When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms.

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

Leukemic transformation during anti-tuberculosis treatment in aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome: A case report and review of literature.

BACKGROUND: Accumulating evidence demonstrates that autoimmune hematopoietic failure and myeloid neoplasms have an intrinsic relationship with regard to clonal hematopoiesis and disease evolution. In approximately 10%-15% of patients with severe aplastic anemia (SAA), the disease phenotype is transformed into myeloid neoplasms following antithymocyte globulin plus cyclosporine-based immunosuppressive therapy. In some of these patients, myeloid neoplasms appear during or shortly after immunosuppressive therapy. Leukemic transformation in SAA patients during anti-tuberculosis treatment has not been reported. CASE SUMMARY: A middle-aged Chinese female had a 6-year history of non-SAA and a 2-year history of paroxysmal nocturnal hemoglobinuria (PNH). With aggravation of systemic inflammatory symptoms, severe pancytopenia developed, and her hemoglobinuria disappeared. Laboratory findings in cytological, immunological and cytogenetic analyses of bone marrow samples met the diagnostic criteria for "SAA." Definitive diagnosis of disseminated tuberculosis was made in the search for infectious niches. Remarkable improvement in hematological parameters was achieved within 1 mo of anti-tuberculosis treatment, and complete hematological remission was achieved within 4 mo of treatment. Frustratingly, the hematological response lasted for only 3 mo, and pancytopenia reemerged. At this time, cytological findings (increased bone marrow cellularity and an increased percentage of myeloblasts that accounted for 16.0% of all nucleated hematopoietic cells), immunological findings (increased percentage of cluster of differentiation 34+ cells that accounted for 12.28% of all nucleated hematopoietic cells) and molecular biological findings (identification of somatic mutations in nucleophosmin-1 and casitas B-lineage lymphoma genes) revealed that "SAA" had transformed into acute myeloid leukemia with mutated nucleophosmin-1. The transformation process suggested that the leukemic clones were preexistent but were suppressed in the PNH and SAA stages, as development of symptomatic myeloid neoplasm through acquisition and accumulation of novel oncogenic mutations is unlikely in an interval of only 7 mo. Aggravation of inflammatory stressors due to disseminated tuberculosis likely contributed to the repression of normal and leukemic hematopoiesis, and the relief of inflammatory stressors due to anti-tuberculosis treatment contributed to penetration of neoplastic hematopoiesis. The concealed leukemic clones in the SAA and PNH stages raise the possibility of an inflammatory stress-fueled antileukemic mechanism. CONCLUSION: Aggravated inflammatory stressors can repress normal and leukemic hematopoiesis, and relieved inflammatory stressors can facilitate penetration of neoplastic hematopoiesis.

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature.

BACKGROUND: Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS. CASE SUMMARY: A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode. CONCLUSION: Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia: A case report and literature review.

BACKGROUND: Myelodysplastic syndrome (MDS) is a hematological neoplasm, and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS. Low-risk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia (AA), whereas advanced MDS is characterized by a phenotype of immune exhaustion. MDS can be normo/hyperplastic or hypoplastic. Generally, bone marrow cellularity and myeloblasts increase with disease progression. Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported. CASE SUMMARY: A middle-aged Chinese woman had a 4-year history of leukocytopenia. Six months prior to admission, the patient developed gradually worsening fatigue and performance status. The leukocytopenia further progressed. She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears, an increased percentage of cluster of differentiation (CD)34+CD33+ progenitors in immunotyping analysis, a normal karyotype in cytogenetic analysis, and the identification of somatic mutations in CBL, KMT2D and NF1 in molecular analysis. Initially, neutropenia was the predominant hematological abnormality, with mild anemia and thrombocytosis, and the degree of fatigue was far more severe than the degree of anemia. In the following months, the patient experienced several febrile episodes. Intravenous antibiotic treatments were able to control the febrile episodes, but the elevated inflammatory indices persisted. The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes. With recurrent flares of the inflammatory condition, agranulocytosis and severe anemia developed, with mild thrombocytopenia. During the patient's hospitalization, computed tomography (CT) scans revealed the presence of extensive inflammatory lesions involving the lungs, mediastinum, pleura, gastrointestinal tract, peritoneum and urinary tract, with imaging features suggestive of the reactivation of disseminated tuberculosis. Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic, and the leukemic cells regressed, suggesting that both normal and leukemic hematopoiesis had been heavily suppressed. Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+ cells and an immunological signature resembling that of severe AA (SAA), confirming the regression of the leukemic cells by autoimmune-mediated attacks. The patient demonstrated resistance to multiple drugs, including antituberculotics, recombinant human granulocyte colony-stimulating factor, broad-spectrum antibiotics, voriconazole, ganciclovir, immune suppressants, eltrombopag and intravenous immunoglobulin, which further worsened the hematological injury and patient's performance status. The patient eventually died of overwhelming infection and multidrug resistance. CONCLUSION: Advanced MDS can transform to aplastic cytopenia with leukemic cell regression and an immunological signature of SAA during inflammatory flare-ups.

