Krüppel-like factor 15 integrated autophagy and gluconeogenesis to maintain glucose homeostasis under 20-hydroxyecdysone regulation.

The regulation of glycometabolism homeostasis is vital to maintain health and development of animal and humans; however, the molecular mechanisms by which organisms regulate the glucose metabolism homeostasis from a feeding state switching to a non-feeding state are not fully understood. Using the holometabolous lepidopteran insect Helicoverpa armigera, cotton bollworm, as a model, we revealed that the steroid hormone 20-hydroxyecdysone (20E) upregulated the expression of transcription factor Krüppel-like factor (identified as Klf15) to promote macroautophagy/autophagy, apoptosis and gluconeogenesis during metamorphosis. 20E via its nuclear receptor EcR upregulated Klf15 transcription in the fat body during metamorphosis. Knockdown of Klf15 using RNA interference delayed pupation and repressed autophagy and apoptosis of larval fat body during metamorphosis. KLF15 promoted autophagic flux and transiting to apoptosis. KLF15 bound to the KLF binding site (KLF bs) in the promoter of Atg8 (autophagy-related gene 8/LC3) to upregulate Atg8 expression. Knockdown Atg8 reduced free fatty acids (FFAs), glycerol, free amino acids (FAAs) and glucose levels. However, knockdown of Klf15 accumulated FFAs, glycerol, and FAAs. Glycolysis was switched to gluconeogenesis, trehalose and glycogen synthesis were changed to degradation during metamorphosis, which were accompanied by the variation of the related genes expression. KLF15 upregulated phosphoenolpyruvate carboxykinase (Pepck) expression by binding to KLF bs in the Pepck promoter for gluconeogenesis, which utilised FFAs, glycerol, and FAAs directly or indirectly to increase glucose in the hemolymph. Taken together, 20E via KLF15 integrated autophagy and gluconeogenesis by promoting autophagy-related and gluconeogenesis-related genes expression.

Bone marrow mesenchymal stem cell-derived exosomal miR-30e-5p ameliorates high-glucose induced renal proximal tubular cell pyroptosis by inhibiting ELAVL1.

BACKGROUND: The rapid increase in the prevalence of diabetes has resulted in more cases of diabetic kidney disease (DKD). Treatment with bone marrow mesenchymal stem cells (BMSCs) may represent an alternative strategy to manage DKD. METHODS: HK-2 cells were treated with 30 mM high glucose (HG). Bone marrow MSC-derived exosomes (BMSC-exos) were isolated and internalized into HK-2 cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) and lactate dehydrogenase (LDH) assays were used to measure viability and cytotoxicity. The secretion of IL-1ß and IL-18 was measured by ELISA. Pyroptosis was assessed by flow cytometry. Quantitative RT-PCR was used to measure the levels of miR-30e-5p, ELAV like RNA binding protein 1 (ELAVL1), IL-1ß, and IL-18. The expression of ELAVL1 and pyroptosis-associated cytokine proteins was determined by western blot analysis. A dual-luciferase reporter gene assay was conducted to confirm the relationship between miR-30e-5p and ELAVL1. RESULTS: BMSC-exos decreased LDH, IL-1ß, and IL-18 secretion and inhibited the expression of the pyroptosis-related factors (IL-1ß, caspase-1, GSDMD-N, and NLRP3) in HG-induced HK-2 cells. Moreover, miR-30e-5p depletion derived from BMSC-exos promoted HK-2 cell pyroptosis. Besides, miR-30e-5p over-expression or ELVAL1 knockdown could directly inhibit pyroptosis. ELAVL1 was a target of miR-30e-5p and knocking down ELAVL1 reversed the effect of miR-30e-5p inhibition in BMSC-exos-treated HK-2 cells. CONCLUSIONS: BMSC-derived exosomal miR-30e-5p inhibits caspase-1-mediated pyroptosis by targeting ELAVL1 in HG-induced HK-2 cells, which might provide a new strategy for treating DKD.

Influence of dietary protein on serum phosphorous levels in peritoneal dialysis patients with different initial transport function.

