Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Herbicide promotes the conjugative transfer of multi-resistance genes by facilitating cellular contact and plasmid transfer.

The global dissemination of antibiotic resistance genes (ARGs), especially via plasmid-mediated horizontal transfer, is becoming a pervasive health threat. While our previous study found that herbicides can accelerate the horizontal gene transfer (HGT) of ARGs in soil bacteria, the underlying mechanisms by which herbicides promote the HGT of ARGs across and within bacterial genera are still unclear. Here, the underlying mechanism associated with herbicide-promoted HGT was analyzed by detecting intracellular reactive oxygen species (ROS) production, extracellular polymeric substance composition, cell membrane integrity and proton motive force combined with genome-wide RNA sequencing. Exposure to herbicides induced a series of the above bacterial responses to promote HGT except for the ROS response, including compact cell-to-cell contact by enhancing pilus-encoded gene expression and decreasing cell surface charge, increasing cell membrane permeability, and enhancing the proton motive force, providing additional power for DNA uptake. This study provides a mechanistic understanding of the risk of bacterial resistance spread promoted by herbicides, which elucidates a new perspective on nonantibiotic agrochemical acceleration of the HGT of ARGs.

A comprehensive approach to stool donor screening for faecal microbiota transplantation in China.

BACKGROUND: Faecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium difficile infections and chronic gastrointestional infections. However, the risks of FMT and the selection process of suitable donors remain insufficiently characterized. The eligibility rate for screening, underlying microbial basis, and core ethical issues of stool donors for FMT are yet to be elucidated in China. RESULTS: The potential stool donors were screened from December 2017 to December 2019 with the help of an online survey, clinical assessments, and stool and blood testing. Bioinformatics analyses were performed, and the composition and stability of gut microbiota in stool obtained from eligible donors were dynamically observed using metagenomics. Meanwhile, we build a donor microbial evaluation index (DoMEI) for stool donor screening. In the screening process, we also focused on ethical principles and requirements. Of the 2071 participants, 66 donors were selected via the screening process (3.19% success rate). Although there were significant differences in gut microbiota among donors, we found that the changes in the gut microbiota of the same donor were typically more stable than those between donors over time. CONCLUSIONS: DoMEI provides a potential reference index for regular stool donor re-evaluation. In this retrospective study, we summarised the donor recruitment and screening procedure ensuring the safety and tolerability for FMT in China. Based on the latest advances in this field, we carried out rigorous recommendation and method which can assist stool bank and clinicians to screen eligible stool donor for FMT.

LncRNA SUMO1P3 promotes proliferation and inhibits apoptosis in colorectal cancer by epigenetically silencing CPEB3.

Colorectal cancer (CRC) is a prevalent malignancy characterized with high morbidity and death rate. Due to late diagnosis, most CRC patients missed the proper timing for radical operation, which led to the high mortality in CRC. Therefore, identifying new prognostic and therapeutic targets is important. Long non-coding RNAs are reported as essential regulators for tumor progression, including in CRC. LncRNA SUMO1P3 has been documented as an oncogene promoting proliferation, cell cycle, and metastasis in several cancers, but its role in CRC has never been unveiled. The purpose of our study is to interrogate the functions and mechanism of SUMO1P3 in colorectal cancer. We validated the upregulation and the prognostic significance of SUMO1P3 in CRC. The loss-of-function assays suggested that SUMO1P3 provoked CRC cell proliferative ability, and retarded apoptotic ability. Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been newly acknowledged as a tumor suppressive gene in several cancers, and has been revealed to present low expression in CRC. We predicted through UCSC database and validated by ChIP assay that EZH2, a crucial regulator of trimethylation of histone H3 at lysine 27 (H3K27me3), bound to CPEB3 promoter. Further, we validated that SUMO1P3 epigenetically repressed CPEB3 through EZH2. Finally, rescue assays indicated that SUMO1P3 provoked proliferation, cell cycle, and retarded apoptosis through CPEB3. Consequently, current study showed that lncRNA SUMO1P3 promoted cell proliferative ability and inhibited apoptotic ability in CRC by epigenetically silencing CPEB3, providing a novel prognostic marker for CRC patients.

