provide powerful resources for molecular markers.

Changes of serum TSH, FT3, and FT4 levels in infants received surgical correction of congenital heart disease under cardiopulmonary bypass.

OBJECTIVE: This study aimed to explore the fluctuations and clinical relevance of serum thyrotropin (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) levels in infants undergoing surgical correction for congenital heart disease (CHD) using cardiopulmonary bypass (CPB). METHODS: In a retrospective design, 58 infants who underwent CHD surgical correction under CPB between January 2021 and January 2022 at our institution were incorporated. These infants were categorized into two groups: simple CHD (n = 34) and complex CHD (n = 24). TSH, FT3, and FT4 serum concentrations were assessed at four intervals: 24 h pre-surgery (T0) and 24 h (T1), 48 h (T2), and 72 h (T3) post-surgery. RESULTS: The simple CHD group displayed a significantly reduced CPB duration compared to the complex CHD group (P < 0.001). Both groups exhibited a notable decline in serum thyroid hormone concentrations at T1 compared to T0. However, from T1 to T3, an upward trend in hormone levels was observed. By T3, though the levels in both groups had risen notably from T1, they remained significantly diminished from T0 (P < 0.01). In both the simple and complex CHD cohorts, significant fluctuations in thyroid hormone levels (TSH, FT3, FT4) were noted across the different timepoints (T0, T1, T3) (P < 0.01). While no significant disparities were found between the two groups' hormone concentrations at T0 and T1 (P > 0.05), at T2 and T3, the simple CHD group manifested higher TSH, FT3, and FT4 levels compared to the complex CHD group (P < 0.05). CONCLUSIONS: Infants undergoing CHD surgical correction under CPB experience significant declines in TSH, FT3, and FT4 serum levels. The post-surgery thyroid hormone recovery was more pronounced in infants with simple CHD compared to those with complex CHD. As such, vigilant monitoring of thyroid hormone levels during the perioperative phase is imperative, and timely intervention measures should be employed when necessary.

A new pathway for the transformation of AML in MDS: APA mechanism regulated by NUDT21 and RUNX1.

We have identified that NUDT21 plays a vital role in MDS transformations, while the transcription factor RUNX1 is essential for normal hematopoiesis, which is a high expression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and we aim to explore the linkage between the two genes and new pathways for MDS transformation to AML. Prediction of RUNX1 expression levels and its relationship with NUDT21 in AML and MDS patients was performed using bioinformatics techniques and validated in patients. Using lentiviral packaging technology, NUDT21 knockdown and overexpression models were developed in AML and MDS cell lines. These models were validated using quantitative polymerase chain reaction (qPCR) and western blotting. The cell cycle, apoptosis, differentiation, and cytokines were examined by flow cytometry, CCK-8 analyzed proliferation, and the intracellular localization of NUDT21 and RUNX1 was examined by immunofluorescence. mRNA transcriptome sequencing was performed on THP-1, MUTZ-1, and Dapars analyzed SKM-1 cell lines and the sequencing data to observe the knockdown effect of NUDT21 on RUNX1. qPCR and western blot revealed a positive correlation between NUDT21 and RUNX1; both were located in the nucleus. Overexpression of NUDT21 reduced apoptosis, promoted cell proliferation, and possibly increased the invasive ability of cells. It also altered the APA site in the RUNX1 3'-UTRs region. NUDT21 regulates RUNX1 gene expression and promotes AML transformation in MDS through an APA mechanism.

Clinical effect of early enteral nutrition support on critically ill neonates with extracorporeal membrane oxygenation.