INTRODUCTION: This cross-sectional study investigated the influence of dietary protein intake (DPI) on serum phosphate levels in peritoneal dialysis (PD) patients and determined the DPI cutoff required to prevent hyperphosphatemia. METHODS: A total of 504 PD patients were categorized into fast (4 h dialysate/plasma [D/P] creatinine clearance ≥0.65) or slow (<0.65) peritoneal transporters. Serum phosphorus and peritoneal solute clearance were compared between the groups with different DPI. RESULTS: The fast peritoneal transporters (n = 233) were older, had lower serum albumin and phosphorus levels, and had higher peritoneal phosphorus clearance (all p < 0.001). Among the slow transporters (n = 271), serum phosphorus levels were significantly higher among patients with DPI > 1.0 g/kg/d (p < 0.001). High DPI only increased the hyperphosphatemia risk in slow transporters (not in high transporters). DPI ≥1.026 g increased the hyperphosphatemia risk in those patients (area under the curve: 0.66, p = 0.001). CONCLUSION: High DPI increases the hyperphosphatemia risk in PD patients with slower peritoneal transport function.

Incidence, clinical characteristics, and outcome of interstitial pneumonia in patients with lymphoma.

Interstitial pneumonia (IP) is a lethal complication in lymphoma patients undergoing chemotherapy. A total of 2212 consecutive patients diagnosed with lymphoma between 2009 and 2014 were enrolled in the present study. IP was defined as diffuse pulmonary interstitial infiltrate found on computed tomography scans. IP was observed in 106 patients. Of these, 23 patients were excluded from the study. Finally, 83 patients with IP were included in this study. The incidence of IP was 3.9% (7/287) in Hodgkin lymphoma and 2.4% (76/1925) in non-Hodgkin lymphoma (P = 0.210). The median number of chemotherapy cycles before IP was 3. The median time from the cessation of chemotherapy to IP was 17 days. Eighty-two (98.8%) patients recovered after the treatment with glucocorticoids. Sixty-six (79.5%) patients had a delay in chemotherapy, and 14 (16.9%) patients had premature termination of chemotherapy. Sixty-nine patients were re-treated with chemotherapy after remission from IP, of which 22 (31.9%) experienced IP recurrence. The incidence of IP recurrence was significantly higher in patients re-treated with a similar regimen than in those re-treated with an alternative regimen (65.4 vs. 11.6%, P < 0.001). In a multivariate Cox regression analysis, B symptoms and a history of drug allergies were identified as risk factors for IP. In conclusion, IP is a life-threatening complication in lymphoma patients. Glucocorticoid therapy with continuous monitoring of chest radiographic changes may be a favourable strategy for treating IP. However, IP may recur, especially in patients re-treated with a similar chemotherapy regimen.

2n megagametophyte formed via SDR contributes to tetraploidization in polyembryonic 'Nadorcott' tangor crossed by citrus allotetraploids.

KEY MESSAGE: 2 n megagametophyte formation plays an important role in polyploidization in polyembryonic citrus and is valuable for plant improvement. Tetraploid plants are frequently observed in the seedlings of diploid polyembryonic citrus genotypes. However, the mechanisms underlying the formation of tetraploids are still indistinct when apomictic citrus genotypes are used as female parent to cross with tetraploids. Herein, 54 tetraploid progenies, which were unexpectedly obtained previously from four 2x × 4x crosses using polyembryonic 'Nadorcott' tangor as seed parent, were analyzed by 22 simple sequence repeat (SSR) markers, aiming to reveal their genetic origin and the mechanism underlying 2n megagametophyte formation. The results showed that 13 tetraploids from all these four crosses were doubled diploids as indicated by their identical SSR allelic profile with their female parent; while the remaining 41 tetraploids apparently exhibited paternally derived alleles, which confirmed their zygotic origin. Furthermore, the genotyping of all hybrids indicated that all of them arose from 2n megagametophytes. Based on the genotypes of 2n megagametophytes, the analysis of maternal heterozygosity restitution (HR) for each marker showed that it varied from 0.00 to 87.80 % with a mean value of 40.89 %. In addition, it was observed that 13 markers displayed a lower rate than 50 %. On the basis of the above results, it can be speculated that the second division restitution (SDR) is the mechanism underlying the 2n megagametophyte formation in 'Nadorcott' tangor. The elucidation of the mechanism of 2n megagametophyte formation will be of great help to optimize further sexual hybridization for polyploids in citrus.

White spot syndrome virus hijacks host PP2A-FOXO axes to promote its propagation.