A solvent-template ethyl cellulose-polydimethylsiloxane crosslinking sponge for rapid and efficient oil adsorption.

Lipophilic adsorbents for oil-water separation are usually synthesized using the template method, in which hydrophobic materials are coated on a ready-made sponge. Herein, a novel solvent-template technique is used to directly synthesize a hydrophobic sponge, by crosslinking polydimethylsiloxane (PDMS) with ethyl cellulose (EC) which plays a vital role in the formation of 3D porous structure. The as-prepared sponge has advantages of strong hydrophobility, high elasticity, as well as excellent adsorption performance. In addition, the sponge can be readily decorated by nano-coatings. After the sponge was simply dipped in nanosilica, the water contact angle increases from 139.2° to 144.5°, and the maximum adsorption capacity for chiroform rises from 25.6 g/g to 35.4 g/g. The adsorption equilibrium can be reached within 3 min, and, the sponge can be regenerated by squeezing, without any change in hydrophobility or evident decline in capacity. The simulation tests of emulsion separation and oil-spill cleanup demonstrate that the sponge has great potential in oil-water separation.

Sexual Dimorphism in Brain Sirtuin-1 and m6A Methylated Sirtuin-1 mRNA, and in Protection with Post-Injury Anti-miR-200c treatment, after Experimental Stroke in Aged Mice.

We previously demonstrated that inhibition of miR-200c was protective against stroke in young adult male mice by augmenting sirtuin-1 (Sirt1). In the present study we assessed the role of miR-200c on injury, Sirt1, and bioenergetic and neuroinflammatory markers in aged male and female mice after experimental stroke. Mice were subjected to 1hr of transient middle cerebral artery occlusion (MCAO) and assessed for post-injury expression of miR-200c, Sirt1 protein and mRNA, N6-methyladenosine (m6A) methylated Sirt1 mRNA, ATP, cytochrome C oxidase activity, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), infarct volume and motor function. MCAO induced a decrease in Sirt1 expression at 1d post-injury only in males. No differences in SIRT1 mRNA were observed between the sexes. Females had greater baseline miR-200c expression and a greater increase in miR-200c in response to stroke, while pre-MCAO levels of m6A SIRT1 was greater in females. Males had lower post-MCAO ATP levels and cytochrome C oxidase activity, and higher TNFα and IL-6. Post-injury intravenous treatment with anti-miR-200c reduced miR-200c expression in both sexes. In males, anti-miR-200c increased Sirt1 protein expression, reduced infarct volume, and improved neurological score. Conversely in females anti-miR-200c had no effect on Sirt1 levels and provided no protection against injury from MCAO. These results provide the first evidence of sexual dimorphism in the role of a microRNA in aged mice after experimental stroke and suggest sex-differences in epigenetic modulation of the transcriptome and downstream effects on miR biological activity may play a role in sexually dimorphic outcomes after stroke in aged brains.

Comprehensively prognostic and immunological analysis of snail family transcriptional repressor 2 in pan-cancer and identification in pancreatic carcinoma.