OBJECTIVE: To investigate the feasibility and clinical outcomes of early enteral nutrition (EN) in critically ill neonates supported by extracorporeal membrane oxygenation (ECMO). METHODS: We retrospectively analyzed the clinical data of 16 critically ill neonates who received ECMO support for respiratory and circulatory failure from July 2021 to December 2022 at our center. The patients were divided into two groups: the early EN group (< 24 h) and the late EN group (> 24 h). The related clinical and nutrition-related indicators between the groups were compared. RESULTS: There was a significant difference in the time from ECMO treatment to the start of EN between the early EN group (9 patients, 56.2%) and the late EN group (7 patients, 43.8%) (P < 0.05). However, there were no significant differences in ECMO duration, hospitalization time, vasoactive-inotropic score (VIS), intestinal oxygen saturation, or routine stool occult blood (OB) test between the two groups (all P > 0.05). The incidence of complications such as intestinal obstruction, abdominal distension, diarrhea, and necrotizing enterocolitis (NEC) was slightly lower in the early EN group, but the differences were not statistically significant (all P > 0.05). The early EN group had a shorter time [3.6 (3.5, 5) vs. 7.5 (5.9, 8.5) d] to reach full gastrointestinal nutrition compared to the late EN group (P < 0.05). CONCLUSION: Providing early nutritional support through enteral feeding to critically ill neonates receiving ECMO treatment is both safe and practical, but close monitoring of clinical and nutritional indicators is essential.

Computed tomography imaging-guided parasternal approach drainage for children with tension pneumomediastinum: a case series.

PURPOSE: Tension pneumomediastinum is a rare and dangerous complication in children that can be fatal, and timely detection and treatment are critical. The aim of this study was to evaluate the safety and feasibility of computed tomography (CT) imaging-guided parasternal approach drainage for tension pneumomediastinum in children. METHODS: From June 2018 to February 2023, we consecutively enrolled 19 children with tension pneumomediastinum in our institution. A pigtail catheter was inserted into the anterior mediastinum by a CT imaging-guided parasternal approach. The catheter was connected to a negative-pressure water seal bottle to drain the pneumomediastinum. Clinical data and outcomes were summarized. RESULTS: The mean age was 3.1 ± 3.4 years, the mean weight was 15 ± 9.1 kg, the mean procedure time was 11.8 ± 2.4 min, and the drainage time was 6.7 ± 3.4 days. No major complications were identified, such as haemothorax, catheter displacement, or mediastinal infection. Effective drainage was obtained in all patients as assessed by comparing images and ventilatory parameters, and no additional surgical treatment was needed. There was no recurrence during the follow-up, which was more than 2 months. In our data, two children with COVID-19 were discharged from the hospital after effective drainage and other clinical treatment. CONCLUSION: CT-guided parasternal approach drainage is safe, minimally invasive, and effective for children with tension pneumomediastinum.

Creating the optimal preoperative nutritional status for neonates undergoing cardiac surgery by implementing a preoperative nutritional support plan.

AIM: The purpose of this study was to explore the effect of a preoperative nutritional support programme on improving preoperative nutritional status and promoting postoperative recovery in neonates undergoing cardiac surgery. METHODS: The clinical data of neonates undergoing cardiac surgery who received preoperative nutritional support therapy in our hospital from March 2021 to December 2021 were collected, and the clinical data of neonates undergoing cardiac surgery who did not receive preoperative nutritional support therapy in our hospital from February 2020 to February 2021 were selected as the control. The nutritional status and postoperative recovery of the two groups were compared. RESULTS: A total of 30 neonates who received nutritional support before cardiac surgery were included in this study. A total of 28 neonates who did not receive nutritional support before cardiac surgery were included in the control group. There were no significant differences in general information or the nutritional status at birth between the two groups. The duration of nutritional support in the intervention group was 16.8 ± 7.1 days. Before the operation, the intervention group was significantly better than the control group in terms of body weight, albumin, prealbumin and haemoglobin, which indicated that the nutritional status of the intervention group was better than that of the control group. The intensive care time, ventilator time and hospital stay time in the intervention group were significantly lower than those in the control group. CONCLUSION: Nutritional support plans after birth for neonates with severe congenital heart disease can effectively improve the nutritional status of patients before surgery and accelerate the speed of postoperative recovery.