Viruses have developed superior strategies to escape host defenses or exploit host components and enable their infection. The forkhead box transcription factor O family proteins (FOXOs) are reportedly utilized by human cytomegalovirus during their reactivation in mammals, but if FOXOs are exploited by viruses during their infection remains unclear. In the present study, we found that the FOXO of kuruma shrimp (Marsupenaeus japonicus) was hijacked by white spot syndrome virus (WSSV) during infection. Mechanistically, the expression of leucine carboxyl methyl transferase 1 (LCMT1) was up-regulated during the early stages of WSSV infection, which activated the protein phosphatase 2A (PP2A) by methylation, leading to dephosphorylation of FOXO and translocation into the nucleus. The FOXO directly promoted transcription of the immediate early gene, wsv079 of WSSV, which functioned as a transcriptional activator to initiate the expression of viral early and late genes. Thus, WSSV utilized the host LCMT1-PP2A-FOXO axis to promote its replication during the early infection stage. We also found that, during the late stages of WSSV infection, the envelope protein of WSSV (VP26) promoted PP2A activity by directly binding to FOXO and the regulatory subunit of PP2A (B55), which further facilitated FOXO dephosphorylation and WSSV replication via the VP26-PP2A-FOXO axis in shrimp. Overall, this study reveals novel viral strategies by which WSSV hijacks host LCMT1-PP2A-FOXO or VP26-PP2A-FOXO axes to promote its propagation, and provides clinical targets for WSSV control in shrimp aquaculture.

[Angioimmunoblastic T cell lymphoma: clinical analysis of 42 cases].

OBJECTIVE: To explore the clinical characteristics and prognosis of patients with angioimmunoblastic T cell lymphoma (AITL). METHODS: The clinical features and prognostic factors of 42 cases newly diagnosed as AITL at Peking University Cancer Hospital from January 2007 to August 2012 were retrospectively analyzed. RESULTS: Their median age was 59(34-76) years. Among them, 97.6% cases (41/42) belonged to Ann Arbor stage III/IV, 73.8% (31/42) cases presented with B symptoms, 85.7% (36/42)cases had painless lymphadenopathy, 52.4% (22/42)cases extranodal involvement, 64.3% (27/42) cases elevated lactate dehydrogenase and 45.2% (19/42) cases elevated ß2-microglobulin at diagnosis. And 40.5% (17/42) cases had 3 points of international prognostic index (IPI) score with the highest proportion.First-line chemotherapy was predominantly CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) or CHOP-like-based and complete response was achieved in 44.7% (17/38) of them. The median follow-up time was 40 (2-106) months The 1, 2, 5-year survival rates were 78%, 57% and 39% respectively.Statistical analysis showed that IPI was an independent prognostic factor (P = 0.009).Other factors included gender (P = 0.311), age (P = 0.263), with or without B symptoms (P = 0.102), Ki-67 index (P = 0.146) as well as the choice of first-line chemotherapy (P = 0.292) each had a tendency of affecting; the survival rate, but failed to reach statistical significance. CONCLUSIONS: Angioimmunoblastic T-cell lymphoma is a major type of peripheral T-cell lymphoma. Most AITL patients are elders with a late stage. The disease generally displays an aggressive clinical course and poor prognosis.

[Primary testicular non-Hodgkin's lymphoma: clinical analysis of 21 cases].

OBJECTIVE: To explore the clinical characteristics and prognosis of patients with primary testicular non-Hodgkin's lymphoma. METHODS: The clinical profiles and prognostic factors of 21 cases newly diagnosed as primary testicular non-Hodgkin's lymphoma at Peking University Cancer Hospital from January 2005 to December 2012 were retrospectively analyzed. RESULTS: Their median age was 59 (34-86) years. And they were classified as Ann Arbor stage I (n = 8), stage II (n = 2) and stage IV (n = 11). There were B symptoms (n = 4), extranodal involvement outside testis (n = 12) and elevated lactate dehydrogenase (LDH) at diagnosis (n = 6). The scores of international prognostic index (IPI) were 0-1 point (n = 10), 3 points (n = 10) and 4 points (n = 1). The regimens included orchidectomy as the initial treatment (n = 15), chemotherapy followed by radiotherapy (n = 7) and CNS prophylaxis during treatment (n = 15). All patients were pathologically diagnosed as diffuse large B-cell lymphoma. And 11 cases belonged to the non-germinal center B cell-like subgroup.First-line chemotherapy was either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or CHOP-like-based regimen. Complete response was achieved in 85.7% of patients. The median follow-up period was 18 (6-58) months. The 1, 2 and 3-year survival rates were 100%, 80% and 60% respectively. Statistical analysis showed that the first-line chemotherapy with rituximab was a prognostic factor (P = 0.038).Other factors included stage (P = 0.275), LDH level (P = 0.179) , ß2-microglobulin level (P = 0.229) and IPI (P = 0.275) . CONCLUSIONS: The prognosis of primary testicular non-Hodgkin's lymphoma is usually poor. The first-line chemotherapy with rituximab is a prognostic factor.