Background: Snail family transcriptional repressor 2 (SNAI2) is a transcription factor that induces epithelial to mesenchymal transition in neoplastic epithelial cells. It is closely related to the progression of various malignancies. However, the significance of SNAI2 in human pan-cancer is still largely unknown. Methods: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were taken to examine the SNAI2 expression pattern in tissues and cancer cells. The link between SNAI2 gene expression levels and prognosis, as well as immune cell infiltration, was investigated using the Kaplan-Meier technique and Spearman correlation analysis. We also explored the expression and distribution of SNAI2 in various tumor tissues and cells by the THPA (Human Protein Atlas) database. We further investigated the relationship between SNAI2 expression levels and immunotherapy response in various clinical immunotherapy cohorts. Finally, the immunoblot was used to quantify the SNAI2 expression levels, and the proliferative and invasive ability of pancreatic cancer cells was determined by colony formation and transwell assays. Results: We discovered heterogeneity in SNAI2 expression in different tumor tissues and cancer cell lines by exploring public datasets. The genomic alteration of SNAI2 existed in most cancers. Also, SNAI2 exhibits prognosis predictive ability in various cancers. SNAI2 was significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations, and immunoregulators. It's worth noting that SNAI2 expression is significantly related to the effectiveness of clinical immunotherapy. SNAI2 expression was also found to have a high correlation with the DNA mismatch repair (MMR) genes and DNA methylation in many cancers. Finally, the knockdown of SNAI2 significantly weakened the proliferative and invasive ability of pancreatic cancer cells. Conclusion: These findings suggested that SNAI2 could be used as a biomarker in human pan-cancer to detect immune infiltration and poor prognosis, which provides a new idea for cancer treatment.

Delineating Visual Habituation Profiles in Preschoolers with Neurofibromatosis Type 1 and Autism Spectrum Disorder: A Cross-Syndrome Study.

Atypical habituation to repetitive information has been commonly reported in Autism Spectrum Disorder (ASD) but it is not yet clear whether similar abnormalities are present in Neurofibromatosis Type 1 (NF1). We employed a cross-syndrome design using a novel eye tracking paradigm to measure habituation in preschoolers with NF1, children with idiopathic ASD and typically developing (TD) children. Eye movements were recorded to examine fixation duration to simultaneously presented repeating and novel stimuli. Children with NF1 showed a bias for longer look durations to repeating stimuli at the expense of novel stimuli, and slower habituation in NF1 was associated with elevated ASD traits. These findings could indicate aberrant modulation of bottom-up attentional networks that interact with the emergence of ASD phenotypes.

Glucocorticoid-induced thrombotic microangiopathy in paroxysmal nocturnal hemoglobinuria: A case report and review of literature.

BACKGROUND: Thrombotic microangiopathy (TMA) is a group of disorders that converge on excessive platelet aggregation in the microvasculature, leading to consumptive thrombocytopenia, microangiopathic hemolysis and ischemic end-organ dysfunction. In predisposed patients, TMA can be triggered by many environmental factors. Glucocorticoids (GCs) can compromise the vascular endothelium. However, GC-associated TMA has rarely been reported, which may be due to the lack of awareness of clinicians. Given the high frequency of thrombocytopenia during GC treatment, particular attention should be given to this potentially fatal complication. CASE SUMMARY: An elderly Chinese man had a 12-year history of aplastic anemia (AA) and a 3-year history of paroxysmal nocturnal hemoglobinuria (PNH). Three months earlier, methylprednisolone treatment was initiated at 8 mg/d and increased to 20 mg/d to alleviate complement-mediated hemolysis. Following GC treatment, his platelet counts and hemoglobin levels rapidly decreased. After admission to our hospital, the dose of methylprednisolone was increased to 60 mg/d in an attempt to enhance the suppressive effect. However, increasing the GC dose did not alleviate hemolysis, and his cytopenia worsened. Morphological evaluation of the marrow smears revealed increased cellularity with an increased percentage of erythroid progenitors without evident dysplasia. Cluster of differentiation (CD)55 and CD59 expression was significantly decreased on erythrocytes and granulocytes. In the following days, platelet transfusion was required due to severe thrombocytopenia. Observation of platelet transfusion refractoriness indicated that the exacerbated cytopenia may have been caused by the development of TMA due to GC treatment because the transfused platelet concentrates had no defects in glycosylphosphatidylinositol-anchored proteins. We examined blood smears and found a small number of schistocytes, dacryocytes, acanthocytes and target cells. Discontinuation of GC treatment resulted in rapidly increased platelet counts and steady increases in hemoglobin levels. The patient's platelet counts and hemoglobin levels returned to the levels prior to GC treatment 4 weeks after GC discontinuation. CONCLUSION: GCs can drive TMA episodes. When thrombocytopenia occurs during GC treatment, TMA should be considered, and GCs should be discontinued.