Surgical experience of extracorporeal membrane oxygenation for neonates with severe respiratory failure.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) has been increasingly used for severe neonatal respiratory failure refractory to conventional treatments. This paper summarizes our operation experience of neonatal ECMO via cannulation of the internal jugular vein and carotid artery. METHODS: The clinical data of 12 neonates with severe respiratory failure who underwent ECMO via the internal jugular vein and carotid artery in our hospital from January 2021 to October 2022 were collected. RESULTS: All neonates were successfully operated on. The size of arterial intubation was 8 F, and the size of venous intubation was 10 F. The operation time was 29 (22-40) minutes. ECMO was successfully removed in 8 neonates. Surgeons successfully reconstructed the internal jugular vein and carotid artery of these neonates. Arterial blood flow was unobstructed in 5 patients, mild stenosis was present in 2 patients, and moderate stenosis was present in 1 patient. Venous blood flow was unobstructed in 6 patients, mild stenosis was present in 1 patient, and moderate stenosis was present in 1 patient. The complications were as follows: 1 case had poor neck incision healing after ECMO removal. No complications, such as incisional bleeding, incisional infection, catheter-related blood infection, cannulation accidentally pulling away, vascular laceration, thrombosis, cerebral haemorrhage, cerebral infarction, or haemolysis, occurred in any of the patients. CONCLUSION: Cannulation of the internal jugular vein and carotid artery can quickly establish effective ECMO access for neonates with severe respiratory failure. Careful, skilled and delicate operation was essential. In addition, during the cannulation process, we should pay special attention to the position of cannulation, firm fixation and strict aseptic operation.

Performance enhancement of an N-polar nitride deep-ultraviolet light-emitting diode with compositionally graded p-AlGaN.

Highly efficient hole injection into a AlGaN quantum well is desirable in nitride deep-ultraviolet light-emitting diodes (DUV LEDs) for high optical performance. In this work, we report the observation of enhanced hole injection in the N-polar AlGaN-based DUV LEDs with compositionally graded p-AlxGa1-xN (x = 0.65-0.75) by simulation and show that the enhanced hole injection leads to the increase of the peak internal quantum efficiency (IQE) and the significant reduction of efficiency droop at high current density. This work might activate researchers to realize the efficient polarization p-type doping of N-polar AlGaN with high Al content and thus to achieve high performance DUV LEDs experimentally.

Detection and Gene Mutation Analysis of Three Variations in Two Unrelated Chinese Hereditary Coagulation Factor XI Deficiency Families.

INTRODUCTION: Three variations including a novel F11 gene variation were detected in two unrelated Chinese families with coagulation factor XI deficiency, and their possible pathogenesis was elucidated. METHODS: The genomic DNA of the probands' pedigrees was extracted, and all exons and flanking sequences of F11 gene were subjected to PCR amplification and Sanger sequencing. ClustalX-2.1-win, Mutation Taster, and Swiss-Pdb Viewer software were used to analyze the conservation and impact of the variations on protein function and structure. RESULTS: DNA sequencing showed that the proband one had p.Gly350Glu and p.Trp501stop complex heterozygous variations, while the proband two took p.Pro338Leu and p.Trp501stop compound heterozygous variations. Conservation, structural, and functional analysis of variant amino acids indicated that these three variations were harmful and probably affected the structure and function of the variable protein. CONCLUSIONS: Three variations including p.Pro338Leu, p.Gly350Glu, and p.Trp501stop responsible for the reduction of the FXI activities were herein detected. Notably, the p.Pro338Leu variation was discovered for the first time in the world. Furthermore, the p.Gly350Glu was first reported in China.

Coagulopathy in cytogenetically and molecularly distinct acute leukemias at diagnosis: Comprehensive study.

We analyzed the characteristics of coagulopathy in cytogenetically and molecularly distinct acute leukemias. We retrospectively analyzed 211 adult patients with de novo non-acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML), and 105 newly diagnosed patients with B-cell acute lymphoblastic leukemia (B-ALL). Disseminated intravascular coagulation (DIC) occurrence was assessed according the International Society of Thrombosis and Haemostasis (ISTH) criteria. Further, we analyzed the associations of the cytogenetics and mutations with DIC development and coagulation profile. Significant differences were observed between APL and non-APL AML (P = 0.001), APL and B-ALL (P = 0.002), and non-APL AML and B-ALL (P = 0.009) in the distribution of ISTH DIC scores of the acute leukemia patients that met the criteria for diagnosis of DIC. Except for the elevated leukocyte count, a normal karyotype with NPM1 mutations or/and FLT3-ITD mutations was independently associated with the development of DIC in non-APL AML, characterized by significant PT prolongation and significantly elevated D-Dimers. The P210BCR-ABL1 transcript strongly predicted hypofibrinogenemia in B-ALL in the final multivariate model, but Philadelphia chromosome negatively affected elevated D-dimers. In conclusion, DIC occurrence and the coagulation profile were associated with the cytogenetics and mutations in acute leukemia.