20-hydroxyecdysone reprograms amino acid metabolism to support the metamorphic development of Helicoverpa armigera.

Amino acid metabolism is regulated according to nutrient conditions; however, the mechanism is not fully understood. Using the holometabolous insect cotton bollworm (Helicoverpa armigera) as a model, we report that hemolymph metabolites are greatly changed from the feeding larvae to the wandering larvae and to pupae. Arginine, alpha-ketoglutarate (α-KG), and glutamate (Glu) are identified as marker metabolites of feeding larvae, wandering larvae, and pupae, respectively. Arginine level is decreased by 20-hydroxyecdysone (20E) regulation via repression of argininosuccinate synthetase (Ass) expression and upregulation of arginase (Arg) expression during metamorphosis. α-KG is transformed from Glu by glutamate dehydrogenase (GDH) in larval midgut, which is repressed by 20E. The α-KG is then transformed to Glu by GDH-like in pupal fat body, which is upregulated by 20E. Thus, 20E reprogrammed amino acid metabolism during metamorphosis by regulating gene expression in a stage- and tissue-specific manner to support insect metamorphic development.

The clinical features, therapeutic responses, and prognosis of the patients with mantle cell lymphoma.

Mantle cell lymphoma(MCL), a special type of non-Hodgkin's lymphoma, is incurable through conventional treatment. This study aimed to analyze the clinical features, therapeutic responses, and prognosis of patients with MCL. Clinical data of 30 patients with MCL treated in our hospital between April 2006 and July 2011 were analyzed. Eighteen patients were treated with CHOP plus rituximab (R-CHOP) regimen, 12 underwent conventional chemotherapy. The median age of the 30 patients was 58 years, 23 were men, all patients had Cyclin D1 overexpression, 29 (96.7%) had advanced disease, 11 (36.7%) had bone marrow involvement, 9 (30.0%) had gastrointestinal involvement, and 15 (50.0%) had splenomegaly. The complete response(CR) rate and overall response rate(ORR) were significantly higher in patients undergoing R-CHOP immunochemotherapy than in those undergoing conventional chemotherapy (38.9% vs. 16.7%, P = 0.187; 72.2% vs. 41.4%, P = 0.098). The difference of 2-year overall survival rate between the two groups was not significant (P = 0.807) due to the short follow-up time. The 2-year progression-free survival (PFS) rate was higher in R-CHOP group than in conventional chemotherapy group (53% vs. 25%, P = 0.083), and was higher in patients with a lower mantle cell lymphoma international prognostic index (MIPI) (51% for MIPI 0-3, 33% for MIPI 4-5, and 0% for MIPI 6-11, P = 0.059). Most patients with MCL were elderly; in an advanced stage; showed a male predominance; and usually had bone marrow involvement, gastrointestinal involvement, or splenomegaly. R-CHOP regimen could improve the CR rate and ORR of MCL patients. MIPI can be a new prognostic index for predicting the prognosis of advanced MCL.

[Safety and adverse event profiling of pegylated L-asparaginase combined chemotherapy in the treatment of lymphoma].

OBJECTIVE: To analyze the safety and adverse event profiling of pegylated L-asparaginase (PEG-asp) combined chemotherapy in the treatment of lymphoma patients. METHODS: The clinical data of 32 lymphoma patients on PEG-asp-based chemotherapy from January 2008 to March 2012 were retrospectively collected and analyzed. RESULTS: There were 22 males and 10 females with a median age of 40 years. They were diagnosed as NK/T cell lymphoma (n = 22) and lymphoblastic lymphoma (n = 10). The overall response rate was 71.9% (23/32). And complete remission was 40.6% (13/32) and partial remission 31.3% (10/32). Myelosuppression was the most common adverse event at an incidence of 81.2% (26/32). Other adverse events included a low level of fibrinogen (n = 13, 40.6%), hypoalbuminemia (n = 8, 25%) and hyperlipidemia (n = 9, 28.1%). No instance of anaphylaxis, acute pancreatitis and thrombosis occurred. CONCLUSION: PEG-asp is both effective and safe in the treatment of lymphoma and it is well-tolerated.