Dual network composite hydrogels with robust antibacterial and antifouling capabilities for efficient wound healing.

Wound dressings play a critical role in the wound healing process; however, conventional dressings often address singular functions, lacking versatility in meeting diverse wound healing requirements. Herein, dual-network, multifunctional hydrogels (PSA/CS-GA) have been designed and synthesized through a one-pot approach. The in vitro and in vivo experiments demonstrate that the optimized hydrogels have exceptional antifouling properties, potent antibacterial effects and rapid hemostatic capabilities. Notably, in a full-thickness rat wound model, the hydrogel group displays a remarkable wound healing rate exceeding 95% on day 10, surpassing both the control group and the commercial 3M group. Furthermore, the hydrogels exert an anti-inflammatory effect by reducing inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), enhance the release of the vascular endothelial growth factor (VEGF) to promote blood vessel proliferation, and augment collagen deposition in the wound, thus effectively accelerating wound healing in vivo. These innovative hydrogels present a novel and highly effective approach to wound healing.

Isolation and Characterization of the Lytic Pseudoxanthomonas kaohsiungensi Phage PW916.

The emergence of multidrug-resistant bacterial pathogens poses a serious global health threat. While patient infections by the opportunistic human pathogen Pseudoxanthomonas spp. have been increasingly reported worldwide, no phage associated with this bacterial genus has yet been isolated and reported. In this study, we isolated and characterized the novel phage PW916 to subsequently be used to lyse the multidrug-resistant Pseudoxanthomonas kaohsiungensi which was isolated from soil samples obtained from Chongqing, China. We studied the morphological features, thermal stability, pH stability, optimal multiplicity of infection, and genomic sequence of phage PW916. Transmission electron microscopy revealed the morphology of PW916 and indicated it to belong to the Siphoviridae family, with the morphological characteristics of a rounded head and a long noncontractile tail. The optimal multiplicity of infection of PW916 was 0.1. Moreover, PW916 was found to be stable under a wide range of temperatures (4-60 °C), pH (4-11) as well as treatment with 1% (v/w) chloroform. The genome of PW916 was determined to be a circular double-stranded structure with a length of 47,760 bp, containing 64 open reading frames that encoded functional and structural proteins, while no antibiotic resistance nor virulence factor genes were detected. The genomic sequencing and phylogenetic tree analysis showed that PW916 was a novel phage belonging to the Siphoviridae family that was closely related to the Stenotrophomonas phage. This is the first study to identify a novel phage infecting the multidrug-resistant P. kaohsiungensi and the findings provide insight into the potential application of PW916 in future phage therapies.

Dynamic changes of intestinal flora in patients with irritable bowel syndrome combined with anxiety and depression after oral administration of enterobacteria capsules.

This study investigated the clinical characteristics and dynamic changes of intestinal bacterial community to evaluate the curative effect of fecal microbiota transplantation (FMT) on irritable bowel syndrome with predominant diarrhea (IBS-D) comorbid with anxiety and depression. Total two treatments were designed in randomize-controlled trial includes oral FMT capsules with 1 week (A1), 8 weeks (A2), and 12 weeks (A3), as well as oral empty capsules with 1 week (B1), 8 weeks (B2), and 12 weeks (B3) as control for comparison. The positive therapeutic effects occurred in FMT colonized patient with IBS-D comorbid psychological disorder, demonstrated at alleviated IBS-D severity (IBS-SSS score from 291.11 reduced to 144.44), altered stool type (from 6 changed to 4), reduced anxiety and depression scores (from 18.33 to 8.39 and from 22.33 to 17.78) after FMT-treated 12 weeks. The FMT therapy improved bacterial alpha diversity and the majority bacterial community predominant by Bacteroidetes and Firmicutes, and the relative abundance (RA) was higher after FMT-treated 12 weeks (50.61% and 45.52%) than control (47.62% and 38.96%). In short, FMT therapy has great potential for IBS-D patients combined with anxiety and depression by alleviated clinical symptoms and restore the intestinal micro-ecology.