Antibiotic and glucocorticoid-induced recapitulated hematological remission in acute myeloid leukemia: A case report and review of literature.

BACKGROUND: Leukemic hematopoietic cells acquire enhanced self-renewal capacity and impaired differentiation. The emergence of symptomatic leukemia also requires the acquisition of a clonal proliferative advantage. Untreated leukemia patients usually experience an aggressive process. However, spontaneous remission occasionally occurs in patients with acute myeloid leukemia (AML), most frequently after recovery from a febrile episode, and this is generally attributed to the triggering of antineoplastic immunity. There may be another explanation for the spontaneous remission as implicated in this paper. CASE SUMMARY: A 63-year-old Chinese man presented with high fever, abdominal pain and urticaria-like skin lesions. He was diagnosed with AML-M4 with t(8;21) (q22;q22)/RUNX1-RUNX1T1 based on morphological, immunological, cytogenetic and molecular analyses. He had a complex chromosome rea-rrangement of 48,XY,t(8;21)(q22;q22),+13,+13[9]/49,idem,+mar[9]/49,idem,+8[2]. He also had a mutated tyrosine kinase domain in fms-like tyrosine kinase 3 gene. He was treated with antibiotics and glucocorticoids for gastrointestinal infection and urticaria-like skin lesions. The infection and skin lesions were quickly resolved. Unexpectedly, he achieved hematological remission along with resolution of the febrile episode, gastrointestinal symptoms and skin lesions. Notably, after relapse, repeating these treatments resulted in a return to hematological remission. Unfortunately, he demonstrated strong resistance to antibiotic and glucocorticoid treatment after the second relapse and died of sepsis from bacterial infection with multidrug resistance. The main clinical feature of this patient was that symptomatic AML emerged with flaring of the gut inflammatory disorder and it subsided after resolution of the inflammation. Learning from the present case raises the possibility that in a subgroup of AML patients, the proliferative advantage of leukemia cells may critically require the presence of inflammatory stresses. CONCLUSION: Inflammatory stresses, most likely arising from gastrointestinal infection, may sustain the growth and survival advantage of leukemic cells.

TNF-α (G308A) Polymorphism and Vascular Parkinson Complicated with Pulmonary Infection.

OBJECTIVE: To analyse relationship between tumour necrosis factor-α (TNF-α) (G308A) polymorphism and Vascular Parkinson (VP) complicated with pulmonary infection. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Zhuji people's Hospital, China, from February 2017 to April 2021. METHODOLOGY: Eighty five patients with VP complicated with pulmonary infection were included in the observation group. Eighty five patients with VP were included in the comparison group. Genotypic analysis of TNF-α (G308A) and serum TNF-α were detected. RESULTS: TNF-α (G308A) polymorphism in both the observation group and control group conformed to the genetic balance rule by the Hardy-Weinberg test. The frequency of each gene satisfied the genetic balance (p=0.175, and p=0.184, respectively). Genotype distribution and alleles of TNF-α (G308A) between the observation group and the control group were different (both p <0.001). Compared with control group, serum TNF-α level in the observation group was higher (p <0.001). In the observation group, serum TNF-α level in cases with GA+AA genotype (carrying A allele) was higher than that in cases with GG genotype (non A allele) (p <0.001). CONCLUSION: TNF-α (G308A) polymorphism is associated with VP complicated with pulmonary infection. VP Patients with TNF-α (G308A) AA genotype and an allele may have a high risk of pulmonary infection. KEY WORDS: Tumor necrosis factor-α (TNF-α), Polymorphism, Vascular Parkinson (VP), Pulmonary infection.

Isolation and Characterization of Germline Stem Cells in Protogynous Hermaphroditic Monopterus albus.