[Prognostic value of maximum standard uptake on pretreatment 18F-FDG PET/CT scan in newly diagnosed diffuse large B cell lymphoma].

OBJECTIVE: To evaluate the prognostic value of maximum standard uptake (SUVmax) on pretreatment (18)F-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) scan in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL). METHODS: The clinical data of 39 DLBCL patients undergoing a PET/CT scan at pre-treatment from December 2009 to October 2011 were analyzed retrospectively. SUVmax on PET/CT was evaluated by SPSS 13.0 for the associations with patient characteristics, prognostic factors, treatment efficacy and survival time. RESULTS: The median SUVmax was higher in non-germinal center B cell-like (non-GCB) patients than that in GCB ones (18.0(2.2 - 40.5) vs 11.6 (5.3 - 18.7), P = 0.039). No difference of SUVmax was observed between the patients with and without bulky disease (P = 0.539). SUVmax was not associated with such patient characteristics as international protein index, age, stage, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, number of extranodal involvement and Ki-67 (all P > 0.05). No significant difference in median SUVmax existed between complete remission (CR) and non-CR patients (P = 0.312). The difference of SUVmax was insignificant for the patients with efficacy and no efficacy (P = 0.243). With the cut-off values of 10, 15, 20, the CR rate, response rate, 2-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate were not different between the patients with SUVmax below and above cut-off value (all P > 0.05). CONCLUSIONS: The prognostic value of SUVmax on PET/CT is indeterminate. And it can not be used to predict the patient prognosis.

Insulin-like Growth Factor 2 Promotes Tissue-Specific Cell Growth, Proliferation and Survival during Development of Helicoverpa armigera.

During development, cells constantly undergo fate choices by differentiating, proliferating, and dying as part of tissue remodeling. However, we only begin to understand the mechanisms of these different fate choices. Here, we took the lepidopteran insect Helicoverpa armigera, the cotton bollworm, as a model to reveal that insulin-like growth factor 2 (IGF-2-like) prevented cell death by promoting cell growth and proliferation. Tissue remodeling occurs during insect metamorphosis from larva to adult under regulation by 20-hydroxyecdysone (20E), a steroid hormone. An unknown insulin-like peptide in the genome of H. armigera was identified as IGF-2-like by sequence analysis using human IGFs. The expression of Igf-2-like was upregulated by 20E. IGF-2-like was localized in the imaginal midgut during tissue remodeling, but not in larval midgut that located nearby. IGF-2-like spread through the fat body during fat body remodeling. Cell proliferation was detected in the imaginal midgut and some fat body cells expressing IGF-2-like. Apoptosis was detected in the larval midgut and some fat body cells that did not express IGF-2-like, suggesting the IGF-2-like was required for cell survival, and IGF-2-like and apoptosis were exclusive, pointing to a survival requirement. Knockdown of Igf-2-like resulted in repression of growth and proliferation of the imaginal midgut and fat body. Our results suggested that IGF-2-like promotes cell growth and proliferation in imaginal tissues, promoting cell death avoidance and survival of imaginal cells during tissue remodeling. It will be interesting to determine whether the mechanism of action of steroid hormones on insulin growth factors is conserved in other species.

[Central nervous system lymphoma and its significance].

