The Chaperone Protein Cct5 is Essential for Hematopoietic Stem Cell Maintenance.

Proper proteostasis is indispensable for the long-term maintenance of hematopoietic stem and progenitor cells (HSPCs). The TRiC/CCT (chaperonin-containing TCP-1) complex, a key constituent of cellular machinery facilitating accurate protein folding, has remained enigmatic in its specific function within HSPCs. Here we show that conditional knockout (KO) of Cct5 significantly impairs the maintenance of murine HSPCs. Primary and secondary transplantation experiments unequivocally demonstrate the incapacity of Cct5 KO HSPCs to reconstitute both myeloid and lymphoid lineage cells in recipient mice, highlighting the pivotal role of the TRiC/CCT complex in governing these cellular lineages. Furthermore, leveraging an integrated approach that merges a Protein-Protein Interaction (PPI) database with RNA sequencing (RNA-seq) data of HSPCs, our analysis reveals intricate interactions between Cct5 and vital transcription factors crucial for HSC homeostasis. Notably, Cct5 engages with MYC, PIAS1, TP53, ESR1, HOXA1, and JUN, intricately regulating the transcriptional landscape governing autophagy, myeloid differentiation, and cytoskeleton organization within HSPCs. Our study unveils the profound significance of TRiC/CCT complex-mediated proteostasis in orchestrating the maintenance and functionality of HSPCs.

Comparative analysis of hypomethylating agents as maintenance therapy after allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia.

We retrospectively analyzed the outcomes of 136 consecutive patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center. Among them, 76 cases used hypomethylating agents (decitabine, n = 40; azacitidine, n = 36) as post-transplant maintenance therapy, whereas 60 contemporaneous patients did not adopt maintenance therapy. The 3-year incidences of relapse in two groups were 16.6% and 39.2% (p = .001). The 3-year OS and DFS in maintenance group were 84.0% and 78.6%, which were remarkably improved than in control group (60.0% and 58.0%) (p = .004, p = .011). Moreover, the 3-year relapse rates for patients receiving decitabine and azacitidine therapy were 8.5% and 25.0%, respectively (p = .019). Patients utilizing decitabine had more common possibility of grade 3-4 neutropenia than azacitidine (20.0% vs. 2.8%, p = .031). These results indicate that maintenance therapies using hypomethylating agents could reduce the risk of post-transplant recurrence, resulting into remarkable superior survival. Decitabine might lower relapse after allo-HSCT with somewhat more severe myelosuppression when being compared to azacitidine.

Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH.

OBJECTIVE: Heterozygous loss-of-function variants in the NPR2 gene cause short stature with nonspecific skeletal abnormalities and account for about 2 ~ 6% of idiopathic short stature. This study aimed to analyze and identify pathogenic variants in the NPR2 gene and explore the therapeutic response to recombinant growth hormone (rhGH). METHODS: NPR2 was sequenced in three Chinese Han patients with short stature via exome sequencing. In vitro functional experiments, homology modeling and molecular docking analysis of variants were performed to examine putative protein changes and the pathogenicity of the variants. RESULT: Three patients received rhGH therapy for two years, and two NPR2 heterozygous variants were identified in three unrelated cases: c.1579 C > T,p.Leu527Phe in patient 1 and c.2842dupC,p.His948Profs*5 in patient 2. Subsequently, a small gene model was constructed, and transcriptional analysis of the synonymous variant (c.2643G > A) was performed in patient 3, which revealed the deletion of exon 17 and the premature formation of a stop codon (p.His840Gln*). Functional studies showed that both NPR2 variants, His948Profs*5 and His840Gln*, failed to produce cGMP in the homozygous state. Furthermore, the Leu527Phe variant of NPR2 was almost unresponsive to the stimulatory effect of ATP on CNP-dependent guanylyl cyclase activity. This loss of response to ATP has not been previously reported. The average age of patients at the start of treatment was 6.5 ± 1.8 years old, and their height increased by 1.59 ± 0.1 standard deviation score after 2 years of treatment. CONCLUSION: In this report, two novel variants in NPR2 gene were described. Our findings broaden the genotypic spectrum of NPR2 variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients.

Comparative transcriptomics provides insights into the pathogenic immune response of brown leaf spots in weeping forsythia.