Prevalence of monoclonal gammopathy of uncertain significance in chronic myeloid leukemia: A case report.

RATIONALE: The abnormal cell types in chronic myeloid leukemia (CML) and monoclonal gammopathy of uncertain (MGUS) are quite different, being myeloid and plasma cells, respectively. The coexistence of CML and MGUS is an uncommon event, which is seldom reported in literature. PATIENT CONCERNS: A 52-year-old female was diagnosed with CML in April 2001. From November 2006, the patient started on imatinib mesylate and kept a complete hematologic and cytogenetic response for nearly 11 years. During her follow-up on July 7, 2017, thrombocytopenia (35*109/L) was found. Bone marrow aspiration revealed 6% plasma cell infiltration. Serum immunoelectrophoresis revealed 1.24 g/dL of serum monoclonal (M) protein of IgG-κ type. DIAGNOSIS: MGUS was diagnosed because of absence of anemia, hypercalcemia, lytic bone lesions, or renal failure. Immune thrombocytopenia (ITP) was also diagnosed in this patient following the detection of antiplatelet autoantibodies. Complex karyotype and missense mutation in PRDM1 were identified. INTERVENTIONS: Because of her obvious decrease of platelets, she started treatment with thalidomide and prednisone. OUTCOMES: Three months later, bone marrow aspirate showed disappearance of plasma cells. There developed an abrupt decrease in IgG and the absence of M-spike in serum immunoelectrophoresis. The platelet count kept normal during 1 year follow-up. LESSONS: Karyotypic event and gene mutation found in this case may be the initiation of disease transformation. Administration of thalidomide and prednisone proved effective in this patient.

Prolyl oligopeptidase inhibitor suppresses the upregulation of ACSDKP in patients with acute myeloid leukemia.

The aim of the current study was to measure the expression of acetyl-N-Ser-Asp-Lys-Pro (ACSDKP) in patients with acute myeloid leukemia (AML) and the effect of prolyl oligopeptidase inhibitor (POPi) on the bone marrow stromal cells of these patients. Serum and bone marrow stromal cell samples were collected from 33 patients with AML admitted to Wuxi Second People's Hospital, Nanjing Medical University between September 2011 and August 2016. ACSDKP levels were measured using a highly specific competitive enzyme immunoassay (EIA). Bone marrow stromal cells were treated with synthetic ACSDKP (10 µM/ml) or different concentrations of POPi S17092 (25, 50 and 100 µg/ml). Cells that received no treatment were used as control. An MTT assay was conducted to measure the proliferation of bone marrow stromal cells. The results demonstrated that serum levels of ACSDKP in patients with AML were significantly higher than those of controls (P<0.05). Following treatment with ACSDKP, cell proliferation was significantly increased compared with untreated cells (P<0.05). However, following treatment with different concentrations of POPi, the expression of ACSDKP was significantly decreased in a dose-dependent manner (P<0.05). Furthermore, the proliferation of bone marrow stromal cells was also decreased in a dose-dependent manner. Therefore, the present study demonstrated that ACSDKP levels were increased in the serum and bone marrow stromal cells of patients with AML and that ACSDKP promoted the proliferation of bone marrow stromal cells of these patients, which was inhibited by POPi. These results may identify a novel target for the treatment of AML.

Idiopathic thrombocytopenic purpura: pathogenesis and potential therapeutic approach.

BACKGROUND: This study sought to clarify the pathogenesis of idiopathic thrombocytopenic purpura (ITP) and make preliminary investigations regarding a therapeutic approach. METHODS: Enzyme-linked immunosorbent assay was used to establish and analyze the standard curve for interferon (IFN) γ, interleukin (IL) 4, and IL-17 in order to determine a measurement method for these cytokines. Subsequently, cellular levels of IFN-γ, IL-4, and IL-17 in the peripheral blood of patients in the treatment group (traditional Chinese medicine) was compared with those in the control group (Western-style care). An ITP mice model was also established and treated with different medications. RESULTS: Th1/Th2 cell quantities in ITP patients were significantly higher than in healthy individuals (P<0.05). Furthermore, IL-17 secreted by Th17 cells was significantly higher in ITP patients than healthy individuals (P<0.01). A combination of traditional Chinese medicine and Western-style care yielded the best treatment effect for ITP mice, followed by Western medicine alone and then Chinese medicine alone. CONCLUSIONS: The experimental results suggested that Th17 cells may be more related to the pathogenesis of ITP, and that application of Western-style care supplemented by traditional Chinese medicine may yield a more optimal treatment for ITP.