TET2 rs2454206, TET2 rs12498609 and ASXL1 rs3746609 single nucleotide polymorphisms in patients with myelodysplastic syndromes.

To study the association between TET2rs2454206, TET2rs12498609 and ASXL1rs3746609 and Myelodysplastic syndromes (MDS), a total of 90 MDS patients and 143 healthy volunteers were included. The clinical data, bone marrow samples of patients and peripheral blood samples of volunteers were obtained. We found TET2rs2454206 G/A genotype, TET2rs12498609 G/C genotype and ASXL1rs3746609 A/G genotype in 13.3%, 11.1%, 10.1% MDS patients and in 42.7%, 22.4%, 23.8% healthy volunteers (P < 0.001; P = 0.029; P = 0.009, respectively). TET2 rs2454206 G/A genotype was associated with higher serum LDH level in MDS (P = 0.025). Patients with TET2rs12498609 G/C genotype were characterized with higher frequency of mutated SRSF2 gene (P = 0.042) and lower occurrence rate of anemia (P = 0.026) than those with C/C genotype. ASXL1rs3746609 A/G genotype linked with higher thrombocyte counts (P = 0.02) and percent of total T lymphocyte (P = 0.029), whereas with lower percent of NK cell (P = 0.032) and B lymphocyte (P = 0.007). None of these three SNPs had impact on the overall survival and disease progression to AML. We concluded that People with TET rs2454206 G/A genotype, TET2rs12498609 G/C genotype or ASXL1rs3746609 A/G genotype were related to lower prevalence of MDS. All of the three SNPs were associated with certain laboratory features in MDS patients.

The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling.

Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti-tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic.

Synthetic Polymer Affinity Ligand for Bacillus thuringiensis ( Bt) Cry1Ab/Ac Protein: The Use of Biomimicry Based on the Bt Protein-Insect Receptor Binding Mechanism.

We report a novel strategy for creating abiotic Bacillus thuringiensis ( Bt) protein affinity ligands by biomimicry of the recognition process that takes place between Bt Cry1Ab/Ac proteins and insect receptor cadherin-like Bt-R1 proteins. Guided by this strategy, a library of synthetic polymer nanoparticles (NPs) was prepared and screened for binding to three epitopes 280FRGSAQGIEGS290, 368RRPFNIGINNQQ379 and 436FRSGFSNSSVSIIR449 located in loop α8, loop 2 and loop 3 of domain II of Bt Cry1Ab/Ac proteins. A negatively charged and hydrophilic nanoparticle (NP12) was found to have high affinity to one of the epitopes, 368RRPFNIGINNQQ379. This same NP also had specific binding ability to both Bt Cry1Ab and Bt Cry1Ac, proteins that share the same epitope, but very low affinity to Bt Cry2A, Bt Cry1C and Bt Cry1F closely related proteins that lack epitope homology. To locate possible NP- Bt Cry1Ab/Ac interaction sites, NP12 was used as a competitive inhibitor to block the binding of 865NITIHITDTNNK876, a specific recognition site in insect receptor Bt-R1, to 368RRPFNIGINNQQ379. The inhibition by NP12 reached as high as 84%, indicating that NP12 binds to Bt Cry1Ab/Ac proteins mainly via 368RRPFNIGINNQQ379. This epitope region was then utilized as a "target" or "bait" for the separation and concentration of Bt Cry1Ac protein from the extract of transgenic Bt cotton leaves by NP12. This strategy, based on the antigen-receptor recognition mechanism, can be extended to other biotoxins and pathogen proteins when designing biomimic alternatives to natural protein affinity ligands.