Weeping forsythia is an important ornamental, ecological and medicinal plant. Brown leaf spots limit the large-scale production of weeping forsythia as a medicinal crop. Alternaria alternata is a pathogen causing brown leaf spots in weeping forsythia; however, its pathogenesis and the immune response mechanisms of weeping forsythia remain unclear. In this study, we identified two mechanisms based on morphological anatomy, physiological indexes and gene expression analyses. Our results showed that A. alternata induced leaf stomata to open, invaded the mesophyll, dissolved the cell wall, destroyed the cell membrane and decreased the number of chloroplasts by up-regulating the expression of auxin-activated signaling pathway genes. Alternaria alternata also down-regulated iron-ion homeostasis and binding-related genes, which caused an increase in the levels of iron ions and reactive oxygen species in leaves. These processes eventually led to programmed cell death, destroying palisade and spongy tissues and causing the formation of iron rust spots. Alternaria alternata also caused defense and hypersensitive responses in weeping forsythia through signaling pathways mediated by flg22-like and elf18-like polypeptides, ethylene, H2O2 and bacterial secretion systems. Our study provides a theoretical basis for the control of brown leaf spots in weeping forsythia.

Bacteroides vulgatus attenuates experimental mice colitis through modulating gut microbiota and immune responses.

Introduction: Bacteroides vulgatus is one of the predominant Bacteroides species in the human gut and exerts a series of beneficial effects. The aim of this study was to investigate the protective role of B. vulgatus Bv46 in a dextran sodium sulfate (DSS) induced colitis mouse model. Methods: Female C57BL/6J mice were given 3% DSS in drinking water to induce colitis and simultaneously treated with B. vulgatus Bv46 by gavage for 7 days. Daily weight and disease activity index (DAI) of mice were recorded, and the colon length and histological changes were evaluated. The effects of B. vulgatus Bv46 on gut microbiota composition, fecal short chain fatty acids (SCFAs) concentration, transcriptome of colon, colonic cytokine level and cytokine secretion of RAW 264·7 macrophage cell line activated by the lipopolysaccharide (LPS) were assessed. Results and Discussion: B. vulgatus Bv46 significantly attenuated symptoms of DSS-induced colitis in mice, including reduced DAI, prevented colon shortening, and alleviated colon histopathological damage. B. vulgatus Bv46 modified the gut microbiota community of colitis mice and observably increased the abundance of Parabacteroides, Bacteroides, Anaerotignum and Alistipes at the genus level. In addition, B. vulgatus Bv46 treatment decreased the expression of colonic TNF-α, IL-1ß and IL-6 in DSS-induced mouse colitis in vivo, reduced the secretion of TNF-α, IL-1ß and IL-6 in macrophages stimulated by LPS in vitro, and downregulated the expression of Ccl19, Cd19, Cd22, Cd40 and Cxcr5 genes in mice colon, which mainly participate in the regulation of B cell responses. Furthermore, oral administration of B. vulgatus Bv46 notably increased the contents of fecal SCFAs, especially butyric acid and propionic acid, which may contribute to the anti-inflammatory effect of B. vulgatus Bv46. Supplementation with B. vulgatus Bv46 serves as a promising strategy for the prevention of colitis.

Prognostic prediction of novel risk scores (AML-DRG and AML-HCT-CR) in acute myeloid leukemia patients with allogeneic hematopoietic stem cell transplantation.

We aimed to validate and prove the novel risk score models of acute myeloid leukemia (AML)-specific disease risk group (AML-DRG) and AML-Hematopoietic Cell Transplant-composite risk (AML-HCT-CR) in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (AHCT). Among the 172 AML patients analysed, 48.3% (n = 83) were females. Median age was 31.5 years (range 14 to 62 years), two patients was more than 60 years old (1.2%). Median follow-up was 44 months (range 1 to 94 months). According to the AML-DRG model, 109, 49 and 14 patients were in low-, intermediate- and high-risk group, respectively. According to the AML-HCT-CR model, 108, 30, 20 and 14 patients were in low-, intermediate-, high- and very high-risk group, respectively. Our results showed that the AML-DRG and AML-HCT-CR models significantly predicted cumulative incidence of relapse (p < 0.001; p < 0.001). But AML-DRG model was not associated with NRM (p = 0.072). Univariate analysis showed that the AML-DRG model could better stratify AML patients into different risk groups compared to the AML-HCT-CR model. Multivariate analysis confirmed that prognostic impact of AML-DRG and AML-HCT-CR models on post-transplant OS was independent to age, sex, conditioning type, transplant modality, and stem cell source (p < 0.001; p < 0.001). AML-DRG and AML-HCT-CR models can be used to effectively predict post-transplant survival in patients with AML receiving AHCT. Compared to AML-HCT-CR score, the AML-DRG score allows better stratification and improved survival prediction of AML patients post-transplant.