OBJECTIVE: To explore the clinical features, diagnosis, treatment and prognosis of central nervous system lymphoma (CNSL). METHODS: Retrospective analysis was conducted for 31 CNSL cases from January 2007 to December 2009 in our hospital. Their clinical data were analyzed by statistical software package SPSS 16.0. RESULTS: Accounting for around 4.7% of all lymphomas at our institution, the present cohort had 21 males and 10 females with a median age of 38 years old. The major clinical manifestations were focal neurological deficits associated with the site of disease or increased intracranial pressure. Most patients were treated with chemotherapy-based regimens. The overall response rate was 67.7% (21/31) with 32.3% (10/31) complete remission rate (CR) and 35.5% (11/31) partial remission rate (PR). Involvement outside CNS or bone marrow, high international prognostic index (IPI) and B symptoms had significant effects on the therapeutic efficacy (P < 0.05). The overall survival rates were 80.7%, 74.2%, 64.5% and 58.1% at 3, 6, 12, 24 months respectively. The median survival time was 22.5 months. Univariate analysis showed that the clinical efficacy had significant effects on the overall survival of patients (OR = 0.030, 95%CI: 0.003 - 0.270, P = 0.000). CONCLUSION: The prognosis of CNSL remains poor. New diagnostic tools and treatment modality need to be explored.

Identification and Functional Analysis of G Protein-Coupled Receptors in 20-Hydroxyecdysone Signaling From the Helicoverpa armigera Genome.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in animals and humans, which transmit various signals from the extracellular environment into cells. Studies have reported that several GPCRs transmit the same signal; however, the mechanism is unclear. In the present study, we identified all 122 classical GPCRs from the genome of Helicoverpa armigera, a lepidopteran pest species. Twenty-four GPCRs were identified as upregulated at the metamorphic stage by comparing the transcriptomes of the midgut at the metamorphic and feeding stages. Nine of them were confirmed to be upregulated at the metamorphic stage. RNA interference in larvae revealed the prolactin-releasing peptide receptor (PRRPR), smoothened (SMO), adipokinetic hormone receptor (AKHR), and 5-hydroxytryptamine receptor (HTR) are involved in steroid hormone 20-hydroxyecdysone (20E)-promoted pupation. Frizzled 7 (FZD7) is involved in growth, while tachykinin-like peptides receptor 86C (TKR86C) had no effect on growth and pupation. Via these GPCRs, 20E regulated the expression of different genes, respectively, including Pten (encoding phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase), FoxO (encoding forkhead box O), BrZ7 (encoding broad isoform Z7), Kr-h1 (encoding Krüppel homolog 1), Wnt (encoding Wingless/Integrated) and cMyc, with hormone receptor 3 (HHR3) as their common regulating target. PRRPR was identified as a new 20E cell membrane receptor using a binding assay. These data suggested that 20E, via different GPCRs, regulates different gene expression to integrate growth and development.

Assessment of liver fibrosis with liver and spleen magnetic resonance elastography, serum markers in chronic liver disease.

BACKGROUND: The accurate assessment of liver fibrosis is essential for patients with chronic liver disease. A liver biopsy is an invasive procedure that has many potential defects and complications. Therefore, noninvasive assessment techniques are of considerable value for clinical diagnosis. Liver and spleen magnetic resonance elastography (MRE) and serum markers have been proposed for quantitative and noninvasive assessment of liver fibrosis. This study aims to compare the diagnostic performance of liver and spleen stiffness measured by MRE, fibrosis index based on the 4 factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and their combined models for staging hepatic fibrosis. METHODS: One hundred and twenty patients with chronic liver disease underwent MRE scans. Liver and spleen stiffness were measured by the MRE stiffness maps. Serum markers were collected to calculate FIB-4 and APRI. Liver biopsies were used to identify pathologic grading. Spearman's rank correlation analysis evaluated the correlation between the parameters and fibrosis stages. Receiver operating characteristic (ROC) analysis evaluated the performance of the four individual parameters, a liver and spleen stiffness combined model, and an all-parameters combined model in assessing liver fibrosis. RESULTS: Liver stiffness, spleen stiffness, FIB-4, and APRI were all correlated with fibrosis stage (r=0.87, 0.64, 0.65, and 0.51, respectively, all P<0.001). Among the 4 individual diagnostic markers, liver stiffness showed the highest values in staging F1-4, F2-4, F3-4 and F4 (AUC =0.89, 0. 97, 0.95, and 0.95, all P<0.001). The AUCs of the liver and spleen stiffness combined model in the F1-4, F2-4, F3-4, and F4 staging groups were 0.89, 0.97, 0.95, and 0.96, respectively (all P<0.001). The corresponding AUCs of the all-parameters combined model were 0.90, 0.97, 0.95, and 0.96 (all P<0.001). The AUCs of the liver and spleen stiffness combined model were significantly higher than those of APRI, FIB-4 in the F2-4, F3-4, and F4 staging groups (all P<0.05). Both combined models were not significantly different from liver stiffness in staging liver fibrosis (all P>0.05). CONCLUSIONS: Liver stiffness measured with MRE had better diagnostic performance than spleen stiffness, APRI, and FIB-4 for fibrosis staging. The combined models did not significantly improve the diagnostic value compared with liver stiffness in staging fibrosis.