Germline stem cells (GSCs) are a group of unique adult stem cells in gonads that act as important transmitters for genetic information. Donor GSCs have been used to produce offspring by transplantation in fisheries. In this study, we successfully isolated and enriched GSCs from the ovary, ovotestis, and testis of Monopterus albus, one of the most important breeding freshwater fishes in China. Transcriptome comparison assay suggests that a distinct molecular signature exists in each type of GSC, and that different signaling activities are required for the maintenance of distinct GSCs. Functional analysis shows that fGSCs can successfully colonize and contribute to the germline cell lineage of a host zebrafish gonad after transplantation. Finally, we describe a simple feeder-free method for the isolation and enrichment of GSCs that can contribute to the germline cell lineage of zebrafish embryos and generate the germline chimeras after transplantation.

Cadherin-dependent adhesion modulated 3D cell-assembly.

The emergence of synthetic biology has opened new avenues in constructing cell-assembly biosystems with specific gene expression and function. The phenomena of cell spreading and detachment during tissue development and cancer metastasis are caused by surface tension, which in turn results from differences in cell-cell adhesion mediated by the dimerization of cadherin expressed on the cell surface. In this study, E- and P-cadherin plasmids were first constructed based on the differential adhesion hypothesis, then they were electroporated into K562 cells and HEK293T cells, respectively, to explore the process of cell migration and assembly regulated by cadherins. Using this approach, some special 3D cell functional components with a phase separation structure were fabricated successfully. Our work will be of potential application in the construction of self-assembling synthetic tissues and organoids.

Recent advances in the rapid detection of microRNA with lateral flow assays.

MicroRNAs (miRNA) are a kind of endogenous non-coding small molecule RNA, which are widely found in plants, animals, and viruses. miRNA can regulate the post-transcriptional cleavage of target message RNA or inhibit its translation process, and plays an important regulatory role in gene expression. Further studies have shown that miRNAs also play an important role in tumorigenesis and host-pathogen interactions. Given the important contribution of miRNAs in gene regulation and biological functions, rapid and accurate detection of miRNAs has become increasingly significant. Lateral flow assay is a detection method derived to achieve rapid detection in the field. It overcomes the problems of cumbersome, time-consuming, and high cost in traditional detection methods, and provides a good platform for accurate, sensitive, and immediate detection of target analytes. With the advantages convenient, cost-saving, and repaid result readout, the lateral flow test strips are now a recognized point-of-care testing (POCT) device and has been widely used in medical diagnosis, agriculture, food, and environmental safety. For the first time, we summarized the research progress of miRNA detection based on lateral flow methods, focusing on the strategies used in the lateral flow assays for miRNA detection and introducing some main experimental operation details, as well as providing an outlook on the future development direction of this field, aiming to provide a general guidance for colleagues preparing to conduct related research.

Combination of monoammonium glycyrrhizinate and cysteine hydrochloride protects mice against acetaminophen-induced liver injury via Keap1/Nrf2/ARE pathway.

OBJECTIVES: Acetaminophen (APAP) overdose has been the primary cause of drug-induced liver injury (DILI) in western countries. Monoammonium glycyrrhizinate (MG) is a primary active ingredient from glycyrrhiza. Cysteine hydrochloride (CH) is a component of glutathione (GSH). The study aimed to explore the therapeutical effect of MG-CH against DILI incurred by intragastric APAP. METHODS: Mice were randomized into eight groups: control, APAP, three groups accepted APAP and the combination of MG and CH (15, 30, 60 mg/kg), two groups accepted APAP and MG (40 mg/kg) or CH (20 mg/kg), moreover, one group received MG-CH (60 mg/kg) without APAP. After pretreatment with MG-CH or MG and CH alone for 3 days, mice were administered APAP by oral gavage. The serum and tissue were collected to detect the activities of liver enzymes and evaluate the change of histomorphology and explore the possible mechanism of MG-CH in protecting against DILI. KEY FINDINGS: MG-CH pretreatment remarkably alleviated hepatic injury and decreased the activities of ALT, AST, ALP and LDH. The hepatic ROS and MDA contents were decreased, and the level of GSH and GSH-PX activities was increased in the serum. Furthermore, MG-CH improved the expression of Nrf2, HO-1, GCLM and NQO1 to increase antioxidant ability and induce detoxification. The expression of IL-10 suppressing excessive inflammatory responses was enhanced. CONCLUSION: The study demonstrated that MG-CH had protective effects against DILI induced by APAP and the potential mechanisms were based on inhibiting oxidative stress and activating the Keap1/Nrf2/ARE pathway.