Active Screening of Intestinal Colonization of Carbapenem-Resistant Enterobacteriaceae for Subsequent Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplantation.

Purpose: To investigate the prevalence, risk factors of intestinal carbapenem-resistant Enterobacteriaceae (CRE) colonization and bloodstream infection (BSI) caused by CRE in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: We analyzed the clinical data of 185 patients with hematological malignancies who underwent allo-HSCT from May 2019 to December 2021. All patients received regular CRE monitoring by rectal swab during allo-HSCT, and some CRE strains were further identified for carbapenemase phenotypes. The rates, distribution and risk factors of CRE colonization, CRE-induced BSI were analyzed. Results: CRE was detected in 44 of 185 recipients, with colonization rate of 23.8%. A total of 46 strains of CRE were isolated, including 22 Escherichia coli, 17 Klebsiella pneumoniae, three Klebsiella oxytoca, two Enterobacter hormaechei, and two other Enterobacteriaceae. Among the 19 strains identified with carbapenemase phenotypes, eight strains of E. coli produced metal ß-lactamase, five K. pneumoniae produced serine carbapenemase, two K. pneumoniae produced metal ß-lactamase, two K. oxytoca produced metal ß-lactamase, a Citrobacter malonic acid-free produced metal ß-lactamase and a Citrobacter freundii produced metal ß-lactamase. In 10 patients developed with CRE-related BSI, the types and combined drug sensitivity of strains detected by rectal swab were highly consistent with blood culture. Multivariate analysis revealed that pulmonary infection, perianal infection and carbapenem application in the 3 months pre-transplant were independent risk factors for rectal CRE colonization, while rectal colonization with carbapenem-resistant K. pneumoniae (CR-KP) was an independent risk factor for CRE-induced BSI. The mortality rate within 30 days of CRE-related BSI was 50.0%, and patients receiving multi-drug therapy within 24 hours showed slightly lower mortality than that in the single-drug treatment group. Conclusion: Allo-HSCT patients with CRE-induced BSI have poor prognosis, and CR-KP rectal colonization is an independent risk factor for CRE-related BSI. Rectal swab screening during allo-HSCT could provide early warning for later CRE-induced BSI.

Invasive Pulmonary Aspergillosis Diagnosis via Peripheral Blood Metagenomic Next-Generation Sequencing.

Invasive pulmonary aspergillosis (IPA) is one of the major causes of morbidity and mortality in immunocompromised patients such as hematological malignancies, hematopoietic stem cell transplantation, and solid organ transplantation. The diagnosis of IPA in these patients is still difficult because it has no obvious specificity in clinical symptoms, signs and imaging, and test sensitivity of blood 1,3-ß-d-glucan test, galactomannan are low. Therefore, we still need to explore more diagnostic methods. In our study, via peripheral blood metagenomic next-generation sequencing (mNGS), five patients were tested positive for Aspergillus DNA and then quickly diagnosed as IPA. Out of the 5 cases, 1 was proven and 4 were probable IPA. The underlying diseases of the 5 patients were myelodysplastic syndrome (2 cases), acute myeloid leukemia (2 cases), and renal transplantation (1 case). Then they were diagnosed as IPA using other methods such as lung histopathology, bronchoalveolar lavage fluid (BALF) mNGS, and sputum culture or sputum mNGS. In case 1, sputum culture suggested Aspergillus flavus. In case 2, both Grocott methenamine silver (GMS) stain of lung histopathology and lung tissue mNGS suggested Aspergillus infection. In cases 3 and 4, BALF-mNGS suggested Aspergillus infection. In case 5, sputum mNGS suggested Aspergillus infection. In conclusion, detecting the cfDNA of Aspergillus via peripheral blood mNGS can be used to diagnose IPA and is a rapid and non-invasive diagnosis method.