Prophylactic Use of Entecavir for Lymphoma Patients With Past Hepatitis B Virus Infection: A Randomized Controlled Trial.

BACKGROUND: The value of prophylactic antiviral therapy in patients with past hepatitis B virus (HBV) infection (HBV surface antigen-negative/anti-HBV core antibody-positive/HBV DNA negative) is still controversial. PATIENTS AND METHODS: This study compared the safety, efficacy, and cost-effectiveness of prophylactic entecavir (ETV) with regular monitoring alone in lymphoma patients with past HBV infection. Patients were randomly assigned to chemotherapy alone (control) or prophylactic ETV before chemotherapy and at least 6 months after completion of chemotherapy. All patients underwent close virologic and biochemical surveillance. The primary end points were the incidence rates of HBV reactivation (appearance of HBV DNA) and HBV reactivation-related hepatitis (defined as a greater than 3-fold increase in serum alanine aminotransferase levels exceeding 100 IU/L). RESULTS: A total of 190 patients were included, 141 (74.2%) of whom were positive for anti-HBV surface antibody (HBs). The incidence rates of HBV reactivation and HBV reactivation-related hepatitis were 0 (0/95) and 0 (0/95) in the prophylactic ETV group, respectively, and 3.2% (3/95) and 1.1% (1/95) in the control group, respectively (P = .246 and 1.000, respectively). One patient experienced HBV reactivation-related hepatitis, resulting in premature termination of chemotherapy. All 3 patients with HBV reactivation recovered after therapeutic ETV treatment. No HBV-related deaths were observed during the follow-up period. The cost in the prophylactic ETV group was higher than that in the control group ($125 per month). CONCLUSION: Prophylactic antiviral therapy is not a cost-effective strategy for the management of lymphoma patients with past HBV infection, especially those positive for anti-HBs.

Noninvasive Evaluation of the Pathologic Grade of Hepatocellular Carcinoma Using MCF-3DCNN: A Pilot Study.

PURPOSE: To evaluate the diagnostic performance of deep learning with a multichannel fusion three-dimensional convolutional neural network (MCF-3DCNN) in the differentiation of the pathologic grades of hepatocellular carcinoma (HCC) based on dynamic contrast-enhanced magnetic resonance images (DCE-MR images). METHODS AND MATERIALS: Fifty-one histologically proven HCCs from 42 consecutive patients from January 2015 to September 2017 were included in this retrospective study. Pathologic examinations revealed nine well-differentiated (WD), 35 moderately differentiated (MD), and seven poorly differentiated (PD) HCCs. DCE-MR images with five phases were collected using a 3.0 Tesla MR scanner. The 4D-tensor representation was employed to organize the collected data in one temporal and three spatial dimensions by referring to the phases and 3D scanning slices of the DCE-MR images. A deep learning diagnosis model with MCF-3DCNN was proposed, and the structure of MCF-3DCNN was determined to approximate clinical diagnosis experience by taking into account the significance of the spatial and temporal information from DCE-MR images. Then, MCF-3DCNN was trained based on well-labeled samples of HCC lesions from real patient cases by experienced radiologists. The accuracy when differentiating the pathologic grades of HCC was calculated, and the performance of MCF-3DCNN in lesion diagnosis was assessed. Additionally, the areas under the receiver operating characteristic curves (AUC) for distinguishing WD, MD, and PD HCCs were calculated. RESULTS: MCF-3DCNN achieved an average accuracy of 0.7396±0.0104 with regard to totally differentiating the pathologic grade of HCC. MCF-3DCNN also achieved the highest diagnostic performance for discriminating WD HCCs from others, with an average AUC, accuracy, sensitivity, and specificity of 0.96, 91.00%, 96.88%, and 89.62%, respectively. CONCLUSIONS: This study indicates that MCF-3DCNN can be a promising technology for evaluating the pathologic grade of HCC based on DCE-MR images.