Frailty is an independent risk factor of one-year mortality after elective orthopedic surgery: a prospective cohort study.

Frailty is associated with perioperative adverse outcomes, especially for the elderly. This study aimed to assess whether frailty was an independent risk factor of one-year mortality in frail patients after elective orthopedic surgery. In this prospective study, three hundred and thirteen patients aged ≥ 65 years, undergoing elective orthopedic surgery were finally included. Frailty assessed by the Clinical Frailty Score (CFS) before the surgery was present in 29.7% (93/313). Among them, 7.7% of patients (24/313) died at one year after surgery. In multivariate logistic analysis, higher CFS (OR = 2.271, 95% CI= 1.472-3.504) was found to be an independent risk factor of one-year mortality after surgery in elderly orthopedic patients. The area under the receiver operating characteristic curve of the model was 0.897 (95% CI 0.834-0.959). In addition, we found higher Charlson comorbidity index (OR= 1.498, 95% CI = 1.082-2.073) was also a significant risk factor. In conclusion, frailty is associated with increased one-year mortality in elderly patients after elective orthopedic surgery, which should be considered as a routine assessment tool in preoperative practice.

Acquired aplastic anemia: Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

ADNP Controls Gene Expression Through Local Chromatin Architecture by Association With BRG1 and CHD4.

ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to rare neural developmental disorders and cancers, including the recently described neurodevelopmental Helsmoortel-Van der Aa syndrome. Recent studies have suggested that ADNP functions as an important chromatin regulator. However, how ADNP-regulated chromatin mechanisms control gene expression and stem cell fate commitment remains unclear. Here we show that ADNP interacts with two chromatin remodelers, BRG1 and CHD4. ADNP is required for proper establishment of chromatin accessibility, nucleosome configuration, and bivalent histone modifications of developmental genes. Loss of ADNP leads to enhancer over-activation and increased ratio of H3K4me3/H3K27me3 at key primitive endoderm (PrE) gene promoters, resulting in prominent up-regulation of these genes and priming ES cell differentiation toward endodermal cell types. Thus, our work revealed a key role of ADNP in the establishment of local chromatin landscape and structure of developmental genes by association with BRG1 and CHD4. These findings provide further insights into the role of ADNP in the pathology of the Helsmoortel-Van der Aa syndrome.

The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States.

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins-whose aberrant activities govern the reprogramed state of coronavirus-infected cells-presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.

Combination of monoammonium glycyrrhizinate and cysteine hydrochloride ameliorated lipopolysaccharide/galactosamine-induced acute liver injury through Nrf2/ARE pathway.

Combination of monoammonium glycyrrhizinate and cysteine hydrochloride (MG-CH) has been used for treatment of chronic liver damage in clinic for several years, however, the effect of MG-CH on acute liver injury (ALI) is still obscure. In this study, we aimed to investigate the effect of MG-CH on ALI induced by co-injection of lipopolysaccharide (LPS) and d-galactosamine (GalN). Our results found that MG-CH produced the optimal therapeutic effect at the ratio of 2:1, as manifested by the increased survival percentage, decreased ALT and AST level and improved hepatic pathology. Both oxidative stress and inflammation induced by LPS/GalN were attenuated by MG-CH. Mechanism study showed that MG-CH promoted the nuclear accumulation of Nrf2 and its transcriptional activity, as well as improved Nrf2-target genes' expression. It was also found that activation of Nrf2 is dependent on the MG, not CH. Blockade of Nrf2 abolished the anti-inflammatory effect of MG-CHinduced by LPS/GalN, while inhibition of NFκB showed no effect on its anti-oxidative effect, though the inhibited phosphorylation of IκB and NFκB were detected in liver. The protective effect of MG-CH against ALI was abolished in Nrf2-/- mice. All of these results suggested that MG-CH ameliorated LPS/GalN induced ALI through Nrf2/ARE pathway.