Evaluation of Diffuse Bone Marrow Infiltration Pattern in Monoclonal Plasma Cell Diseases by Quantitative Whole-body Magnetic Resonance Imaging.

RATIONALE AND OBJECTIVES: To analyze diffuse infiltration pattern in monoclonal plasma cell diseases by diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) and quantitative chemical-shift encoded MRI. MATERIALS AND METHODS: Ninety-nine patients with monoclonal plasma cell diseases and 15 healthy control subjects were retrospectively analyzed. All patients underwent whole-body MRI (including DWIBS and mDIXON Quant) and were divided into three groups: monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM). Apparent diffusion coefficient (ADC), fat fraction (FF), and T2* values for each group were calculated then analyzed by one-way ANOVA and receiver operating characteristic curve. Correlations of ADC, FF, and T2* with clinical indices were analyzed with Spearman correlation test. RESULTS: The ADC and T2* values of MM were significantly higher than those of the healthy control, MGUS and SMM (ADC: p = 0.003, p = 0.003, and p = 0.042; T2*: all with p < 0.001). The FF values of MM were significantly lower than those of the healthy control, MGUS and SMM (p < 0.001, p < 0.001 and p = 0.034). The ADC, FF, and T2* thresholds for recognizing MM and MGUS+SMM were 0.51 × 10-3 mm2/s, 31.14%, and 10.53 ms, respectively. The ADC, FF, and T2* values were identified to be significantly associated with bone marrow plasma cells and hemoglobin in patients (all with p < 0.001). CONCLUSION: ADC, FF, and T2* were significantly correlated with clinical indices related to monoclonal plasma cell diseases. MM with the diffuse infiltration pattern can be distinguished more objectively from MGUS and SMM by quantitative functional MRI parameters.

Donor cell leukemia/myelodysplastic syndrome after allogeneic stem cell transplantation: a rare phenomenon with more challenges for hematologists.

Donor cell leukemia (DCL) or Donor cell myelodysplastic syndrome (DC-MDS) is a rare type of leukemia or MDS and originates from the donor cells. It has very low frequency, but it seems to be steadily increasing as the physiopathology and mechanisms remain largely unknown. Here we report one case of acute lymphocytic leukemia (ALL) and one case of MDS of donor origin after allogeneic hematopoietic stem cell transplantation (HSCT). We also collated and reviewed literatures regarding DCL, and discuss the morbidity of DCL, the methods used to confirm donor origin and the etiology and pathogenesis of DCL. A new proposed theory will help us to better understand the mechanism for the oncogenesis of DCL.

Quantitative whole-body MR imaging for assessment of tumor burden in patients with multiple myeloma: correlation with prognostic biomarkers.

BACKGROUND: To assess the quantification of tumor burden in multiple myeloma (MM) patients using whole-body magnetic resonance imaging (MRI) and to identify the correlation between MRI parameters and prognostic biomarkers. METHODS: We retrospectively analyzed 95 newly diagnosed MM patients treated at our hospital from June 2018 to March 2020. All patients underwent whole-body MRI examination, including diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), modified Dixon chemical-shift imaging (mDIXON), and short TI inversion recovery (STIR) sequences. The MRI presentation was used to determine MM infiltration patterns and calculate apparent diffusion coefficient (ADC) and a fat fraction (FF). The one-way ANOVA and Kruskal-Wallis test were used to compare the differences of these values between DS, ISS, and R-ISS stages in different MM infiltration patterns. Spearman correlation test was used for correlation analysis of ADC and FF against prognostic biomarkers, and two independent sample t-test was used to evaluate the differences of ADC and FF in different free light-chain ratio groups. RESULTS: The MRI presentation was classified into normal pattern (36 patients; 37.9%), diffuse (27 patients; 28.4%), and focal (32 patients; 33.7%) infiltration patterns. Statistically significant ADC and FF differences between different DS, ISS, and R-ISS stages were observed in normal/diffuse infiltration patterns but not in focal infiltration patterns. The ADC and FF of the normal/diffuse infiltration pattern showed correlations with hemoglobin, ß2-microglobulin, bone marrow plasma cells, flow cytometry of bone marrow cells, and serum monoclonal protein. In contrast, ADC in focal infiltration patterns was negatively correlated with ß2-microglobulin and C-reactive protein. The FF of patients with a normal/diffuse infiltration pattern was higher in the low free light-chain ratio group than that in the high free light-chain ratio group (P=0.023). CONCLUSIONS: Our observations indicate that quantitative whole-body functional MRI examination may serve as an effective complement to imaging diagnosis based on morphology and provide further information on the tumor burden of patients with MM.