Aptamers in hematological malignancies and their potential therapeutic implications.

Aptamers are short DNA/RNA oligonucleotides selected by the process called Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Due to their functional similarity to monoclonal antibodies with some superior characters, such as high specificity and affinity, flexible modification and stability, and lack of toxicity and immunogenicity, they are promising alternative and complementary targeted therapy for hematologic malignancies. The trends in aptamer technology including production, selection, modifications are briefly discussed in this review. The key aspect is to illustrate aptamers against cancer cells in hematologic malignancies especially those that have entered clinical trials. We also discuss some challenges remain in the application of aptamers.

[Clinical Comparation of Two Kinds of Chemotherapy Regimen in the Treatment of Elderly MDS Patients with AML Transformed by Abnormal Proliferation of Bone Marrow].

OBJECTIVE: To investigate the clinical efficacy and safety of "3+7" regimen and decitabine + HAG pre-excitation regimen in the treatment of elderly MDS patients with AML transformed by abnormal proliferation of bone marrow. METHODS: Fifty elderly patients with AML transformed by abnormal proliferation of bone marrow in the period from March 2012 to May 2014 were chosen and randomly divided into 2 groups including A group (25 elderly patients treated with "3+7" regimen) and B group (25 elderly patients treated with decitabine+HAG pre-excitation regimen), and the clinical effeicacy, the median survival time and the incidence of drug adverse effects in 2 groups were compared. RESULTS: The clinical total remission rate in B group was significantly higher than that in A group(P<0.05). The leukopenia time, neutropenia time and recovery time of leukocyte and neutrophilia in B group were significantly shorter than those in A group, the differences were statistically significant (P<0.05). The rate of lung infection in B group was significantly lower than that in A group. There was no significant difference in the incidence of other drug adverse effects between 2 groups(P>0.05). The life quality of patients in B group was significantly prior to patients in A group, and the difference was statistically significant (P<0.05). The average survival time and the median survival time of patients in B group was significantly longer than those in A group(P<0.05). CONCLUSION: Compared with "3+7" regimen, the decitabine+HAG pre-excitation regimen in the treatment of elderly patients with AML transformed by abnormal proliferation of bone marrow can efficiently delay the disease progression process, shorten the time of bone marrow suppression, decrease the rate of lung infection and prolong the survival time.

CD86 +1057G/A polymorphism and risk of chronic immune thrombocytopenia.

The G to A transition at position +1057 single nucleotide polymorphism site in CD86 gene results in the alanine to threonine substitution, which further affects the antigen-presenting cells' signal transduction. Thus, the purpose of this study was to determine the association between CD86 +1057G/A polymorphism and the risk for chronic immune thrombocytopenia (cITP). The CD86 +1057G/A polymorphism in 158 cITP patients and 150 healthy controls were detected by polymerase chain reaction restriction fragment length polymorphism and then confirmed by DNA sequencing. In the patients with cITP, the frequencies of GG, AG and AA genotypes and G and A alleles were 18.4%, 58.8%, 22.8%, 47.8% and 52.2%, respectively. No difference in genotype and allele frequencies was detected in total cITP patients and normal controls (p = 0.913 and 0.845, respectively). Cases were subsequently classified by age at diagnosis, gender or clinical responses to glucocorticoids, and still no obvious discrepancy of genotype and allele frequencies was found between each of the groups and normal controls. In conclusion, this study suggests that CD86 +1057G/A polymorphism may be not associated with the genetic susceptibility to cITP in a Chinese population.