A scientometric analysis on hepatocellular carcinoma magnetic resonance imaging research from 2008 to 2017.

BACKGROUND: With the development of new magnetic resonance imaging (MRI) techniques, an increasing number of articles have been published regarding hepatocellular carcinoma magnetic resonance imaging (HCCMRI) in the past decade. However, few studies have statistically analyzed these published articles. In this study, we aim to systematically evaluate the scientific outcomes of HCCMRI research and explore the research hotspots from 2008 to 2017. METHODS: The included articles regarding HCCMRI research from 2008 to 2017 were downloaded from the Web of Science Core Collection and verified by two experienced radiologists. Excel 2016 was used to analyze the literature data, including the publication years and journals. CiteSpace V was used to perform co-occurrence analyses for authors, countries/regions and institutions and to generate the related collaboration network maps. Reference co-citation analysis (RCA) and burst keyword detection were also performed using CiteSpace V to explore the research hotspots in the past decade. RESULTS: A total of 835 HCCMRI articles published from 2008 to 2017 were identified. Journal of Magnetic Resonance Imaging published the most articles (79 publications, 9.46%). Extensive cooperating relationship were observed among countries/regions and among authors. South Korea had the most publications (199 publications, 21.82%), followed by the United States of America (USA) (190 publications, 20.83%), Japan (162 publications, 17.76%), and the People's Republic of China (148 publications, 16.23%). Among the top 10 co-cited authors, Bruix J (398 citations) was ranked first, followed by Llovet JM (235 citations), Kim YK (170 citations) and Forner A (152 citations). According to the RCA, ten major clusters were explored over the last decade; "LI-RADS data system" and "microvascular invasion" (MVI) were the two most recent clusters. Forty-seven burst keywords with the highest citation strength were detected over time. Of these keywords, "microvascular invasion" had the highest strength in the last 3 years. The LI-RADS has been constantly updated with the latest edition released in July 2018. However, the LI-RADS still has limitations in identifying certain categories of lesions by conceptual and non-quantitative probabilistic methods. Plenty of questions still need to be further answered such as the difference of diagnostic efficiency of each major/ancillary imaging features. Preoperative prediction of MVI of HCC is very important to therapeutic decision-making. Some parameters of Gd-EOB-DTPA-enhanced MRI were found to be useful in prediction of MVI, however, with a high specificity but a very low sensitivity. Comprehensive predictive model incorporating both imaging and clinical variables may be the more preferable in prediction of MVI of HCC. CONCLUSIONS: HCCMRI-related publications displayed a gradually increasing trend from 2008 to 2017. The USA has a central position in collaboration with other countries/regions, while South Korea contributed the most in the number of publications. Of the ten major clusters identified in the RCA, the two most recent clusters were "LI-RADS data system" and "microvascular invasion", indicative of the current HCCMRI research hotspots.

The ISApl1 2 Dimer Circular Intermediate Participates in mcr-1 Transposition.

Objectives: The mobile colistin resistance gene mcr-1 is a serious threat to global human and animal health. The composite transposon Tn6330 and its circular intermediate were proposed to be involved in the spread of mcr-1 but their roles remain poorly understood. Methods: To further explore the intermediates during the transposition of Tn6330, we engineered Escherichia coli strains that carry an intact Tn6330 transposon or its deletion derivatives. PCR assays were performed to detect IR-IR junctions and possible circular intermediates. We carried out transposition experiments to calculate transposition frequency. The transposition sites were characterized by whole genome sequence and ISMapper-based analyses. Results: The presence of an intact Tn6330 was demonstrated to be essential for the successful transposition of mcr-1, although both Tn6330 and Tn6330-ΔIR could form circular intermediates. The insertion sequence junction structure was observed in all constructed plasmids but the ISApl1 dimer was only formed in one construct containing an intact Tn6330. The average frequency of mcr-1 transposition in an E. coli strain possessing an intact Tn6330 was ∼10-6 per transformed cell. We identified 27 integration sites for the Tn6330 transposition event. All the transposition sites were flanked by 2 bp target duplications and preferentially occurred in AT-rich regions. Conclusion: These results indicate that mcr-1 transposition relies on the presence of an intact Tn6330. In addition, formation of the tandem repeat ISApl1 2 could represent a crucial intermediate. Taken together, the current investigations provide mechanistic insights in the transposition of mcr-1.