Cyclovirobuxine D Induced-Mitophagy through the p65/BNIP3/LC3 Axis Potentiates Its Apoptosis-Inducing Effects in Lung Cancer Cells.

Mitophagy plays a pro-survival or pro-death role that is cellular-context- and stress-condition-dependent. In this study, we revealed that cyclovirobuxine D (CVB-D), a natural compound derived from Buxus microphylla, was able to provoke mitophagy in lung cancer cells. CVB-D-induced mitophagy potentiates apoptosis by promoting mitochondrial dysfunction. Mechanistically, CVB-D initiates mitophagy by enhancing the expression of the mitophagy receptor BNIP3 and strengthening its interaction with LC3 to provoke mitophagy. Our results further showed that p65, a transcriptional suppressor of BNIP3, is downregulated upon CVB-D treatment. The ectopic expression of p65 inhibits BNIP3 expression, while its knockdown significantly abolishes its transcriptional repression on BNIP3 upon CVB-D treatment. Importantly, nude mice bearing subcutaneous xenograft tumors presented retarded growth upon CVB-D treatment. Overall, we demonstrated that CVB-D treatment can provoke mitophagy and further revealed that the p65/BNIP3/LC3 axis is one potential mechanism involved in CVB-D-induced mitophagy in lung cancer cells, thus providing an effective antitumor therapeutic strategy for the treatment of lung cancer patients.

Philadelphia chromosome-positive B-lymphoblastic lymphoma successfully treated with chemotherapy regimen containing imatinib: A rare case report and literature review.

RATIONALE: B-lymphoblastic lymphoma (B-LBL) with BCR/ABL mutation (Ph+ B-LBL) is a rare type of cancer in both childhood and adults. Its clinical manifestations are similar to those of other types lymphoma. However, the targeted therapy can substantially improve the outcome of Ph+ B-LBL. PATIENT CONCERNS: A 19-year-old male with blood type O, Rh+ was admitted into our hospital on August 14, 2018, due to a recurrent fever and hypocytosis for 6 months. DIAGNOSES: Routine blood exam showed pancytopenia. Bone marrow sample flow cytometry (FCM) exam showed abnormal cells were 2.27% of the nucleated cells, and was classified as the abnormal early B-lineage lymphoblastic cells. FISH testing showed the BCR/ABL positive cells were 13.6%. Karyotype analysis showed the 46, XY, t(9;22)(q34;q11). Molecular analysis of BCR/ABL mutation on ABL kinase showed that BCR/ABL T315I mutation. Patient was diagnosed with B-LBL with BCR/ABL mutation (Ph+ B-LBL). INTERVENTIONS: The patient was given chemotherapy with VDPI regimen (Vinorelbine, daunorubicin, prednisone, imatinib). OUTCOMES: The patient achieved complete remission after 2 courses' treatment, followed by one course of clarithromycin regimen and another two courses of VDPI regimen. Patient remains in complete remission as of March 10, 2021. LESSONS: In B-LBL, a BCR/ABL mutation can happen in some of these patients. It is important to guide the pathologist to perform appropriate gene mutation detection, in addition to routine Immunohistochemistry test, to ensure an accurate diagnosis and use the targeted agent for treatment. According to the literature and our results, it seems that intensive chemotherapy plus TKI regimen is effective in inducing complete remission, and allo-SCT should be used as a long-term strategy.

HSCs transdifferentiate primarily to pneumonocytes in radiation-induced lung damage repair.

Accumulative radiation exposure leads to hematopoietic or tissue aging. Whether hematopoietic stem cells (HSCs) are involved in lung damage repair in response to radiation remains controversial. The aim of this study is to identify if HSC can transdifferentiate to pneumonocytes for radiation-induced damage repair. To this end, HSCs from male RosamT/mG mice were isolated by fluorescence-activated cell sorting (FACS) and transplanted into lethally irradiated female CD45.1 mice. 4 months after transplantation, transplanted HSC was shown to repair the radiation-induced tissue damage, and donor-derived tdTomato (phycoerythrin, PE) red fluorescence cells and Ddx3y representing Y chromosome were detected exclusively in female recipient lung epithelial and endothelial cells. Co-localization of donor-derived cells and recipient lung tissue cells were observed by laser confocal microscopy and image flow cytometry. Furthermore, the results showed HSC transplantation replenished radiation-induced lung HSC depletion and the PE positive repaired lung epithelial cells were identified as donor HSC origin. The above data suggest that donor HSC may migrate to the injured lung of the recipient and some of them can be transdifferentiated to pneumonocytes to repair the injury caused by radiation.

Clinical Analysis of Bloodstream Infections During Agranulocytosis After Allogeneic Hematopoietic Stem Cell Transplantation.

PURPOSE: To explore the epidemiological characteristics and risk factors of bloodstream infections (BSI) in patients who develop agranulocytosis fever after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study also provides a basis for the clinical treatment of BSI. METHODS: A retrospective analysis of 397 allo-HSCT patients in the Department of Hematology of our hospital was conducted from January 2013 to December 2017 to analyze the incidence of BSI, the distribution and types of pathogenic bacteria, and drug resistance rates. We also determined whether various parameters are risk factors to BSI, including the patient age, gender, disease type, transplantation method, stem cell source, pre-treatment with anti-thymocyte globulin (ATG), and agranulocytosis time. RESULTS: Among the 397 allo-HSCT patients, 294 had a fever during the period of agranulocytosis, and 52 cases were found to have BSI. The incidence of BSI in patients with agranulocytosis fever was 17.7% (52/294). Among the 60 pathogens detected, 43 (71.67%), 10 (16.67%), and 7 (11.67%) were Gram negative strains, Gram positive strains, and fungi, respectively. The most common bacteria were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The detection rate of extended-spectrum ß-lactamase (ESBL) was 40.0%, and carbapenem-resistant Enterobacteriaceae (CRE) accounted for 17.9%. Single-factor and multi-factor analyses showed that pre-treatment with ATG, agranulocytosis time (≥21 days), and stem cell source were risk factors for BSI. CONCLUSION: We found that in our hospital, BSIs in allo-HSCT patients are mainly caused by Gram-negative bacteria, and the resistance rate to carbapenem drugs is high. Pre-treatment with ATG, agranulocytosis time (≥21 days), and stem cell source are risk factors for BSI.

Characteristics of Mucormycosis in Hematological Patients and a Death Prediction Model.

Mucormycosis is an angioinvasive fungal infection, associated with high mortality. The aim of our study was to explore the high-risk factors and predict the death of hematological disease complicated with mucormycosis. We retrospectively analyzed clinical data of 31 patients with hematological disease complicated with mucormycosis, adopted random forest to establish the death prediction model, and validated the model in another 15 patients. The median age of the 31 cases was 46 (28-51) years, male to female ratio 1.38:1, and 90-day mortality rate 54.8%. The most common underlying disease was acute myeloid leukemia (58.1%). The main clinical symptoms were fever (100%), cough (87.1%), sputum (80.6%), chest pain (61.3%), and hemoptysis (19.4%). Reversed halo sign (83.9%) was the most common computed tomography sign. A total of 48.4% of patients also had aspergillus or bacterial infections. Discriminative models were constructed by random forest with 17 non-survivors and 14 survivors. Procalcitonin, the duration of intravenous administration of amphotericin B or amphotericin B liposomes, and neutropenia at death or 90 days of survival were the leading risk factors for poor prognosis, with area under the curve of 0.975 (95% CI 0.934-1). We chose 0.6775 as death prediction threshold (with 82.3% sensitivity and 100% specificity) and validated the model successfully in another 15 patients. Chest pain and reversed halo sign are specific clinical and image signs of hematological disease complicated with mucormycosis. Neutropenia, elevated procalcitonin, and insufficient use time of amphotericin B or amphotericin B liposomes are risk factors for death.

Selective production of phenolic monomers via high efficient lignin depolymerization with a carbon based nickel-iron-molybdenum carbide catalyst under mild conditions.

Lignin is an abundant renewable source of bio-aromatics and its valorization is of great importance. In this work, an efficient non-precious carbon based metal-Mo2C catalytic system for selective production of phenolic monomers (PMs) from organosolv lignin depolymerization is proposed. With the optimized catalyst of Ni-Fe-Mo2C, 89.56% of liquefaction and 35.53% of PMs yields were achieved under 260 ℃ for 4 h with water-methanol (4:1 v/v) solvent. Characterization of the catalysts shows that the induction of Ni-Fe species was favor for the formation of ß-Mo2C, and efficiently promoted the lignin liquefaction. The decoration of Ni/Fe can also change the side chain hydrogenolysis ability of the catalyst and exhibite high yield for 4-ethylphenol (14.77%) production. Methanol, used as co-solvent, was found to play an important role in PMs production and lignin depolymerization. These results demonstrated that the Ni-Fe-Mo2C catalytic system has potential to produce valuable phenolic monomers from lignin under mild conditions.

A Dual Role of Type I Interferons in Antitumor Immunity.

Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8+ T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on the surface of dendritic cells and other bone marrow cells and inhibits their antitumor immunity. This review outlines these dual functions of IFN-Is in antitumor immunity and elucidates the involved mechanisms, as well as their applications in tumor therapy.

Loss of Atg7 causes chaotic nucleosome assembly of mouse bone marrow CD11b+Ly6G- myeloid cells.

Atg7, a critical component of autophagy machinery, is essential for counteracting hematopoietic aging. However, the non-autophagic role of Atg7 on hematopoietic cells remains fundamentally unclear. In this study, we found that loss of Atg7, but not Atg5, another autophagy-essential gene, in the hematopoietic system reduces CD11b myeloid cellularity including CD11b+Ly6G+ and CD11b+Ly6G- populations in mouse bone marrow. Surprisingly, Atg7 deletion causes abnormally accumulated histone H3.1 to be overwhelmingly trapped in the cytoplasm in the CD11b+Ly6G-, but not the CD11b+Ly6G+ compartment. RNA profiling revealed extensively chaotic expression of the genes required in nucleosome assembly. Functional assays further indicated upregulated aging markers in the CD11b+Ly6G- population. Therefore, our study suggests that Atg7 is essential for maintaining proper nucleosome assembly and limiting aging in the bone marrow CD11b+Ly6G- population.

Downregulation of circRNA_0000285 Suppresses Cervical Cancer Development by Regulating miR197-3p-ELK1 Axis.

BACKGROUND: Circular RNAs (circRNAs) are involved in the development of human cancers, including cervical cancer (CC). However, the role and mechanism of the circRNA hsa_circ_0000285 (circ_0000285) in CC development remain largely unknown. METHODS: Thirty paired CC and adjacent normal tissue samples were harvested. CC cell lines SiHa and HeLa were cultured in this study. The expression of circ_0000285, miR197-3p and ELK1 was detected via qRT-PCR or Western blot. CC development was assessed via cell viability, colony formation, apoptosis, cell cycle, and autophagy using MTT, colony-formation assays, flow cytometry and Western blot. The target association was analyzed via dual luciferase-reporter assay, RNA immunoprecipitation, and RNA pull-down. The role of circ_0000285 in CC in vivo was analyzed using a xenograft model. RESULTS: circ_0000285 abundance was enhanced in CC tissue and cells and mainly located in cytoplasm. Silence of circ_0000285 suppressed cell viability and colony formation, arrested the cell cycle at the G0/G1 phase, and induced apoptosis and autophagy in CC cells. miR197-3p was targeted by circ_0000285, and miR197-3p knockdown reversed the effect of circ_0000285 silence on CC development. miR197-3p directly targeted ELK1 to inhibit CC development. circ_0000285 regulated ELK1 by modulating miR197-3p. Knockdown of circ_0000285 reduced xenograft tumor growth in vivo. CONCLUSION: Knockdown of circ_0000285 repressed CC development by increasing miR197-3p and decreasing ELK1.